Sortilin Modulators

Abstract

The present invention relates to compounds of formula (I) and (II), or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention and their use in the treatment or prevention of medical conditions in which modulation of sortilin is beneficial.

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) or (II), which have surprisingly been shown to modulate the activity of sortilin. The invention also relates to pharmaceutical compositions containing these compounds and their use in the treatment or prevention of medical conditions in which modulation of sortilin activity is beneficial. In particular, the compounds of the invention may cross the blood-brain barrier and therefore may be particularly useful in the treatment of diseases of the central nervous system. [Background technology]

[0002] Sortilin is a type I transmembrane protein that acts as a receptor for several ligands (Petersen et al., 1997). Sortilin is abundantly expressed in neurons and microglia of the nervous system, the inner ear, and several peripheral tissues involved in metabolic regulation (Tauris et al., 2020; Goettsch et al., 2017; Willnow et al., 2011; Kjolby et al., 2010). Sortilin not only acts as a signaling receptor but also mediates the sorting of selected cargo between the trans-Golgi network at the cell surface and the endosomal pathway (Nykjaer & Willnow, 2012; Willnow, Petersen, & Nykjaer, 2008). Sortilin has a large extracellular domain called VPS10, which defines a family of receptors termed sortilin or VS10p domain receptors. The VPS10P domain in sortilin is homologous to yeast VPS10P and is composed of a 10-bladed beta-propeller structure and a cysteine-rich 10CC module (Nykjaer & Willnow, 2012; Zheng, Brady, Meng, Mao, & Hu, 2011).

[0003] Sortilin binds to multiple ligands, including pro-nerve growth factor (pro-NGF), pro-BDNF, pro-neurotrophin-3, neurotensin, and ApoB ( Chen et al., 2005 ; Kjolby et al., 2010 ; Mazella et al., 1998 ; Nykjaer et al., 2004 ; Quistgaard et al., 2009 ; Yano, Torkin, Martin, Chao, & Teng, 2009). Furthermore, sortilin binds to progranulin (PGRN), a secreted protein involved in many cellular functions, such as ensuring lysosomal processing, anti-inflammatory responses, and neurotrophic stimulation (Galimberti, Fenoglio, & Scarpini, 2018). Sortilin targets PGRN for rapid endocytosis and degradation. It is now well established that sortilin is the most important clearance receptor for PGRN (Hu et al., 2010). Thus, sortilin negatively regulates the extracellular concentration of PGRN not only in the brain but also in the periphery. Indeed, the absence or blockade of this receptor increases plasma PGRN concentrations in both mice and humans (Carrasquillo et al., 2010; Gass, Prudencio, Stetler, & Petrucelli, 2012; Hu et al., 2010; Lee et al., 2014; Miyakawa et al., 2020; Pottier et al., 2018 ).

[0004] Frontotemporal dementia is a highly heritable dementia, with haploinsufficiency of the PGRN gene accounting for up to 25% of all cases (Gijselinck, Van Broeckhoven, & Cruts, 2008). Patients with heterozygous loss-of-function mutations in PGRN have a greater than 50% reduction in the extracellular concentration of the protein and are therefore invariably predisposed to FTD. Therefore, PGRN is the causative gene for this disease (Baker et al., 2006; Carecchio et al., 2011; Cruts & Van Broeckhoven, 2008; Galimberti et al., 2010). Additionally, PGRN mutant alleles have been identified in patients with Alzheimer's disease (AD) (Brouwers et al., 2008; Sheng, Su, Xu, & Chen, 2014), and high concentrations of extracellular PGRN are protective in models of ALS, Parkinson's disease, stroke, arthritis, and atherosclerosis (Egashira et al., 2013; Laird et al., 2010; Martens et al., 2012; Tang et al., 2011; Tao, Ji, Wang, Liu, & Zhu, 2012; Van Kampen, Baranowski, & Kay, 2014).

[0005] However, sortilin is not required for PGRN to exert its function, and therefore neurons lacking sortilin expression respond equally to PGRN-induced neuronal growth (De Muynck et al., 2013; Gass, Lee, et al., 2012). Furthermore, PGRN is successfully delivered to neuronal lysosomes in sortilin-deficient cells, suggesting the existence of an alternative transport pathway. Indeed, PGRN can bind to the lysosomal protein prosaposin (PSAP). Binding of PSAP to its cognate receptors, the cation-independent mannose-6-phosphate receptor and LRP1, results in PGRN being transported to lysosomes (Zhou et al., 2015). Furthermore, a phase II clinical trial using a monoclonal anti-sortilin antibody showed normal markers of lysosomal integrity (NCT03987295).

[0006] Although a functional PGRN receptor has yet to be identified, studies suggest that PGRN promotes neuronal survival, suppresses inflammation, and increases Aβ endocytosis by microglia (Martens et al., 2012; Pickford et al., 2011; Yin et al., 2010).

[0007] Binding of PGRN to sortilin requires three amino acids at the C-terminus of PGRN (QLL in humans and PLL in mice), and a peptide derived from the last 24 amino acids of PGRN binds with affinity similar to that of the full-length protein (Zheng et al., 2011). This binding mode has been proposed to be structurally similar to that of neurotensin, i.e., binding to the NTIS1-binding site of sortilin (Zheng et al., 2011). In collaboration with Aarhus University, small molecule screens have been conducted and successful blockers of neurotensin binding to sortilin have been identified (Andersen et al., 2014; Schroder et al., 2014).

[0008] Sortilin exists as a full-length, selectivity receptor, but can also form multimeric signaling receptor-ligand complexes. Parts of sortilin can also be released from the plasma membrane to scavenge ligands (NTs in pain) and regulate their activity. For example, sortilin is involved in synaptic plasticity by regulating the rate of conversion of pro-BDNF to BDNF. This may also be true for other pro-neurotrophins.

[0009] The ligand of this receptor, the propeptide of sortilin, also called spadin, has been demonstrated to regulate the activity of the membrane transporter TREK-1, which is a target of major depression, among other diseases. Structurally, sortilin has the amino acid sequence set forth in SEQ ID NO: 1, and includes a signal peptide, a propeptide, a Vps10p domain, a 10cc domain (10CCa+10CCb), a transmembrane domain, and a cytoplasmic domain. The luminal domain of sortilin contains six potential N-linked glycosylation sites, while the cytoplasmic tail allows for the recruitment of various adaptor proteins.

[0010] Sortilin binds to a vast number of ligands and membrane receptors, thereby participating in functions known to be important in cell signaling and sorting. For example, sortilin is involved in signaling by the pro-neurotrophins pro-form of nerve growth factor (pro-NGF), pro-form of brain-derived neurotrophic factor (pro-BDNF), and pro-form of neurotrophin-3 (proNT3). In complex with the protein p75NTR (p75 neurotrophin receptor), sortilin has been reported to form a receptor for pro-neurotrophin-mediated apoptotic actions, which cause degeneration and cell death in cell and animal models (Jansen et al., 2004). al., 2007; Tenk et al., 2005; Nykjaer et al., 2004).

[0011] Previous studies have suggested a role for sortilin in cell sorting and signaling associated with diseases such as diabetes and obesity (Huang et al., 2013). Sortilin promotes GLUT4 translocation to the plasma membrane and rescues it from lysosomal degradation (Pan et al., 2017). Sortilin levels have been shown to be regulated by the level of inflammation associated with these diseases. The proinflammatory cytokine TNFα reduces both sortilin mRNA and protein levels in mouse and human cultured adipocytes and in vivo when injected into mice (Kaddai et al., 2009). Sortilin can also affect cytokine secretion. Targeting sortilin in immune cells has been proposed to reduce inflammation and inhibit the progression of atherosclerosis (Mortensen et al., 2014). Furthermore, US Patent Application Publication No. 2016 / 0331746 describes various small molecule scaffolds that can bind to the active site of sortilin, which is involved in the regulation of glucose uptake (Shi & Kandror, 2005) and the development of lipid disorder diseases (Gao et al., 2017).

[0012] Furthermore, plasma sortilin concentrations have been reported as a potential biomarker for identifying patients with coronary heart disease or diabetes (Oh et al., 2017; Moller et al., 2021). Patients who showed elevated plasma sortilin concentrations and were therefore identifiable as suffering from these conditions also showed elevated glucose concentrations, suggesting that sortilin is a therapeutic target for treating these conditions. Soluble sortilin has also been proposed as a therapeutic agent for type 2 diabetes (WO2021116290, 2021).

[0013] TAR DNA-binding protein 43 (TDP-43) is involved in various neurodegenerative diseases, for example, TDP-43 inclusions have been found in cases of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD) ( Meneses et al., 2021 ).

[0014] TDP-43 regulates the splicing of several gene products, including sortilin. In humans, splicing involves the inclusion of the cryptic exon 17b (between exons 17 and 18), which introduces a stop codon within the stalk and potentially generates a non-membrane-bound fragment (Prudencio et al. et al., 2012). Furthermore, PGRN has been shown to be able to reduce the concentration of insoluble TDP-43 and delay axon degeneration (Beel et al., 2018). Since sortilin inhibition increases PGRN concentration, sortilin inhibition This may be beneficial for the treatment of neurodegenerative diseases involving TDP-43.

[0015] Sortilin has been implicated in a variety of conditions affecting the central nervous system (CNS). Several studies have suggested a role for circulating sortilin in patients with psychiatric disorders such as depression, and circulating sortilin may be involved in altered neurotrophic factor activity (Buttenshon et al., 2015). Sortilin has also been reported to play a role in brain aging, Alzheimer's disease, and frontotemporal dementia (Xu et al., 2019). However, delivering therapeutic agents that can cross the blood-brain barrier to the CNS presents a major challenge.

[0016] The blood-brain barrier (BBB) ​​is a highly selective, semipermeable boundary formed by endothelial cells that prevents nonselective entry of solutes from circulating blood into the extracellular fluid of the CNS, where neurons reside. Therefore, the limited penetration of therapeutic agents across the BBB limits the treatment of neurological disorders.

[0017] Therefore, therapeutic agents for CNS disorders must be able to cross the blood-brain barrier. In addition, therapeutic agents must have sufficient unbound drug concentrations in the brain, because according to the free drug hypothesis, only unbound compounds can interact to elicit pharmacological effects.

[0018] The unbound fraction of the test compound (F ub The supernatant samples may be analyzed by methods such as liquid chromatography with tandem mass spectrometry (LC-MS / MS) to determine the unbound fraction. The peak area ratios obtained for each matrix may then be used to calculate the unbound fraction according to the following formula: F ub =C PBS / C plasma In the formula, C PBS and C plasma are the analyte concentrations in PBS (receiver) and plasma (donor), respectively.

[0019] Recovery samples may be prepared for each condition but without dialysis and used to estimate recovery from dialysis experiments using the following formula: Recovery rate % = 100 × (V PBS ×C PBS +V plasma ×C plasma ) / V plasma ×C recovery In the formula, V PBS is the volume of the receiver side (PBS) of the dialysis machine, V plasma is the volume of the donor side (plasma) of the dialyzer. C recovery is the analyte concentration measured from the collected sample. Compounds such as propranolol or fluoxetine may be included in the experiment as controls.

[0020] The unbound fraction in the brain (F ub,brain ) was calculated by taking into account the dilution factor used in preparing the brain homogenate (F ub,meas ) can also be calculated from:

[0021]

number

[0022] Brain / plasma unbound partition coefficient (K puu ) may be determined as the ratio of the free compound concentrations in plasma and brain:

[0023]

number

[0024] Alternatively, the ratio of AUCs can be used to calculate K puu The compound of interest is administered orally or intravenously to a relevant species of interest at a known concentration. The time course of the compound's concentration in plasma and cerebrospinal fluid (CSF) is measured. The plasma concentration is corrected to determine the unbound fraction of the compound. The areas under the CSF concentration curve and the plasma free fraction concentration curve are calculated using known methods, and the ratio is determined to give: K puu =AUC0-infcsf / (AUC0-infplasma×(%Fuplasma / 100))

[0025] For the treatment of CNS disorders, puuIt is desirable for K to be greater than 0 and as high as possible. A value around 1 indicates that the free fraction compound freely permeates the blood-brain barrier; a value greater than 1 suggests the involvement of an active influx transport mechanism at the blood-brain barrier; and a value less than 1 indicates that the free fraction compound is poorly permeable or is recognized by an active efflux mechanism, reducing exposure in the CNS and transporting back through the blood-brain barrier into the plasma or CSF. puu A value of 0 or close to 0 indicates either poor compound permeability or a highly active efflux mechanism, either of which would be highly unlikely to achieve meaningful exposure of the desired active species in the CNS. Summary of the Invention

[0026] In view of the above, there is an unmet need for compounds that can be used to treat and prevent medical conditions in which modulation of sortilin is beneficial. In particular, there is an unmet need for sortilin modulators that are able to cross the blood-brain barrier and are therefore useful in treating diseases of the central nervous system. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a graph showing the concentration of Example 3 in microdialysis samples from the hippocampus of adult male Sprague Dawley rats after oral administration of the compound, corrected for a probe recovery of 69.8%. [Figure 2] FIG. 2 is a graph showing the concentration of Example 3 in the plasma of adult male Sprague Dawley rats after oral administration of the compound. [Figure 3] FIG. 3 is a graph showing the relative pharmacodynamic responses of PGRN in hippocampal microdialysates of adult male Sprague Dawley rats after oral administration of vehicle or Example 3. [Figure 4]FIG. 4 is a graph showing the concentration of PGRN in the plasma of adult male Sprague Dawley rats after oral administration of Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0028] Disclosure of the Invention Surprisingly, the compounds of formula (I) and (II) modulate the activity of sortilin and As such, they may be found to be useful in the treatment or prevention of conditions in which modulation of sortilin is beneficial. Furthermore, because the compounds may cross the blood-brain barrier, they may be particularly useful in the treatment of diseases of the central nervous system.

[0029] In a first aspect of the present invention, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, During the ceremony, R 1 but

[0030] [ka] and;

[0031] X is CR 3 or N, where R 3 is selected from the group consisting of H, halo, and C1-C3 alkyl; Each Y is independently CHR 4 , N.R. 5 , C.R. 6 R 6 , C(O), or O, where R 4 is independently selected from the group consisting of H, halo, and C1-C4 alkyl; R 5is independently selected from the group consisting of H, halo, C1-C4 alkyl, C2-C4 hydroxyalkyl, —(C2-C4 alkyl)-O—(C1-C4 alkyl), —C(O)—(C1-C4 alkyl), and —C(O)O—(C1-C4 alkyl); and R 6 is independently selected from the group consisting of halo and C1-C4 alkyl; R 2 is selected from the group consisting of H, C1-C4 alkyl, C2-C4 hydroxyalkyl, and C1-C3 haloalkyl; The compound is a compound of:

[0032] [ka]

[0033] Not one of; Provided are compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0034] Preferably, the compound of formula (I) is the following compound: [ka] It's not one of them.

[0035] R 2 is preferably selected from the group consisting of H, CH3, CH2F, CHF2, and CF3, and more preferably, R 2 is selected from the group consisting of H, CH3, CHF2, and CF3.

[0036] R 3 is preferably H or C1-C3 alkyl, more preferably H or methyl.

[0037] Each R 4 is preferably H.

[0038] Each R5 are preferably independently H, C1-C3 alkyl, or —C(O)O—(C1-C4 alkyl), more preferably H, methyl, or —C(O)O-(tert-butyl), more preferably H or methyl, and most preferably H.

[0039] Each Y is independently CHR as defined above. 4 , N.R. 5 , C.R. 6 R 6 , C(O), or O. In one embodiment of the invention, each Y is independently CHR 4 , N.R. 5 , C.R. 6 R 6 , or O.

[0040] As defined above, R 1 is a partially saturated fused bicyclic ring system. The ring system may be attached to the rest of the molecule at any suitable position on the aromatic ring. However, in particularly preferred embodiments of the invention, R 1 is selected from one of the following groups:

[0041] [ka]

[0042] R 1 The partially saturated ring of the group may contain one or more heteroatoms. However, it is preferred that no more than two atoms in the partially saturated ring are heteroatoms. Thus, one or no more than two Y's are preferably NR 5 or O, and the remaining Y's are preferably C(O), CHR 4 , or CR 6 R 6 is.

[0043] R 1The carbon atoms of the partially saturated ring of the group may be substituted with one or two substituents as defined above. However, it is preferred that any carbon atom of the partially saturated ring be substituted with no more than one substituent. Thus, when a ring atom of the partially saturated ring is carbon, it is preferably C(O) or CHR. 4 is.

[0044] Thus, in a particularly preferred embodiment of the present invention, no more than two Y's are NR 5 or O, and the remaining Y's are independently C(O) or CHR 4 is.

[0045] R 1 Preferred examples of groups include: [ka]

[0046] The above preferred R 1 In the group, each Y is independently NR 5 or O. However, if a partially saturated ring contains two Y atoms, one Y may be O and the other Y may be O or N. It is preferable that:

[0047] Each R 7 are independently selected from the group consisting of H, halo, and C1-C4 alkyl, or 7 together with the carbon atom to which it is attached form an oxo group.

[0048] It is also preferred that only one of the carbon atoms of the partially saturated ring is substituted with a substituent. 7 The group is preferably selected from the group consisting of H, halo, and C1-C4 alkyl, or 7 forms an oxo group together with the carbon atom to which it is attached, and 7 All groups are H. More preferably, one R 7 The group is H or 7forms an oxo group together with the carbon atom to which it is attached, and 7 All the groups are H.

[0049] In the compounds of formula (I), R 1 X may be CH and Y may be O when the group is attached to the remainder of the molecule at a position ortho to a saturated ring.

[0050] In a more preferred embodiment of the present invention, R 1 is selected from one of the following groups: [ka]

[0051] More preferably, R 1 is selected from one of the following groups: [ka]

[0052] Most preferably, R 1 is selected from one of the following groups: [ka]

[0053] In another preferred embodiment of the present invention, R 1 is selected from one of the following groups: [ka]

[0054] In another preferred embodiment of the present invention, R 1 is selected from one of the following groups: [ka]

[0055] In another preferred embodiment of the present invention, R 1is selected from one of the following groups: [ka]

[0056] In another preferred embodiment of the present invention, R 1 is selected from one of the following groups: [ka]

[0057] Specific compounds according to the first aspect of the present invention are listed below. (2S)-2-{[(1S)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0058] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0059] (2S)-5,5-dimethyl-2-{[(1R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid: [ka]

[0060] (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydronaphthalen-2-yl)methyl]amino}hexanoic acid: [ka]

[0061] (2S)-2-[({1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinolin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid: [ka]

[0062] (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0063] ·(2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-( 5,6,7,8-Tetrahydroquinolin-3-yl)ethyl]amino}hexanoic acid: [ka]

[0064] (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydroquinolin-3-yl)methyl]amino}hexanoic acid: [ka]

[0065] (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid: [ka]

[0066] (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0067] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0068] (2S)-5,5-dimethyl-2-{[(1R)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid: [ka]

[0069] (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)-2,2,2-trifluoroethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0070] (2S)-2-{[(1R)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0071] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0072] (2S)-2-[({5H,6H,7H-cyclopenta[b]pyridin-3-yl}methyl)amino]-5,5-dimethylhexanoic acid: [ka]

[0073] (2S)-2-{[(2,3-dihydro-1H-inden-5-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0074] (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro -2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid: [ka]

[0075] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0076] (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0077] (2S)-5,5-dimethyl-2-[({5H,7H,8H-pyrano[4,3-b]pyridin-3-yl}methyl)amino]hexanoic acid: [ka]

[0078] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0079] (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0080] (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0081] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0082] (2S)-5,5-Dimethyl-2-[({2H,3H,4H-pyrano[2,3-b]pyridin-6-yl}methyl)amino]hexanoic acid: [ka]

[0083] (2S)-2-{[(1R)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0084] (2S)-5,5-dimethyl-2-{[(5-methyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}hexanoic acid: [ka]

[0085] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7 -yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0086] (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0087] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0088] (2S)-5,5-dimethyl-2-{[(1S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid: [ka]

[0089] (2S)-5,5-dimethyl-2-{[(1R)-1-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid: [ka]

[0090] (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0091] (2S)-2-[({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid: [ka]

[0092] (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0093] (2S)-5,5-Dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid: [ka]

[0094] (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0095] (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0096] (2S)-2-{[(2,3-dihydro-1-benzofuran-6-yl)methyl]amine 5,5-dimethylhexanoic acid: [ka]

[0097] (2S)-5,5-dimethyl-2-{[(7-methyl-2,3-dihydro-1H-inden-5-yl)methyl]amino}hexanoic acid: [ka]

[0098] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0099] (2S)-2-{[(1R)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0100] (2S)-2-{[(1,3-dihydro-2-benzofuran-4-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0101] (2S)-2-{[(2,3-dihydro-1-benzofuran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0102] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-8-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0103] (2S)-2-{[(2H-1,3-benzodioxol-5-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0104] (2S)-5,5-Dimethyl-2-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}hexanoic acid: [ka]

[0105] (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0106] (2S)-5,5-Dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid: [ka]

[0107] (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4- Tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0108] (2S)-2-{[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0109] (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0110] (2S)-2-{[(1R)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0111] (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0112] (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0113] (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0114] (2S)-5,5-Dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid: [ka]

[0115] (2S)-2-{[(2,3-dihydro-1H-inden-4-yl)methyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0116] (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0117] (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0118] (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydro Quinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0119] (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid: [ka]

[0120] (2S)-5,5-Dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid: [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug of the above compound.

[0121] In a second aspect of the present invention, a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof is provided.

[0122] In one embodiment, R 8 is selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; R 9is phenyl or pyridine, where phenyl and pyridine are independently selected from 5-membered heterocycloalkyl, triazolyl, -O-phenyl, and -NR 10 R 11 and is substituted with one or more substituents selected from the group consisting of:

[0123] R 10 and R 11 are independently selected from H or C1-C3 alkyl, preferably H or CH3, more preferably CH3.

[0124] Preferably, R 8 is selected from the group consisting of H, CH3, CHF2, and CF3, more preferably from the group consisting of H and CH3.

[0125] Preferably, R 9 is pyrrolidinyl, triazolyl, -O-phenyl, or -NR 10 R 11 or R 9 is an -O-phenyl substituted pyridine.

[0126] More preferably, R 9 is selected from one of the following groups: [ka] wherein the phenyl and pyridine are substituted as defined above.

[0127] Most preferably, R 9 is selected from one of the following groups: [ka]

[0128] In another embodiment of the second aspect of the invention, R 8 is C1-C3 hydroxyalkyl, and R 9is phenyl optionally substituted with C1-C3 alkoxy.

[0129] Preferably, R 8 is -(C2H4)-OH.

[0130] Preferably, R 9 is phenyl optionally substituted with —O—CH3.

[0131] More preferably, R 9 teeth [ka] is.

[0132] Specific compounds according to the second aspect of the present invention are listed below.

[0133] (2S)-5,5-Dimethyl-2-{[(2-phenoxypyridin-4-yl)methyl]amino}hexanoic acid: [ka]

[0134] (2S)-5,5-Dimethyl-2-{[(6-phenoxypyridin-3-yl)methyl]amino}hexanoic acid: [ka]

[0135] (2S)-5,5-dimethyl-2-({[3-(pyrrolidin-1-yl)phenyl]methyl}amino)hexanoic acid: [ka]

[0136] 2-{[(1S)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0137] (2S)-5,5-dimethyl-2-{[(1R)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid: [ka]

[0138] (2S)-5,5-dimethyl-2-{[(1S)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid: [ka]

[0139] (2S)-5,5-Dimethyl-2-{[(4-phenoxyphenyl)methyl]amino}hexanoic acid: [ka]

[0140] (2S)-2-({[3-(dimethylamino)phenyl]methyl}amino)-5,5- Dimethylhexanoic acid: [ka]

[0141] (2S)-2-{[(1R)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0142] (2S)-5,5-Dimethyl-2-{[(3-phenoxyphenyl)methyl]amino}hexanoic acid: [ka]

[0143] (2S)-2-{[(1S)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0144] (2S)-2-{[(1R)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid: [ka]

[0145] (2S)-5,5-dimethyl-2-({[3-(1H-1,2,4-triazol-1-yl)phenyl]methyl}amino)hexanoic acid: [ka]

[0146] Or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug of the above compound.

[0147] According to a third aspect of the present invention, there is a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0148] According to a fourth aspect of the invention there is provided a compound or pharmaceutical composition according to the invention for use in therapy.

[0149] According to a fifth aspect of the invention there is provided a compound or pharmaceutical composition according to the invention for use in the treatment or prevention of a neurodegenerative disease, a psychiatric disease, an inflammatory disease, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, kidney disease, psoriasis, a genetic eye disease, hearing loss, or a disease characterised by misfolded tau.

[0150] Preferably, the neurodegenerative disease is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy.

[0151] The neurodegenerative disease is preferably characterized by misfolded TAR DNA-binding protein 43 (tdp-43).That is, the neurodegenerative disease is characterized by truncated tdp-43 and inclusion bodies.Examples of such diseases include amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, and frontotemporal dementia.

[0152] Preferably, the psychiatric disorder is selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder.

[0153] Preferably, the inflammatory disease is selected from inflammatory diseases and neuroinflammation.

[0154] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colon cancer.

[0155] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0156] Preferably, the hearing loss is selected from noise-induced hearing loss, ototoxicity-induced hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0157] According to a sixth aspect of the invention there is provided a compound according to the invention for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease, a psychiatric disease, an inflammatory disease, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, kidney disease, psoriasis, a genetic eye disease, hearing loss, or a disease characterised by misfolded tau.

[0158] According to a seventh aspect of the present invention there is provided a method for the treatment or prevention of a disease or condition responsive to sortilin modulation comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0159] The compounds of the present invention include isotopically labeled and / or isotopically enriched forms of the compounds. The compounds of the present invention herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, for example: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0160] The compounds of the present invention may be used as they are or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts). The pharmacologically acceptable addition salts described below are intended to include therapeutically active non-toxic acid and base addition salt forms that the compounds can form. Compounds that have basic properties can be converted to pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Examples of acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, and ascorbic acid. Compounds with acidic properties can be converted into pharmaceutically acceptable base addition salts by treating their acid form with a suitable base.Examples of base addition salt forms include sodium salts, potassium salts, and calcium salts, as well as salts with pharmaceutically acceptable amines, such as ammonia, alkylamines, benzathine, and amino acids, such as arginine and lysine.The term addition salts used herein also includes solvates, such as hydrates and alcoholates, that can be formed by compounds and their salts.

[0161] Throughout this disclosure, a given chemical formula or chemical name is intended to encompass all of its pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and / or prodrug forms. The compounds of the present invention should be understood to include any and all hydrates and / or solvates of the compound formula. It is understood that certain functional groups, such as hydroxy, amino, and similar groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Thus, the above formula should be understood to encompass and represent various hydrates and / or solvates thereof.

[0162] The compounds of the present invention also include tautomeric forms. Tautomers result from the interchange of a single bond with the adjacent double bond, accompanied by the migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and overall charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0163] The compounds described herein can be asymmetric (e.g., they may have one or more stereoisomeric centers). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated as optically active forms or racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, and include, for example, resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins and C=N double bonds, etc., can also be present in the compounds described herein; such isomers can be used in various applications. All stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0164] In the case of compounds containing asymmetric carbon atoms, the present invention relates to the D-form, the L-form, and D,L mixtures, as well as to diastereomeric forms when more than one asymmetric carbon atom is present. Compounds of the present invention that contain asymmetric carbon atoms and generally occur as racemates can be resolved into optically active isomers in known manner, for example, using an optically active acid. However, it is also possible to use optically active starting materials from the start and then obtain the corresponding optically active or diastereomeric compounds as final products.

[0165] Preferably, the compounds of formula (I) and (II) are compounds of formula (Ia) and (IIa), respectively: [ka]

[0166] The term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention by transformation under physiological conditions or by transformation by solvolysis. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the present invention. Prodrugs are typically rapidly transformed in vivo, such as by hydrolysis in blood, to produce the parent compound of the present invention. Prodrug compounds usually offer advantages of solubility, tissue compatibility, or delayed release in mammals (Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), pp. 498-549. In preparing prodrugs of the compounds of the invention, functional groups, such as hydroxy, amino, or mercapto groups present in the compounds of the invention, may be modified in such a way that the modification is cleaved, either in routine manipulation or in vivo, to yield the parent compound of the invention. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxy functional groups, or phenylcarbamate derivatives of amino functional groups.

[0167] The compounds of the present invention may be inhibitors, binders, modulators, or antagonists of sortilin. As used herein, the terms "sortilin antagonist," "sortilin inhibitor," "sortilin binder," or "sortilin modulator" (used interchangeably) refer to substances that interfere with, block, or otherwise attenuate the binding of sortilin protein to progranulin, or neurotensin or other extracellular ligands, or pro-neurotrophins (e.g., proNGF, proNT3, proBDNF), or that prevent the formation of a trimeric complex between sortilin, p75NTR, and pro-neurotrophins. The term "sortilin antagonist" also includes substances or agents that interfere with the formation of a high-affinity trimeric complex. In the latter scenario, sortilin binds to p75NTR (but not proNGF). It is recognized that a trimeric complex can form in which p75NTR can simultaneously bind to the NGF domain of proNGF (which is absent from the receptor) and p75NTR can simultaneously bind to the NGF domain of proNGF. However, the resulting trimeric complex may have a lower affinity for its receptor, and as a result, its ability to stimulate apoptosis via the above mechanism may be significantly reduced. Skeldal et al. (2012) demonstrated that deletion of the intracellular domain of sortilin abolishes the apoptotic function of the trimeric complex. The term "sortilin antagonist" also includes substances or agents that interfere with, block, or otherwise attenuate the interaction of the sortilin protein with p75NTR. This interaction may be completely inhibited, thereby preventing the formation of the trimeric complex. Alternatively, it may be only partially inhibited, in which case the trimeric complex may form but its biological efficacy may be reduced. showed that complex formation between sortilin and p75NTR depends on contact points within the extracellular domain of the receptor, and that the interaction critically depends on a 23-amino acid sequence located near the extracellular membrane of p75NTR. Thus, sortilin antagonists may interfere with this 23-amino acid sequence or nearby sequences within the molecule. A "sortilin antagonist" may act as an inhibitor of cellular uptake of a ligand, which may be progranulin, neurotensin, BDNF, or the like.

[0168] The compounds of the present invention may be particularly useful in treating or preventing diseases of the central nervous system, such as neurodegenerative diseases selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; psychiatric disorders selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; hearing loss selected from noise-induced hearing loss, ototoxicity-induced hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors, retinopathy, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau.

[0169] The compounds of the present invention have a K puu , for example, 0.1-10, 0.1-5, 0.1-3, 0.1-2, 0.1-1, 0.1-0.8, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2 K. puu may have

[0170] As used herein, the term "treatment" includes prevention of the named disorder or condition, or amelioration or elimination of the disorder once it has been established. The term "prevention" refers to the prevention of the named disorder or condition.

[0171] The methods provided herein include methods in which a subject is identified as needing a particular defined treatment. Identification of a subject in need of such treatment can be by the subject or the judgment of a medical professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0172] In other aspects, the methods herein include methods that further comprise monitoring the subject's response to the administration of the treatment. Such monitoring may include periodically imaging or sampling the subject's tissues, body fluids, specimens, cells, proteins, chemical markers, genetic material, etc. as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as in need of such treatment by assessing relevant markers or indicators that indicate suitability for such treatment.

[0173] The present invention provides a method for monitoring the progress of a treatment, the method comprising administering to a subject a therapeutically effective amount of a compound as defined herein. The method includes determining the concentration or diagnostic measurement (e.g., screening, assay) of a diagnostic marker (e.g., any target or cell type defined herein that is modulated by a compound herein) in a subject suffering from or susceptible to a disease or symptom thereof, wherein the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptom. The concentration of the marker determined by this method can be compared to known concentrations of the marker in healthy controls or other affected patients to determine the disease status of the subject. In preferred embodiments, a second concentration of the marker in the subject is determined at a time later than the determination of the first concentration, and the two concentrations are compared to monitor the progress of the disease or the effectiveness of the treatment. In certain preferred embodiments, a pre-treatment concentration of the marker in the subject is determined before initiation of treatment according to the present invention, and the pre-treatment concentration of the marker can then be compared to the concentration of the marker in the subject after initiation of treatment to determine the effectiveness of the treatment.

[0174] The level of the marker or marker activity in a subject may be determined at least once. Comparing the marker level with other measurements of the marker level, for example, obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful for determining whether a treatment according to the present invention is having the desired effect and thereby adjusting the dosage appropriately. Measuring the marker level may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first obtained from the subject. Examples of suitable samples include blood, urine, tissue, oral or cheek cells, and hair samples containing hair roots. Other suitable samples will be known to those skilled in the art. Measuring the protein concentration and / or mRNA concentration (e.g., marker concentration) in the sample may be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence, and real-time PCR.

[0175] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It will be understood that the compounds of the present invention may be administered with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein may be administered by any suitable route, preferably orally, rectally, nasally, topically (e.g., ophthalmic, buccal, and sublingual), sublingually, transdermally, intrathecally, transmucosally, or parenterally (e.g., subcutaneously, intramuscularly, intravenously, and intradermally). Other formulations may conveniently be provided in unit dosage forms, such as tablets, sustained-release capsules, and liposomes, and may be prepared by any method well known in the pharmaceutical arts. Pharmaceutical formulations are typically prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients include water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, and colloidal silicon dioxide. Such formulations may also contain other pharmacologically active agents, as well as stabilizers, wetting agents, emulsifiers, flavorings, and buffers. Typically, the active compound(s) comprise 0.1 to 95% by weight of the formulation, preferably 0.2 to 20% by weight for parenteral formulations and more preferably 1 to 50% by weight for oral formulations. Formulations can also be prepared by known methods, such as granulation, compression, microencapsulation, and spray coating. Formulations may be prepared in conventional dosage forms, such as tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injectables. Liquid formulations may be prepared by dissolving or suspending the active substance(s) in water or other suitable vehicles. Tablets and granules may be coated by conventional methods. To maintain therapeutically effective plasma concentrations for extended periods, the compounds disclosed herein may be incorporated into sustained release formulations.

[0176] The dosage and frequency of administration of a specific compound may vary depending on various factors, such as the efficacy of the specific compound used, the metabolic stability and duration of action of the compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the condition being treated, and the patient being treated. The daily dosage may range, for example, from about 0.001 mg to about 100 mg per kg of body weight, and may be administered in single or multiple doses, for example, from about 0.01 mg to about 25 mg. Typically, such doses are administered orally, but parenteral administration may also be selected.

[0177] definition As used herein, the term "sortilin" may refer to full-length sortilin (also referred to as immature sortilin), comprising a signal peptide, a propeptide, a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail, and having the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. Alternatively, the term may refer to mature sortilin, comprising a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail, and having the amino acid sequence set forth in SEQ ID NO: 3, or a naturally occurring fragment, homolog, or variant thereof. The terms "sortilin" or "sortilin molecule" are used interchangeably herein. It is understood that sortilin can interact with a proneurotrophin molecule to form a sortilin / proneurotrophin complex. This sortilin / proneurotrophin complex may or may not be capable of interacting with a p75NTR molecule to form a trimeric complex comprising sortilin, proneurotrophin, and p75NTR. This trimeric complex is understood to be potentially responsible for adverse biological responses, such as stimulating apoptosis in retinal and ganglion cells and regulating growth cone retraction of projecting axons (Jansen et al., 2007; Nykjaer et al., 2004; Santos et al., 2012; Skeldal et al., 2012).

[0178] As used herein, the term "pro-neurotrophin" refers to a larger precursor of a neurotrophin, which undergoes proteolytic cleavage to generate the mature form of the neurotrophin. Neurotrophins are a family of proteins, commonly referred to as growth factors, that induce the survival, development, and function of neurons. Pro-neurotrophins are biologically active and have roles distinct from their neurotrophin counterparts, such as inducing apoptosis. Examples of pro-neurotrophins include pro-NGF, pro-BDNF, pro-NT3, and pro-NT4. Pro-neurotrophins may also regulate synaptic plasticity. While mature neurotrophins induce synaptic strength, their pro-forms may weaken synapses.

[0179] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0180] The term "heteroatom" means O, N, or S.

[0181] "(C1~C n The term "(C1-C) alkyl" refers to a straight, branched, cyclic, or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3, ... or n carbon atoms. n For a "(C1-C) alkyl" group to contain a cyclic moiety, it must be formed of at least three carbon atoms. n For "alkyl" subranges, all subgroups thereof are contemplated. For example, (C1-C6) Within the scope of alkyl, all subgroups are contemplated, such as (C1-C5) alkyl, (C1-C4) alkyl, (C1-C3) alkyl, (C1-C2) alkyl, (C1) alkyl, (C2-C6) alkyl, (C2-C5) alkyl, (C2-C4) alkyl, (C2-C3) alkyl, (C2) alkyl, (C3-C6) alkyl, (C3-C5) alkyl, (C3) alkyl, (C4-C6) alkyl, (C4-C5) alkyl, (C4) alkyl, (C5-C6) alkyl, and (C6) alkyl. Examples of "C1-C6 alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, branched or cyclic or partially cyclic pentyl and hexyl, and the like.

[0182] "(C1~C n The term "haloalkyl" refers to any of the C1-C groups described above substituted with at least one halogen atom. n The halogen atom is preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0183] "(C1~C n The term "hydroxyalkyl" refers to any of the above C1-C hydroxyalkyl groups substituted with at least one -OH group. n Indicates alkyl.

[0184] "(C1~C n The term "alkoxy" refers to -O-((C1-C n ) alkyl) in which (C1-C n ) denotes an alkyl group as defined above, attached to the remainder of the compound via an oxygen atom.

[0185] Where the term denotes a range, such as "1 to 6 carbon atoms" in the definition of (C1-C6)alkyl, each integer, i.e., 1, 2, 3, 4, 5 and 6, is considered to be disclosed.

[0186] The term "halo" refers to a halogen atom, preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0187] The term "5-membered heterocycloalkyl" refers to a non-aromatic ring having 5 ring atoms, with at least one ring atom being a heteroatom. Preferably, each heteroatom is independently selected from N, S, or O, more preferably N. Preferably, no more than two ring atoms are heteroatoms. More preferably, only one ring atom is a heteroatom.

[0188] An "effective amount" refers to an amount of a compound of the present invention that confers a therapeutic effect on a treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0189] As used herein, the term "administration" or "administering" refers to the route of administration for the compounds disclosed herein. Non-limiting examples of routes of administration include oral, intraocular, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration may vary depending on various factors, such as the components of the pharmaceutical composition containing the compounds disclosed herein, the site of the potential or actual disease, and the severity of the disease.

[0190] As used herein, the terms "subject" and "patient" are used interchangeably. They refer to a human or other mammal (such as a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that may or may not be affected by a disease or disorder, but that may or may not be affected by the disease or disorder. Preferably, the subject is a human.

[0191] The compounds of the present invention may be disclosed by name or by chemical structure. In the event of a discrepancy between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0192] The present invention will now be further described by the following non-limiting examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All documents and publications cited herein are incorporated by reference in their entirety.

[0193] Preparation of Compounds of the Invention The compounds of the present invention can be prepared by methods well known and understood in the art, according to the following general synthetic procedure schemes. Suitable reaction conditions are well known in the art, and appropriate substitution of solvents and auxiliary reagents is within the skill of one of ordinary skill in the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified by a variety of well-known techniques, as necessary or desired, and that intermediates can often be used directly in subsequent synthetic steps with little or no purification. Furthermore, those skilled in the art will understand that in some circumstances, the order in which moieties are introduced is not critical. The specific order of steps required to prepare compounds of formula (I) or (II) will depend on the specific compound being synthesized, the starting compound, and the relative liabilities of the substituting moieties, as will be well understood by those skilled in the art. Unless otherwise specified, all substituents are as defined above, and all reagents are well known and understood in the art.

[0194] Suitable starting materials and protected amino acids of general formula AA-1, optically active as single enantiomers or racemic mixtures, are commercially available or may be prepared by various methods. For example, as shown in Scheme 1 of the general synthetic procedure, the carboxylic acid functionality of an appropriately substituted amino acid of general formula AA-1 can be used as the free acid (PG=H) or protected as a suitable derivative, such as a methyl ester. Insertion of a substituent on the primary amine present in AA-1 can be achieved by various methods, for example, by a reductive amination step using an appropriately substituted carbonyl compound Int-1, an aldehyde, or a ketone, and a reducing reagent, such as, but not limited to, sodium triacetoxyborohydride, in a suitable solvent mixture, such as acetic acid and dichloromethane. Another method for introducing a substituent on the primary amine present in AA-1 uses an alkylation step between an appropriately protected AA-1 and a reagent of type Int-2, as shown in the general synthetic procedure. In the latter, LG represents a reactive leaving group such as a bromine atom, which can be selectively displaced by a free amine in AA-1 in the presence of a suitable base, such as potassium carbonate, in a suitable solvent such as acetonitrile. Alternatively, Scheme 2 shows an example of a complementary general synthetic strategy, which may be advantageous, for example, when intermediates of type Int-3 or Int-4 are sterically hindered. Advantageously, intermediates of type AA-2 or AA-3 can be obtained from intermediates of type AA-1 by procedures known to those skilled in the art, can be purchased from commercial sources, or can be synthesized.

[0195] General synthetic procedure [ka]

[0196] [ka]

[0197] Compounds of general formula (I) or (II) can be prepared by a variety of procedures, some of which are described below. The products of each step can then be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.

[0198] The compounds of general formula (I) or (II) may contain one or more stereocenters. These can be introduced from available single enantiomers or optically active AA-1 type starting materials. The integrity of any stereocenters present can be confirmed by analytical techniques well known to those skilled in the art, such as chiral-supported high-pressure chromatography. Alternatively, it will be appreciated that when racemic starting materials are used, single isomeric products can be obtained, if desired, as single enantiomers or as single diastereomers by known techniques such as preparative chiral-supported high-pressure chromatography.

[0199] Those skilled in the art will also understand that not all substituents in a compound of formula (I) or (II) will tolerate the particular reaction conditions used in the synthesis of that compound. These moieties may be introduced at any convenient point in the synthesis or may be protected and subsequently deprotected as necessary or desired, as is well known in the art. Those skilled in the art will understand that protecting groups may be removed at any convenient point in the synthesis of a compound of the invention. Methods for introducing or removing protecting groups used in the present invention will be within the skill of those in the art. These groups are well known in the art, see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons, New York (2006). [Example]

[0200] Abbreviation approx.: about; aq: aqueous; br: broad; ca.: approximately; CDI: 1,1'-carbonyldiimidazole; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl; h: hour (hour) rs); min: minute; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V); HPLC: high-performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: molar concentration, molecular ion; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: quartet; rt: room temperature (approximately 20°C); R T : retention time; s: singlet, solid; SPPS: solid phase peptide synthesis; t: triplet; TBAF: tetrabutylammonium fluoride; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra performance liquid chromatography; UV: ultraviolet.

[0201] Other abbreviations are intended to have their generally accepted meanings.

[0202] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to the cited literature. Reaction mixtures were magnetically stirred and reactions were carried out at room temperature (approximately 20° C.) unless otherwise noted.

[0203] Column chromatography was carried out using prepacked silica (40 μm) cartridges on an automated flash chromatography system such as the CombiFlash Rf system unless otherwise stated.

[0204] 1 H-NMR spectra were recorded at 400 MHz using a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane unless otherwise noted. The following abbreviations, or combinations thereof, are used for the multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0205] Analysis method 1 H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane unless otherwise noted. The following abbreviations, or combinations thereof, are used for the multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0206] Method 1: UPLC_AN_BASE, Instrument: Waters IClass; Binary Pump: UPIBSM, UPISMFTN with SM:SO; UPCMA, PDA:UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: Gas pressure 40 psi, Drift tube temperature: 50 °C; Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 µm, Temperature: 25 °C, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t2.0 min = 98% B, t2.7 min = 98% B, Post time: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH = 9.5), Eluent B: acetonitrile.

[0207] Method 2: PREP_ACID-AS4A, Instrument: Agilent Technologies G6130B Quadrupole; HPLC Instrument Type: Agilent Technologies 1290 Preparative LC; Column: Waters XSelect CSH (C18, 100 × 30 mm, 10μ); Flow: 55 mL / min; Column Temperature: Room temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile, Linear Gradient: t = 0 min 20% B, t = 2 min 20% B, t = 8.5 min 60% B, t = 10 min 100% B, t = 13 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) Mass Range: 100-1000; Fraction Collection based on MS and DAD.

[0208] Method 3: UPLC_AN_ACID, Instrument: Waters IClass; Binary Pump: UPIBSM, UPISMFTN with SM:SO; UPCMA, PDA:UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: Gas pressure 40 psi, Drift tube temperature: 50 °C; Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 µm, Temperature: 40 °C, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t2.0 min = 98% B, t2.7 min = 98% B, Post time: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile.

[0209] Method 4: Instrument: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100 x 30 mm, 10μ); Flow: 55 mL / min; Column temperature: room temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) Mass range: 100-1000; Fraction collection based on MS and DAD.

[0210] Method 5: Instrument: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; Column: Waters XSelect (C18, 100 x 30 mm, 10 μm); Flow: 55 mL / min prep pump; Column temperature: room temperature; Eluent A: 10 mM ammonium bicarbonate in water pH = 9.5; Eluent B: 100% acetonitrile; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) Mass range: 100-800; Fraction collection based on MS and DAD.

[0211] Method 6: Apparatus: Waters IClass; Binary Pump: UPIBSM, UPISMFTN with SM:SO; UPCMA, PDA:UPPDATC, 210-320 nm, SQD:MS:QDA ESI, pos / neg 100-800; Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, Temperature: 25 °C, Flow: 0.6 mL / min, Gradient: t0 = 5% B, t1.3 min = 98% B, t1.7 min = 98% B, Post Time: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water Sodium (pH = 9.5), eluent B: acetonitrile. MS parameters: Source: ESI; Capillary: 2500 V; Cone: 20 V; Extractor: 3.0 V; RF: 2.5 V; Source Temperature: 150 °C; Desolvation Temperature: 600 °C; Cone Gas Flow: 80 L / h; Desolvation Gas Flow: 1000 L / h; Full MS Scan: MS Range 100–800 (positive and negative modes); Scan: 0.4 s.

[0212] Method 7: UPLC_AN_BASE. Instrument: Waters I-Class UPLC, Binary Solvent Manager (BSM), Sample Manager-FTN (SM-FTN) and Sample Organizer (SO), Column Manager (CM-A), PDA 210-320 nm, QDa ESI 100-800 (pos) 100-800 (neg). Column: XSelect CSH C18 XP (50 × 2.1 mm 2.5 μm). Flow: 0.6 mL / min; Column Temperature: 25 °C. Eluent A: 10 mM ammonium bicarbonate in water (pH 9.5). Eluent B: acetonitrile. Gradient: t = 0 min 5% B, t = 2 min 98% B, t = 2.7 min 98% B. Postrun: 0.3 min.

[0213] Method 8: MS instrument type: Agilent Technologies G6120AA Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Atlantis T3 (C18, 150 x 19 mm, 10µ); Flow: 25 mL / min; Column temperature: room temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; copy lin. Gradient from gradient method info here; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) Mass range: 100-1000; Fraction collection based on MS and DAD.

[0214] Method #acid3min - UPLC acid method Equipment:Waters HClass;Binary Solvent Pump, SM-FTN, CMA, PDA, QDa Column: Waters ACQUITY UPLC® CSH C18, 1.7 μm, 2.1 × 30 mm, 40°C Detection: UV from 210 to 400 nm, MS with electrospray ionization unless otherwise noted Solvents: A: 0.1% formic acid in water, B: MeCN gradient:

[0215] [Table 1]

[0216] Method #basic3min - UPLC basic method Equipment:Waters HClass;Binary Solvent Pump, SM-FTN, CMA, PDA, QDa Column: Waters ACQUITY UPLC® BEH C18, 1.7 μm, 2.1 × 30 mm, 40°C Detection: UV from 210 to 400 nm, MS with electrospray ionization unless otherwise noted Solvents: A: 0.2% ammonia in water, B: MeCN gradient:

[0217] [Table 2]

[0218] Method #acid3minb Equipment: Agilent 1260; Quaternary Pump, HiP Sampler, Column Compartment, DAD: G6150 MSD Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 μm, 40°C Detection: UV at 260 nm ± 90 nm, MS with electrospray ionization unless otherwise noted Solvents: A: 0.1% formic acid in water, B: MeCN gradient:

[0219] [Table 3]

[0220] Method #basic3minb Equipment: Agilent 1260; Quaternary Pump, HiP Sampler, Column Compartment, DAD: G6150 MSD Column: Phenomenex Evo C18, 30 x 2.1 mm, 2.6 μm, 40°C Detection: UV at 260 nm ± 90 nm, MS with electrospray ionization unless otherwise noted Solvent A: 0.2% ammonia in water, B: MeCN gradient:

[0221] [Table 4]

[0222] Intermediates Intermediate 1 [ka]

[0223] Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde A solution of 7-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (250 mg, 1 equiv., 1.11 mmol), PdCl(dppf).CHCl (80 mg, 0.089 equiv., 98 μmol), EtN (336 mg, 0.46 mL, 3 equiv., 3.32 mmol), and triethylsilane (386 mg, 0.53 mL, 3 equiv., 3.32 mmol) in DMF (5 mL) was degassed under a stream of N for 5 min before sealing. It was then purged with N (×3) and charged with CO (1.5 bar), and the reaction mixture was heated to 90 °C for 2.5 h. The reaction mixture was taken up in EtOAc (40 mL) and then washed with saturated aqueous NHCl (40 mL), water:brine (2 × 1:1, 40 mL), and brine (40 mL). The organic phase was dried over MgSO, filtered, and concentrated onto silica (approximately 1 g). The crude product was purified by silica gel chromatography (12 g cartridge, 0-5% (1% EtN / MeOH) / DCM) to give 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde (219 mg, 1.0 mmol, 90%, 80% purity) as a brown oil. LCMS(Method #basic3minb,1.25min;M+H=176.2.1H NMR(500MHz,DMSO)δ9.93(s,1H),7.66(dd,J=7.9,1.7Hz,1H),7.60(d,J=1.8Hz,1H),7.34 (d,J=7.8Hz,1H),3.58(s,2H),2.91(t,J=5.9Hz,2H),2.63(t,J=5.9Hz,2H),2.37(s,3H).

[0224] The following intermediates were prepared in a similar manner to Intermediate 1, starting from the corresponding aryl bromides. [Table 5]

[0225] [Table 6]

[0226] Example Example 1 [ka]

[0227] Synthesis of (S)-2-((isochroman-6-ylmethyl)amino)-5,5-dimethylhexanoic acid hydrochloride A suspension of isochroman-6-carbaldehyde (102 mg, 0.628 mmol; 1.0 equiv.), (S)-2-amino-5,5-dimethylhexanoic acid (100 mg, 0.63 mmol), and sodium acetate (77 mg, 0.942 mmol; 1.5 equiv.) in dichloromethane (2 mL) was stirred at room temperature for 2 h, after which sodium triacetoxyborohydride (266 mg, 1.26 mmol, 2 equiv.) was added. The remaining suspension was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and purified by acidic preparative HPLC (Method 2). The product-containing fractions were concentrated, reconstituted with 1 M aqueous HCl, and concentrated to give (S)-2-((isochroman-6-ylmethyl)amino)-5,5-dimethylhexanoic acid hydrochloride (123.7 mg, 0.362 mmol, 57.6% yield) as a white solid. LCMS (Method 1, 0.906 min; M+H=306.5; calcd. 306.2). 1 H-NMR(400MHz,DMSO)δ14.02(br,1H),9.37(s,2H),7.31-7.27(m,2H),7.10(d,J=7.9Hz,1H),4.69(s,2H),4.10(s,2H),3.98-3 .78(m,3H),2.79(t,J=5.7Hz,2H),1.99-1.70(m,2H),1.33(td,J=13.1,4.8Hz,1H),1.11(td,J=12.9,4.4Hz,1H),0.86(s,9H).

[0228] The following examples were prepared in a manner similar to Example 1, starting from the corresponding aldehyde.

[0229] [Table 7]

[0230] Example 3 [ka]

[0231] Synthesis of (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid mesylate Isochroman-7-carbaldehyde (2.26 g, 13.93 mmol; 1.0 equiv.) was added to a mixture of (S)-2-amino-5,5-dimethylhexanoic acid (2.219 g, 13.93 mmol) and sodium acetate (1.715 g, 20.90 mmol; 1.5 equiv.) in methanol (20 mL). The mixture was stirred at room temperature for 2 hours, after which sodium triacetoxyborohydride (6.61 g, 31.2 mmol; 2.0 equiv.) was added. The mixture was stirred at room temperature for 16 hours. The precipitated product was collected by filtration. The residue was washed with methanol (5 mL) to give (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid (1.42 g, 4.65 mmol, 33% yield). The mother liquor was concentrated in vacuo. The residue was taken up in EtOAc and washed with water (2x) and brine. The product crashed out of the organic layer and was collected by filtration. The residue was washed with a small amount of EtOAc and dried in vacuo to give (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid (1.04 g, 3.41 mmol, 24% yield). (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid (1.37 g, 4.48 mmol) was taken up in methanesulfonic acid (0.1 M in MeCN) (44.8 mL, 4.48 mmol; 1 equiv.). 50 mL of water was added and the mixture was stirred at 40 °C until the product was completely dissolved. The solution was lyophilized to give (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid compound 7 along with methanesulfonic acid (1.638 g, 4.08 mmol, 29% yield). LCMS (Method 1, 0.902 min; M+H=306.1; calcd. 306.2). 1H-NMR(400MHz,DMSO)δ10.03(br,2h),7.25(d,J=7.8Hz,1H),7.19(d,J=7 .8Hz,1H),7.13(s,1H),4.68(s,2H),4.11-3.99(m,2H),3.88(t,J=5.7Hz,2 H),3.75-3.67(m,1H),2.79(t,J=5.8Hz,2H),2.30(s,3H),1.86-1.67(m,2H ),1.30(td,J=12.9,4.9Hz,1H),1.13(td,J=12.7,4.7Hz,1H),0.85(s,9H).

[0232] The following examples were prepared in a similar manner to Example 3, starting from the corresponding aldehyde. [Table 8]

[0233] Example 7 [ka]

[0234] Synthesis of (S)-5,5-dimethyl-2-(((5,6,7,8-tetrahydroquinolin-3-yl)methyl)amino)hexanoic acid-methanesulfonic acid To a solution of (5,6,7,8-tetrahydroquinolin-3-yl)methanamine dihydrochloride (77 mg, 0.326 mmol, 1.0 equiv) in dichloromethane (0.9 mL) containing triethylamine (148 μL, 1.061 mmol, 3.25 equiv), a solution of methyl (R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (100 mg, 0.326 mmol, 1.0 equiv) in DCM (0.9 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated by nitrogen blow-drying. The crude product was redissolved in acetonitrile:water (2 mL, 1:1). Lithium hydroxide (68.5 mg, 1.632 mmol, 5.0 equiv.) was added, and the mixture was stirred for 16 hours. The mixture was purified by acidic preparative T3 HPLC (Method 8) to give (S)-5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexanoic acid (12.4 mg, 0.039 mmol, 17% yield). The product was dissolved in acetonitrile (1.1 mL), and methanesulfonic acid (1.0 equiv.) was added. The mixture was lyophilized to give (S)-5,5-dimethyl-2-(((5,6,7,8-tetrahydroquinolin-3-yl)methyl)amino)hexanoic acid along with methanesulfonic acid (13.1 mg, 0.033 mmol, 10.02% yield). LCMS (Method 7, 0.900 min; M+H-MsO - = 305.2; calculated value 305.2). 1 H-NMR(400MHz,DMSO)δ8.35(s,1H),7.58(s,1H),4.10(s,2H),2.86-2.72(m,4H),2 .29(s,3H),1.88-1.71(m,6H),1.37-1.24(m,1H),1.18-1.09(m,1H),0.86(s,9H).

[0235] The following examples can be prepared in a manner analogous to Example 7, starting from the corresponding amine. [Table 9]

[0236] Example 10 [ka]

[0237] Synthesis of (S)-5,5-dimethyl-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, mesylate A solution of 6-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (129 mg, 1 equiv., 570 μmol), triethylamine (173 mg, 239 μL, 3 equiv., 1.71 mmol), triethylsilane (199 mg, 273 μL, 3 equiv., 1.71 mmol), and PdCl(dppf)-CHCl (30 mg, 0.064 equiv., 37 μmol) in DMF (3.5 mL) was degassed under a stream of N for 5 min before sealing. It was then purged with N (×3) and charged with CO (1.5 bar), and the reaction mixture was heated to 90 °C for 6 h. The reaction mixture was taken up in EtOAc (30 mL) and then washed with saturated aqueous NHCl (20 mL), water:brine (2 × 1:1, 20 mL), and brine (20 mL). The organic phase was dried over MgSO, filtered, and concentrated onto silica (approximately 1 g). The crude product was purified by silica gel chromatography (12 g cartridge, 0–5% (1% EtN in MeOH) / DCM) to give 2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (54 mg, 0.30 mmol, 52%, 96% purity) as a brown gum.

[0238] A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (49 mg, 1 equiv., 0.31 mmol), 2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (54 mg, 1 equiv., 0.31 mmol), and triethylamine (31 mg, 43 μL, 1 equiv., 0.31 mmol) in MeOH (5.0 mL) was stirred at 40 °C for 2 h to give a solution. The mixture was cooled to 0 °C, and then sodium borohydride (12 mg, 1 equiv., 0.31 mmol) was added. Stirring was continued at room temperature for 1 h. AcOH (0.1 mL) was added, and the reaction mixture was concentrated onto Celite (approximately 1 g). The crude product was purified by chromatography using a RP Flash C18 (12 g cartridge, 10–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)). The isolated fraction was purified by 2 M The crude product was taken up in NaOH (0.5 mL) and re-purified by chromatography on RP Flash C18 (12 g cartridge, 15–50% MeCN / 10 mM ammonium bicarbonate) to give the free base. Treatment of the free base with MeOH (1 mL) and addition of 0.1 M MsOH in MeCN (1 equiv.) gave (S)-5,5-dimethyl-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, mesylate (19 mg, 39 μmol, 13%, 85% purity) as a colorless solid. UPLC(Method #basic3min,0.72min;M+H=319.3.1H NM R (500 MHz, DMSO) δ 7.03-6.98 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 3.61-3.55 (m, 1H), 3.44-3.36 (m, 3H), 3.19-3.13 (m, 1H), 2.77 (t, J = 6.0 Hz, 2H), 2.59-2.52 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 1.46-1.11 (m, 4H), 0.81 (s, 9H), 3 × no exchangeable hydrogens observed.

[0239] Example 11 [ka]

[0240] Synthesis of (R)-2-hydroxy-5,5-dimethylhexanoic acid To (R)-2-amino-5,5-dimethylhexanoic acid (12 g, 75 mmol, 1.0 equiv.) in water (220 mL) was added 1 M aqueous sulfuric acid (226 mL, 226 mmol, 3.0 equiv.). The mixture was cooled to -5 °C, and a solution of sodium nitrite (31.2 g, 452 mmol, 6.0 equiv.) in water (220 mL) was added dropwise, maintaining the temperature below 0 °C. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 h.

[0241] The mixture was extracted with EtO (4 × 200 mL), and the combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 74.4% yield) as a yellow solid. H-NMR (400 MHz, CDCl) δ 4.28 (dd, J = 7.2, 4.2 Hz, 1H), 1.92-1.80 (m, 1H), 1.75-1.62 (m, 1H), 1.41-1.27 (m, 2H), 0.90 (s, 9H).

[0242] Synthesis of (R)-2-hydroxy-5,5-dimethylhexanoate To (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 1 equiv.) in methanol (120 mL) was added SOCl (12 mL, 164 mmol, 2.93 equiv.) at 0 °C. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was alkalized to pH 9 by the addition of saturated aqueous NaHCO and extracted with EtO (2 × 400 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give methyl (R)-2-hydroxy-5,5-dimethylhexanoate (10.01 g, 55.0 mmol, 98% yield) as a yellow oil. It contained 4.2% (w / w) MeOH. 1H-NMR (400MHz, CDCl3) δ4.18(dd,J=7.2,4.2Hz,1H),3.80(s,3H),1.84-1.72(m,1H),1.67-1.52(m,1H),1.37-1.21(m,2H),0.89(s,9H).

[0243] Synthesis of methyl (R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate Trifluoromethanesulfonic anhydride (4.65 mL, 27.5 mmol, 1.10 equiv.) was added dropwise to a solution of (R)-2-hydroxy-methyl 5,5-dimethylhexanoate (4.36 g, 25.02 mmol, 1.0 equiv.) and triethylamine (4.19 mL, 30.0 mmol, 1.2 equiv.) in dichloromethane (100 mL) at 0 °C. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 h. Water (100 mL) was added, and the mixture was extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-methyl 5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (7.14 g, 23 0.31 mmol, 49% corrected yield, was obtained as a dark brown oil. 1H-NMR (400 MHz, CDCl3) δ 5.12 (dd, J = 6.9, 5.0 Hz, 1H), 3.85 (s, 3H), 2.05-1.90 (m, 2H), 1.36-1.24 (m, 2H), 0.90 (s, 9H).

[0244] Synthesis of (S)-5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexanoic acid methanesulfonic acid Methyl (R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (70 mg, 0.229 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added dropwise to a solution of (R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-amine (40.1 mg, 0.229 mmol, 1.0 equiv.) in dichloromethane (1 mL). The dichloromethane was removed and the residue was taken up in acetonitrile:water (2 mL, 1:1). Lithium hydroxide (27.4 mg, 1.143 mmol, 5.0 equiv.) was added and the mixture was stirred for 16 h. The mixture was subjected to acidic preparative HPLC (Method 2) to give (S)-5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexanoic acid (12.4 mg, 0.039 mmol, 17% yield). The product was dissolved in acetonitrile (1.1 mL) and methanesulfonic acid (0.1 M in acetonitrile) (390 μL, 0.039 mmol, 0.171 equiv.) was added. The mixture was lyophilized to give (S)-5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexanoic acid-methanesulfonic acid (20.5 mg, 0.050 mmol, 21.7% yield). LCMS (Method 1, 1.239 min; M+H-MsO - =318.5; calculated value 318.4). 1 H-NMR(400MHz,DMSO)δ7.18(d,J=7.8Hz,2H),7.10(d,J=7.7Hz,1H),4.26(d,J=6.9Hz,1H),3.54-3.40(m,2H),2.71(d,J=5.7Hz,4H) ,2.30(s,3H),1.74(h,J=3.8Hz,4H),1.52(d,J=6.7Hz,3H),1.27(td,J=13.0,4.7Hz,1H),1.03(td,J=12.8,3.9Hz,1H),0.85(s,9H).

[0245] The following examples can be prepared in an analogous manner to Example 11, starting from the corresponding enantiomeric secondary amines. [Table 10]

[0246] Example 15 [ka]

[0247] Synthesis of (S)-2-((3,4-dimethylbenzyl)amino)-5,5-dimethylhexanoic acid, mesylate A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (61 mg, 1.0 equiv., 0.38 mmol), tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 1 equiv., 383 μmol), and EtN (40 mg, 55 μL, 1.0 equiv., 0.39 mmol) in MeOH (3 mL) was heated at 40 °C for 2 h, then cooled in an ice bath and treated with NaBH (15 mg, 1.0 equiv., 0.40 mmol). The mixture was allowed to warm to room temperature, concentrated to dryness, and suspended in water (5 mL). Acetic acid (42 mg, 40 μL, 1.8 equiv., 0.70 mmol) was added and filtered. This material was suspended in water (10 mL) and acetone (2 mL) and heated at 60 °C for 30 min. After cooling to room temperature, the Boc-protected free base (112 mg, 0.28 mmol, 74% yield) was obtained. %) was recovered by filtration.

[0248] A sample of the free base (61 mg, 0.15 mmol) was taken up in DCM (3 mL) and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 h, then diluted with MeOH (4 mL) and loaded onto an SCX (approximately 1 g). This was washed with MeOH, and the required material was eluted with 7 M NH3 in MeOH (5 column volumes) and concentrated. This was then dissolved in MeOH (2 mL), and 0.1 M MsOH in MeCN (1 equivalent) was added, after which the material was concentrated to dryness to give (S)-5,5-dimethyl-2-(((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, mesylate (67 mg, 0.16 mmol, 43%, 98% purity) as a colorless solid. LCMS(Method #acid3minb,0.13min;M+H=305.2.1H NMR(500MHz,DMSO)δ9.01(s,2H),7.32-7.18(m,2H),4.27(s,2H),3.95-3.89(m,1H),3.87-3.81(m,1H),3.73-3.65(m,1H),3.42-3. 36(m,2H),3.02-2.96(m,2H),2.80-2.72(m,1H),2.30(s,3H),1.70-1.59(m,2H),1.29-1.12(m,2H),0.85(s,9H),1×No exchangeable H observed.

[0249] The following examples were prepared in a similar manner to Example 15, starting from the corresponding aldehyde. [Table 11]

[0250] Example 19 [ka]

[0251] Synthesis of (S)-5,5-dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid, mesylate A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (112 mg, 1 equiv., 705 μmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (125 mg, 1 equiv., 705 μmol), and EtN (71.9 mg, 99.0 μL, 1.01 equiv., 710 μmol) in MeOH (5.00 mL) was heated at 40 °C for 2.5 h, then cooled in an ice bath and treated with NaBH (27.0 mg, 1.01 equiv., 714 μmol). The mixture was then allowed to warm to room temperature and stirred for 2.5 h before being filtered. The solvent was removed from the filtrate in vacuo. The solid was triturated with water (3 mL), filtered, and washed with MeCN (5 mL) to give a white solid. This material was purified by chromatography on RP Flash C18 (4 g cartridge, 5–40% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give (S)-5,5-dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid (29.0 mg, 86 μmol, 12%, 95% purity) as a cream-colored solid. LCMS(Method #acid3minb,1.34min;M+H=320.2.1H NMR(500MHz,MeOD)δ0.92(s,9H),1.28-1.43(m,2H),1.73-1.88(m,2H),2.92(s,3H),3.28-3.31(m,3H),3.44(t,J=6.0Hz,1H),3.95(d ,J=13.0Hz,1H),4.08(d,J=12.9Hz,1H),4.26-4.31(m,2H),6.74(d,J=8.2Hz,1H),6.85(d,J=2.1Hz,1H),6.91(dd,J=2.1,8.2Hz,1H).

[0252] (S)-5,5-Dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid (29.0 mg, 95 wt%, 1 equiv., 86.0 μmol) was stirred in MeOH (2.50 mL), followed by the addition of methanesulfonic acid (0.1 M in MeCN) (8.26 mg, 860 μL, 0.10 mol, 1 equiv., 86.0 μmol). The resulting solution was stirred at 25° C. for 30 minutes and then concentrated in vacuo to give the product, which was dried in a vacuum desiccator at 25° C. for 15 hours. (S)-5,5-Dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid, mesylate (27.0 mg, 64 μmol, 75%, 99% purity) was obtained as a green / yellow solid. LCMS(Method #acid3minb,0.97min;M+H=320.5.1H NMR(500MHz,DMSO)δ14.00(bs,1H),9.07(bs,1H),8.99(bs,1H),6.85(dd,J=8.2,2.1H z,1H),6.81(d,J=2.0Hz,1H),6.71(d,J=8.3Hz,1H),4.25-4.20(m,2H),4.00-3.97(m,2 H),3.81(bs,1H),3.28-3.22(m,2H),2.84(s,3H),2.29(s,3H),1.89-1.79(m,1H),1.78 -1.69(m,1H),1.30(td,J=13.1,4.7Hz,1H),1.09(td,J=13.0,4.3Hz,1H),0.85(s,9H).

[0253] The following examples can be prepared in an analogous manner to Example 19, starting from the corresponding aldehyde.

[0254] [Table 12]

[0255] [Table 13]

[0256] [Table 14]

[0257] The following examples are based on other examples starting from the corresponding ketones, aldehydes, or esters. Prepared in a similar manner to Example 1. [Table 15]

[0258] [Table 16]

[0259] [Table 17]

[0260] The following examples were synthesized in a similar manner to the other examples. [Table 18]

[0261] [Table 19]

[0262] [Table 20]

[0263] [Table 21]

[0264] [Table 22]

[0265] [Table 23]

[0266] [Table 24]

[0267] [Table 25]

[0268] [Table 26]

[0269] Biological data Neurotensin scintillation proximity assay Exemplary compounds of the present invention were tested in the Neurotensin (NTS) Scintillation Proximity Assay (SPA). IC 50 The data are shown in the table below. NTS, a 13 amino acid neuropeptide, is a ligand for sortilin. IC 50 is an indication of the amount of compound required to inhibit 50% of the binding of NTS to sortilin. 50 It will be appreciated that the lower the value, the less compound is needed to achieve the desired effect, thereby reducing the chance of unwanted off-target effects.

[0270] In SPA format, [ 3 Compound affinity was determined by measuring the displacement of [H]-neurotensin binding. A total volume of 40 μL was made up in assay buffer of 50 mM HEPES pH 7.4 containing CaCl2, 0.1% BSA, and 0.1% Tween-20. Compounds were pre-incubated with 150 nM 6his-Sortilin for 30 min at room temperature, followed by 5 nM [ 3H]-neurotensin and Ni-chelating imaging beads (Perkin Elmer) were added and after 6 hours the plates were read on a ViewLux with an exposure time of 360 seconds. Compound dose-response evaluation was performed at eight drug concentrations (covering three orders of magnitude). IC 50 Values ​​were calculated by nonlinear regression with a sigmoidal concentration response (variable slope) using CDD Vault software. All values ​​reported are the average of at least two determinations.

[0271] The data in the table below demonstrate that the compounds of the present invention are sortilin inhibitors. [Table 27]

[0272] [Table 28]

[0273] Creoptix (GCI) method - Use of SEQ ID NO: 4 (mouse sortilin) The GCI assay is specifically enhanced to detect the binding of small entities to proteins. is based on the well-known surface plasmon resonance methodology. The K on and K. off Velocity, and K d This methodology does not require the use of an additional tracer and can be used with or without the element of competition with a known ligand.

[0274] reagent: [Table 29]

[0275] All buffers mentioned were filtered using a 0.2 μm filter (product number: 10300461, Nalgene) and degassed for 15 minutes before use.

[0276] A flow cell temperature of 25°C was used throughout the experiment.

[0277] Chip conditioning and immobilization Conditioning of the 4PCH chip was performed across all flow cells using a preconfigured conditioning wizard (WAVE Control Software) with 0.2x running buffer (1x HBS-N, pH 7.4, 3.4 mM EDTA, 1% DMSO) followed by three start-up injections of 0.2x running buffer, followed by an injection of 0.1 M borate, 1 M NaCl (pH 9).

[0278] A buffer exchange was performed and 1x running buffer (1x HBS-N, pH 7.4, 3.4mM EDTA, 1% DMSO) was used during the immobilization procedure: The first injection of EDC / NHS (mixed at a 1:1 ratio) was performed over all four flow cells. The surface was activated for amine coupling of the ligand.

[0279] Aliquots of recombinant sortilin were quickly thawed by hand and centrifuged at 13,300 rpm for 10 min. Afterwards, 10 μg / mL protein solutions were prepared in acetate at pH 5.0 and injected once for 20 min on flow cells 2, 3, and 4, respectively, for human, human (flow cells 2 & 3), and mouse sortilin, followed by a 60 s dissociation time.

[0280] Finally, all flow cells received a 7-minute passivation injection of 50 mM Tris.

[0281] A flow rate of 10 μL / min was used in all conditioning and fixation cycles.

[0282] Rapid kinetics: intermediate binders Compound screening was performed at 1 μM using the built-in "intermediate binders" settings: 100 μL / min, 45 s baseline, 25 s association, 300 s dissociation, blank every 5 samples, and DMSO correction (1.5% DMSO at the beginning and end of the experiment and every 20 cycles). An acquisition rate of 10 Hz was used throughout the experiment.

[0283] Compounds were screened at a final assay concentration of 1 μM with a final DMSO concentration of 1%. To achieve this, compounds were diluted in DMSO from a 10 mM stock to 100 μM (100× final assay concentration) and then diluted 1:100 into running buffer without DMSO to give a final assay concentration of 1 μM compound and a final DMSO concentration of 1% [DMSO].

[0284] Compounds and DMSO were mixed by shaking the plate at 1000 rpm for 60 seconds using a Bioshake apparatus.

[0285] A flow rate of 100 μL / min was used throughout the experiment.

[0286] Data Evaluation: Data were evaluated using the RAPID kinetic analysis tool in GCI WAVE_control software, with data fitted using a standard 1:1 kinetic BioModel.

[0287] The results for the compounds of the present invention are shown in the table below. [Table 30]

[0288] [Table 31]

[0289] The compounds of the present invention have a K dIt is advantageous to have the generated K d The data demonstrate that examples of the present invention bind directly to sortilin protein and bind to both human and mouse sortilin protein in a generally similar manner, thus demonstrating pharmacokinetics. and demonstrates advantages in the development of non-human models of disease.

[0290] Blood-brain barrier permeability To determine whether compounds of the present invention can cross the blood-brain barrier, compounds of Example 3 and a sortilin modulator not according to the present invention, which has the following structure: [ka] For Comparative Example 1 having K puu was calculated.

[0291] Plasma protein binding and brain homogenate binding of study compounds in mice, dogs, and rats by rapid equilibrium dialysis Mice were administered the compound of Comparative Example 1, and rats and dogs were administered the compound of Example 3. At specific time points, plasma and brain were removed and analyzed for compound concentration. Separately, the proportion of compound bound to plasma proteins or brain homogenates was measured, allowing the free proportion to be assessed.

[0292] The free drug hypothesis states that only unbound compounds can penetrate biological membranes and interact to elicit pharmacological effects. Therefore, it is desirable for compounds to have high free brain concentrations. However, only the free, unbound drug portion is subject to clearance mechanisms.

[0293] Indeed, in vitro rapid equilibrium dialysis was used to assess the unbound fraction in plasma and brain tissue. Separately, in vivo pharmacokinetic studies were performed in which the compound of interest was administered at T = 0 h and the total concentrations of the compound in plasma, and separately in brain samples, were analyzed at subsequent time points (e.g., 0.5 h, 1 h, and 4 h). These total concentrations were then adjusted with the unbound fraction to obtain the unbound concentrations in plasma and brain. The unbound partition coefficient (K puu ) was determined as the ratio of free compound concentrations between the compartments of interest, i.e., here brain / CNS and plasma.

[0294] rapid equilibrium dialysis Test compounds were incubated in triplicate at 5 μM in plasma and brain homogenates from relevant species using a RED device (8K MWCO, Thermo Scientific) equipped with inserts for 4 hours at 37°C. 350 μL of 150 mM phosphate-buffered saline (PBS, pH 7.4) was used as the receiver solution. Samples were collected from both sides after a 4-hour equilibration period, and the matrices were made similar by diluting donor samples with blank PBS and receiver samples with blank plasma / phosphate-buffered saline. After incubation, an aliquot of donor matrix was diluted with an equal volume of blank receiver matrix, and an aliquot of receiver matrix was diluted with an equal volume of blank donor matrix. Proteins were precipitated for all samples by adding two volumes of acetonitrile containing 100 nM repaglinide as an internal standard. After 10 minutes of centrifugation at 13,200 rpm, sample supernatants were analyzed by LC-MS / MS to determine the unbound fraction of test compound (F). ub The unbound fraction was calculated from the peak area ratio obtained for each matrix. : F ub =C PBS / C plasma ; In the formula, C PBS and C plasmaare the analyte concentrations in PBS (receiver) and plasma (donor), respectively.

[0295] Recovery samples were prepared for each condition but without dialysis and used to estimate recovery from the dialysis experiments using the following formula: Recovery rate % = 100 × (V PBS ×C PBS +V plasma ×C plasma ) / V plasma ×C recovery In the formula, V PBS is the volume in the receiver side (PBS) of the dialyzer, and V plasma is the volume at the donor side (plasma). C recovery is the analyte concentration measured from the recovered sample.

[0296] As control compounds, propranolol (1 μM) and fluoxetine (5 μM) were included in the experiment.

[0297] The unbound fraction in the brain (F ub,brain ) was calculated by taking into account the dilution factor used in preparing the brain homogenate (F ub,meas ) calculated from:

number

[0298] Analysis method Instrument: Waters Acquity UPLC + Waters Xevo TQ-XS Triple Quadrupole MS Column: Waters Acquity HSS T3 (2.1 × 50 mm, 1.8 μm) column with pre-column filter Gradient elution; A = 0.1% formic acid, B = acetonitrile

[0299] [Table 32]

[0300] Temperature: 40℃ Injection volume: 1.5 μL Ion source: ESI+ Capillary voltage: 2400V Source temperature: 150℃ Desolvation temperature: 650℃ Cone gas flow: 240L / hour Desolvation gas flow: 1200L / hour Nebulizer gas flow: 7 Bar Collision gas flow: 0.15 mL / min Software: MassLynx 4.2

[0301] [Table 33]

[0302] Equilibrium dialysis results The unbound proportions of the compounds of Example 3 and Comparative Example 1 in the plasma and brain homogenates of mouse plasma, mouse brain, rat brain, and dog plasma are shown in the table below. [Table 34]

[0303] Blood-brain barrier permeability of investigational compounds in mice after IV administration Compounds are administered to animals in a suitable vehicle at T = 0 time. 0.5 hours after administration, plasma, and separately brain, is removed, prepared, and analyzed for total compound concentration.

[0304] General sample processing procedure (plasma): Protein Precipitation (PPT) using 96-well plates 1) 5 μL aliquots of unknown samples, calibration standards, quality controls and dilution quality controls (if available), single blank, and double blank samples were added to a 96-well plate, respectively; 2) Each sample (except double blank) was quenched with 200 μL of IS1 (6-in-1 internal standard (labetalol & tolbutamide & verapamil & dexamethasone & glyburide & celecoxib, each 100 ng / mL) in MeOH (double blank sample was quenched with 200 μL of MeOH), then the mixture was vortex mixed at 800 rpm for 10 minutes and centrifuged at 3220 × g, 4 °C for 15 minutes; 3) An aliquot of 60 μL of the supernatant was transferred to another clean 96-well plate and centrifuged at 3220 × g at 4 °C for 5 min, after which the supernatant was directly injected for LC-MS / MS analysis.

[0305] Dilution Procedure Description: 1) Dilution factor 10: Add a 2µL aliquot of the unknown sample to an 18µL blank. Added to the coumatrix;

[0306] General sample processing procedure (brain homogenate): Protein Precipitation (PPT) using 96-well plates 1) 20 μL aliquots of unknown samples, calibration standards, quality controls and dilution quality controls (if available), single blank, and double blank samples were added to a 96-well plate, respectively; 2) Each sample (except the double blank) was quenched with 800 μL of IS1 (the double blank sample was quenched with 800 μL of MeOH), and then the mixture was vortex-mixed at 800 rpm for 10 minutes and centrifuged at 3220 × g and 4 °C for 15 minutes; 3) 60 μL of the supernatant was transferred to another clean 96-well plate and centrifuged at 3220 × g and 4 °C for 5 minutes, after which the supernatant was directly injected for LC-MS / MS analysis.

[0307] Analysis method Instrument: LC-MS / MS-CB_Triple Quad 6500 plus Column: Waters ACQUITY UPLC HSS T3 1.8 μm 2.1 × 50 mm Gradient elution; A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile [Table 35] Temperature: 45℃ Injection volume: 1.5 μL for brain, 4 μL for plasma Ion source: ESI+, SRM detection

[0308] [Table 36]

[0309] result Example 3 and Comparative Example 1 were formulated at 1.50 mg / mL in 10% DMSO, 5% Tween 80, 40% PG, 45% saline pH = approximately 7 (pH strips), clear solution, and administered intravenously at 3 mg / kg to male CD1 (ICR) mice.

[0310] The results are shown in the table below. In Example 3, the plasma concentration was 292 ng / mL and the brain concentration was 61.2 ng / g 0.5 hours after administration. That is, the observed brain concentration was 21% of the plasma concentration. On the other hand, in Comparative Example 1, the plasma concentration was 3087 ng / mL and the brain concentration was 5 ng / g 0.5 hours after administration. This means that the ratio of the brain concentration to the plasma concentration was less than 1%.

[0311] For the treatment of CNS diseases, brain / plasma ratio values ​​above 1%, preferably above 10% and 20% are advantageous. Thus, Example 3 is particularly useful for the treatment of CNS diseases.

[0312] [Table 37]

[0313] Non-bonded partition coefficient (K puu ) was determined as the ratio of free compound concentrations in plasma and brain:

number

[0314] Therefore, K in Comparative Example 1 puu is calculated to be less than 0.1, indicating that Comparative Example 1 does not effectively penetrate the blood-brain barrier.

[0315] K in dogs puu Decision Example 3 was packaged in enteric-coated capsules (0#) as solid batch number C2210502. Approximately 30 minutes before administration of the test compound, fasted male beagle dogs were administered pentagastrin (0.25 mg / mL, 0.024 mL / kg) at 6 μg / kg by intramuscular (IM) injection. Capsules containing 20 mg / kg of Example 3 were orally administered, and plasma and CSF samples were collected before administration and 0.5, 1, 2, 4, 8, 12, and 24 hours after administration, and analyzed for Example 3 concentrations in a manner similar to the study described above.

[0316] result [Table 38]

[0317] Analysis Data [Table 39]

[0318] Non-bonded partition coefficient (K puu ) was determined as the ratio between the areas under the curve corrected for free compound concentrations in plasma and CSF.

[0319] K puu=AUC0-infcsf / (AUC0-infplasma×(%Fuplasma / 100))

[0320] K puu =6414 / (23816×(55.5 / 100))=6414 / 13218=0.49

[0321] Therefore, K in Example 3 puu is greater than 0.1, indicating that some of the unbound compound in the plasma penetrates the blood-brain barrier, making this compound particularly useful for treating CNS disorders.

[0322] Rat K in Comparative Example 2 puu Comparative Example 2 is a sortilin modulator not according to the present invention having the following structure: [ka]

[0323] K of Comparative Example 2 in rats puu was determined as follows:

[0324] The compound of Comparative Example 2 was administered orally or intravenously to the animals in a single dose. Blood samples were collected from the animals at predetermined time points via the saphenous vein (sv) or vena cava (vc). The final sample was collected under isoflurane anesthesia. One or two blood samples were collected from each animal.

[0325] Within 30 minutes of sampling, blood samples were centrifuged (10 minutes, 2700G, RT) for plasma separation. Samples were transferred to pre-labeled plastic tubes, frozen, and stored at -80°C until analysis.

[0326] Blank blood was collected into a K2EDTA syringe by cardiac puncture under isoflurane anesthesia from animals that had not received the compound of Comparative Example 2. The blood was centrifuged (2700 G, 10 minutes, room temperature) for plasma separation. The blank plasma was frozen and stored at -80°C until analysis. .

[0327] Brains were collected from selected animals at designated time points. Under terminal anesthesia, the animals underwent laparotomy, and a final blood sample was collected from the vena cava. The heart was exposed for perfusion, and the major vein leading to the right atrium was severed. A blunt needle was then inserted into the left ventricle of the heart, and approximately 30–50 mL of chilled saline was injected to remove any remaining blood. Tissue samples were then immediately collected, frozen in liquid nitrogen, and stored at −80°C until analysis. Blank brain material was similarly collected from animals not administered the compound in Comparative Example 2.

[0328] Rat brain samples were homogenized with an Omni Bead Ruptor 24 using four volumes of 150 mM phosphate buffered saline (PBS, pH 7.4) per part of tissue (eg, 100 mg of brain tissue + 400 μL of PBS).

[0329] Protein precipitation was performed by mixing one part of the sample (rat plasma or brain homogenate) with three parts of 1% formic acid in acetonitrile containing an internal standard cocktail (e.g., mixing 30 μL of plasma with 90 μL of the solution). The sample was mixed on a benchtop shaker for 3 minutes and then centrifuged at 2272 × g for 20 minutes. The supernatant was transferred to an analysis plate, diluted 1:1 with ultrapure water, and subjected to analysis.

[0330] For standard sample preparation, blank rat plasma and brain homogenate were spiked to give analyte concentrations ranging from 0.1 ng / mL to 20,000 ng / mL (5 μL of standard + 45 μL of blank plasma).

[0331] Quality control (QC) samples were prepared in triplicate and spiked with blank rat plasma and brain homogenate to give analyte concentrations of 0.3, 3, 30, 300, and 3000 ng / mL (5 μL QC + 45 μL blank matrix).

[0332] Standards and quality controls were prepared for analysis in the same manner as the samples.

[0333] Brain and plasma samples were analyzed by ultra-performance liquid chromatography (UPLC) coupled with mass spectrometry (MS) to determine the concentration of the compound of Comparative Example 2. puu was calculated.

[0334] The results for both intravenous and oral administration of the compound are shown in the table below. The data in the table are the average results of samples taken from 2-3 animals.

[0335] This data is the K puu is less than 0.1, thus indicating that the compound does not effectively penetrate the blood-brain barrier.

[0336] Intravenous administration [Table 40]

[0337] Oral administration [Table 41]

[0338] Microdialysis research The following experiment was carried out using the compound of Example 3 as a mesylate salt.

[0339] Materials and Methods In vitro experiments To measure the recovery of the compound of Example 3, an in vitro experiment was performed using a MetaQuant microdialysis probe (CRL Groningen, The Netherlands) equipped with a 4 mm bare ethylene vinyl alcohol (EC20) membrane. For this purpose, the probe was placed in a beaker containing 10 nM of the compound of Example 3 in artificial CSF (aCSF: ultrapure water containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl, and 1.2 mM MgCl). The contents of the beaker were continuously stirred and maintained at a constant temperature of 37°C. The probe was perfused with a slow flow of aCSF at a rate of 0.12 μL / min and a carrier flow of ultrapure water at a rate of 0.8 μL / min. After a 2-hour pre-stabilization period, five consecutive microdialysis samples were taken at 30-minute intervals. Samples of the beaker contents were taken at the beginning and end of the microdialysis experiment. All samples were collected in 0.5 mL LoBind Eppendorf tubes (Eppendorf, Germany; 0030108035) and stored at −80°C until analysis.

[0340] In vivo experiments Thirteen adult male Sprague Dawley rats were used in the experiment. A push-pull microdialysis probe (CRL Groningen, The Netherlands) with a guide and a 4 mm exposed polyethersulfone (PES200) membrane was placed in the left hippocampus of the rats. Animals receiving the test compound were placed in the left hippocampus with a guide and a 4 mm exposed ethylene vinyl alcohol membrane. A MetaQuant microdialysis probe (CRL Groningen, The Netherlands) equipped with a PET (EC20) membrane was placed in the right hippocampus. The probe tip coordinates were as follows: AP = -5.3 mm (relative to bregma), lateral ±4.8 mm (relative to midline), and ventral -8.0 mm (relative to dura). The incisor bar was set at -3.3 mm. All coordinates are based on "The rat brain in stereotaxic coordinates" by Paxinos and Watson (2009). The probe was attached to the skull with stainless steel screws and dental cement.

[0341] Animals receiving test compounds had indwelling cannulae (35-42 mm) placed in the jugular vein and exteriorized through an incision in the top of the skull to allow for blood sampling. The ends of each cannula were fixed in place with dental cement and attached to the skull with stainless steel screws.

[0342] The compound of Example 3 was formulated at a concentration of 20 mg / mL in 20% sulfobutylether-β-cyclodextrin (SBE-β-CD) in deionized water and given by oral gavage at 100 mg / kg in a volume of 5 mL / kg.

[0343] Experiments began one day after probe implantation. Push-pull and MetaQuant microdialysis probes were connected to a microperfusion pump (Harvard Apparatus, USA) using flexible PEEK tubing (Western Analytical Products, USA; PK005-020). The probes were perfused with artificial CSF (aCSF: 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl, and 1.2 mM MgCl) at a flow rate of 0.5 μL / min (push-pull probe) or with a slow flow of aCSF at a flow rate of 0.12 μL / min and a carrier flow of ultrapure water at a flow rate of 0.8 μL / min (MetaQuant probe). After 2 h of pre-stabilization, microdialysis samples were collected at 60-min intervals. Three basal samples were collected. Food was removed at t = -120 min, followed by compound administration at t = 0 min and again at t = 180 min and 360 min. Food was returned after the third administration. Microdialysate samples were collected 720 min after the first compound administration. Samples were collected in 0.5 mL LoBind Eppendorf tubes. All samples were stored at -80°C until analysis.

[0344] During the experiment, blood samples were collected via the jugular vein catheter. Blood samples were collected in K2-EDTA collection vials. After centrifugation, the resulting plasma samples were divided into two aliquots using low-binding pipette tips and placed in 0.5 mL LoBind Eppendorf tubes. All samples were stored at -80°C until analysis.

[0345] At the end of the experiment, the animals were sacrificed and terminal brain tissue was collected for verification of probe positioning.

[0346] The concentration of the compound of Example 3 was measured by HPLC with tandem mass spectrometry (MS / MS) detection. The microdialysis sample was mixed with acetonitrile, formic acid, ultrapure water, and an internal standard (labetalol). The plasma sample was mixed with acetonitrile, formic acid, and the internal standard, followed by centrifugation. The resulting supernatant was mixed with acetonitrile and formic acid in ultrapure water and then used for HPLC-MS analysis. An aliquot of each analytical sample was injected onto the HPLC column using an automatic sample injection system (Shimadzu Corporation, Japan). Chromatographic separation was performed using a Kinetex XB-C18 column (50 × 2.1 mm, 2.6 μm) set at 35 °C. The mobile phase consisted of A: 0.1% formic acid in ultrapure water, and B: 0.1% formic acid in acetonitrile. The compounds were eluted using a linear gradient of phases A and B at a total flow rate of 0.4 mL / min.

[0347] MS analysis was performed using an API 4000 MS / MS detector and a Turbo Ion Spr The analysis was performed using an API 4000 MS / MS system consisting of a 3000 Hz ion exchanger and a 3000 Hz ion exchanger (both from Applied Biosystems, The Netherlands). Acquisition was performed in positive ionization mode using settings optimized for the analyte. The instrument was operated in multiple reaction monitoring (MRM) mode.

[0348] Weighted (1 / x) regression was used to fit appropriate in-run calibration curves, and these calibration curves were used to determine sample concentrations. Accuracy was verified by quality control samples after each sample series. Data were calibrated and quantified using an Analyst™ data system (Applied Biosystems). The MRM transitions of the analytes are shown in the table below.

[0349] [Table 42]

[0350] Weighted (1 / x) regression was used to fit appropriate in-run calibration curves, and these calibration curves were used to determine sample concentrations. Accuracy was verified by quality control samples after each sample series. Data were calibrated and quantified using the Analyst® data system (Applied Biosystems).

[0351] A commercially available ELISA kit (AG-45A-0043YEK-KI01, AdipoGen, Switzerland) was used to quantify rat PGRN in the study samples. Study samples were added to the plate at a dilution based on the previous study key 2819. Plasma samples were analyzed in duplicate. Samples that fell outside the detection limit were reanalyzed on a separate plate with a more appropriate dilution. Additionally, samples with a %CV of >30% for duplicate analysis were also reanalyzed on a separate plate. Absorbance at 450 nm was measured using a Multiskan FC (ThermoFischer Scientific, USA).

[0352] Data were processed in Microsoft Excel and plotted in Prism 9 for Windows®, version 9.3.1 (GraphPad Software, Inc., 1992–2021).

[0353] For evaluation of pharmacodynamic microdialysis data, the average of three pre-dose samples was taken as 100%. Relative basal sample concentrations below 50% or above 150% were considered outliers and were not used in baseline calculations. All post-dose samples were expressed as a percentage of the basal value within the same subject. Prior to statistical analysis, an outlier analysis was performed: values ​​that deviated by more than two standard deviations from the relative mean value at one time point within the same treatment group were excluded by one iteration.

[0354] Statistical analysis of relative data was performed using SigmaPlot 12.5 (Systat Software, 2011). Treatment and time effects were compared between treatment groups using two-way ANOVA for repeated measures followed by Bonferroni post-hoc test. Treatment and time were main factors. Main effects were evaluated only if there was no statistically significant interaction between the two main factors. If there was a significant interaction between the two main factors, the main effect was not considered. In this case, the interaction effect was evaluated as follows: For each dose, the time course was assessed relative to the concentration at t = 0 min; The differences in concentrations after different treatments at each individual time point were compared.

[0355] The level of statistical significance was defined a priori as p<0.05.

[0356] Reported microdialysate concentrations are corrected for dilution. Corrections for probe recovery are provided in the text, where applicable.

[0357] result In vitro recovery rate of Example 3 Using aCSF as the perfusate and a MetaQuant microdialysis probe with a 4 mm bare EC20 membrane, the relative in vitro recovery for Example 3 averaged 69.8±3.40%.

[0358] The in vitro recovery of PGRN using a push-pull microdialysis probe perfused with aCSF and equipped with a 4 mm exposed PES200 membrane was previously 26.9 ± 0.86% in study key 2819B.

[0359] Histological verification Visual evaluation of the brain showed that all probes were in the correct position.

[0360] Pharmacokinetics Figure 1 shows the concentration of Example 3 in microdialysis samples from the hippocampus of adult male Sprague Dawley rats after oral administration of 100 mg / kg of Example 3 (t = 0, 180, and 360 min; indicated by arrows). At t = -120, -60, and 0 min, the concentration of Example 3 was below the lower limit of quantitation (LLOQ) of 7.31 ng / mL in the microdialysate. Data are expressed as mean + SEM (n = 7). Data have been corrected to account for the 69.8% probe recovery measured in vitro.

[0361] Figure 2 shows the concentration of Example 3 in the plasma of adult male Sprague Dawley rats after oral administration of 100 mg / kg of Example 3 (at t = 0, 180, and 360 minutes; indicated by arrows). At t = -120 minutes, the concentration of Example 3 was below the LLOQ of 50.0 ng / mL in plasma. Data are expressed as mean + SEM (n = 7).

[0362] The table below shows the basal concentrations of PGRN in microdialysates and plasma from the hippocampus. [Table 43]

[0363] Figure 3 shows the relative pharmacodynamic responses of PGRN in hippocampal microdialysates from adult male Sprague Dawley rats after oral administration (at t = 0, 180, and 360 minutes; indicated by arrows) of vehicle or 100 mg / kg of Example 3. Data are presented as mean + SEM (n = 5-6 / group).

[0364] Pharmacodynamics Relative PGRN data from the hippocampus of animals treated in Example 3 were statistically evaluated by two-way analysis of variance for repeated measures, revealing a significant interaction between treatment and time. A significant difference was observed (p<0.001). In post-hoc evaluation, PGRN levels in animals treated with Example 3 were elevated at t=540-720 min when compared to t=0 min. Focusing on treatment, PGRN levels in animals treated with Example 3 were significantly higher than in the vehicle group during the time period t=540-720 min. Details of the statistical analysis are shown in the table below.

[0365] [Table 44]

[0366] Figure 4 shows the concentration of PGRN in the plasma of adult male Sprague Dawley rats after oral administration (at t = 0, 180, and 360 minutes; indicated by arrows) of 100 mg / kg of Example 3. Data are expressed as mean + SEM (n = 7).

[0367] conclusion The above data show that the compound of the present invention (Example 3) can cross the blood-brain barrier after oral delivery. This surprising finding indicates that the compounds of the present invention may be useful for treating disorders of the central nervous system. The data also show that the compound of Example 3 increased PGRN levels in the brain of rats. This further surprising finding suggests that the compounds of the present invention may have the ability to treat conditions in which increasing PGRN levels in the brain may be useful. For example, the compounds of the present invention may be useful for treating frontotemporal dementia, which is characterized by reduced PGRN levels. Patients with reduced PGRN levels in the brain are statistically more likely to develop frontotemporal dementia. Therefore, the data presented herein suggest that the compounds of the present invention may be useful for preventing and treating frontotemporal dementia and related conditions.

[0368] Embodiments of the invention Embodiment 1. Formula (I): [ka]

[0369] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, During the ceremony, R 1 but

[0370] [ka] and;

[0371] X is CR 3 or N, where R 3 is selected from the group consisting of H, halo, and C1-C3 alkyl; Each Y is independently CHR 4 , N.R. 5 , C.R. 6 R 6 , or O, where R 4are independently selected from the group consisting of H, halo, oxo, and C1-C4 alkyl; R 5 is independently selected from the group consisting of H, halo, C1-C4 alkyl, C2-C4 hydroxyalkyl, —(C2-C4 alkyl)-O—(C1-C4 alkyl), —C(O)—(C1-C4 alkyl), and —C(O)O—(C1-C4 alkyl); and R 6 is independently selected from the group consisting of halo and C1-C4 alkyl; R 2 is selected from the group consisting of H, C1-C4 alkyl, C2-C4 hydroxyalkyl, and C1-C3 haloalkyl; The compound is a compound of:

[0372] [ka] Not one of; The compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0373] Embodiment 2. R 2 is selected from the group consisting of H, CH3, CH2F, CHF2, and CF3, preferably R 2 is selected from the group consisting of H, CH3, CHF2, and CF3.

[0374] Embodiment 3. Each Y is independently CHR 4 , N.R. 5 or O; and / or R 3 is H or C1-C3 alkyl, preferably H or methyl; and / or Each R 4 are independently H or oxo; and / or Each R 5are independently H, C1-C3 alkyl, or —C(O)O—(C1-C4 alkyl), preferably H, methyl, or —C(O)O-(tert-butyl), more preferably H or methyl; The compound of embodiment 1 or 2.

[0375] Embodiment 4. R 1 is the following group: [ka] wherein preferably no more than one or two Y are NR 5 or O, and the remaining Y is CHR 4 The compound of any one of embodiments 1-3, wherein

[0376] Embodiment 5. R 1 is the following group: [ka] wherein each Y is independently selected from one of NR 5 or O, preferably one R 4 group is H or oxo, and other R 4 The compound of embodiment 4, wherein all groups are H.

[0377] Embodiment 6. R 1 is the following group: [ka] The compound of embodiment 5, wherein the compound is selected from one of:

[0378] Embodiment 7. R 1 is the following group: [ka] The compound of embodiment 6, wherein the compound is selected from one of:

[0379] Embodiment 8. R 1 is the following group: [ka] The compound of embodiment 7, wherein the compound is selected from one of:

[0380] Embodiment 9. (2S)-2-{[(1S)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydronaphthalen-2-yl)methyl]amino}hexanoic acid; (2S)-2-[({1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinolin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydroquinolin-3-yl)ethyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydroquinolin-3-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)-2,2,2-trifluoroethyl]amino}-5,5-dimethylhexanoic acid;

[0381] (2S)-2-{[(1R)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-[({5H,6H,7H-cyclopenta[b]pyridin-3-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(2,3-dihydro-1H-inden-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-[({5H,7H,8H-pyrano[4,3-b]pyridin-3-yl}methyl)amino]hexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[({2H,3H,4H-pyrano[2,3-b]pyridin-6-yl}methyl)amino]hexanoic acid;

[0382] (2S)-2-{[(1R)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(5-methyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-[({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-2-{[(2,3-dihydro-1-benzofuran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0383] (2S)-5,5-dimethyl-2-{[(7-methyl-2,3-dihydro-1H-inden-5-yl)methyl]amino}hexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1,3-dihydro-2-benzofuran-4-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(2,3-dihydro-1-benzofuran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-8-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(2H-1,3-benzodioxol-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid;

[0384] (2S)-2-{[(1R)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid; (2S)-2-{[(2,3-dihydro-1H-inden-4-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0385] Embodiment 10. Formula (II) [ka]

[0386] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, During the ceremony, R 7 is selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl, preferably from the group consisting of H, CH3, CHF2, and CF3, preferably from the group consisting of H and CH3; R 8 is phenyl or pyridine, wherein phenyl and pyridine are independently selected from 5-membered heterocycloalkyl, triazolyl, -O-phenyl, and -NR 9 R 10 and R is substituted with one or more substituents selected from the group consisting of 9 and R10 are independently selected from H or C1-C3 alkyl, preferably H or CH3, more preferably CH3; or R 7 is C1-C3 hydroxyalkyl, preferably —(C2H4)—OH; R 8 is phenyl optionally substituted with C1-C3 alkoxy, preferably phenyl is optionally is substituted with -O-CH3, The compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0387] Embodiment 11. R 7 is selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; R 8 is pyrrolidinyl, triazolyl, -O-phenyl, or -NR 9 R 10 or R 8 is pyridine substituted with -O-phenyl; or R 7 is C1-C3 hydroxyalkyl, and R 8 is phenyl optionally substituted with C1-C3 alkoxy; The compound of embodiment 10.

[0388] Embodiment 12. (2S)-5,5-Dimethyl-2-{[(2-phenoxypyridin-4-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(6-phenoxypyridin-3-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-({[3-(pyrrolidin-1-yl)phenyl]methyl}amino)hexanoic acid; 2-{[(1S)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid; (2S)-5,5-Dimethyl-2-{[(4-phenoxyphenyl)methyl]amino}hexanoic acid; (2S)-2-({[3-(dimethylamino)phenyl]methyl}amino)-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-Dimethyl-2-{[(3-phenoxyphenyl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-({[3-(1H-1,2,4-triazol-1-yl)phenyl]methyl}amino)hexanoic acid; or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0389] Embodiment 13. A pharmaceutical composition comprising a compound according to any one of embodiments 1-12 and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0390] Embodiment 14. A compound according to any one of embodiments 1 to 12, or a pharmaceutical composition according to embodiment 13, for use in therapy.

[0391] Embodiment 15. Neurodegenerative diseases, psychiatric disorders, inflammatory diseases, cancer, pain, diabetes, A compound according to any one of embodiments 1 to 12, or a pharmaceutical composition according to embodiment 13, for use in the treatment or prevention of chronic retinopathy, glaucoma, uveitis, cardiovascular disease, kidney disease, psoriasis, inherited eye disease, hearing loss, or a disease characterized by misfolded tau; The neurodegenerative disease is preferably selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke, and preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy; The neurodegenerative disease is preferably a neurodegenerative disease characterized by misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia; The psychiatric disorder is preferably selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; The inflammatory disease is preferably selected from inflammatory diseases and neuroinflammation; The cancer is preferably selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; The cardiovascular disease is preferably selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; and The hearing loss is preferably selected from noise-induced hearing loss, ototoxicity-induced hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; Compound or pharmaceutical composition.

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[0398] Santos, A. M. et al., Sortilin Participates in Light-dependent Photoreceptor Degeneration in Vivo. PLoS ONE (2012), 7(4), pp. e36243-e36243.16. Kuruvilla, R. et al., A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of Tr kA trafficking and retrograde signalling. Cell (2004), 118(2), pp. 243-255; Shi, J. & Kandror, K. V., Sortilin Is Essential and Sufficient for the Formation of Glut4 Storage Vesicles in 3T3-L1 Adipocytes. Developmental Cell (2005), 9, pp. 99-108; Schroder, T. et al., The identification of AF38469: an orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin. Bioorg Med Chem Lett (2014), 24(1), pp. 177-180; Sheng, J. et al.,Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer’s disease. Gene (2014), 542(2), pp. 141-145;Skeldal, S. et al., Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis. J Biol Chem (2012), 21(287), pp. 43798-43809;

[0399] Tauris, J., et al., Proneurotrophin-3 May Induce Sortilin-Dependent Death In Inner Ear Neurons. Eur J Neuroscience (2020), 33(4), pp.622-31; Tang, W. et al., The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science (2011), 332(6028), pp. 478-484; Tao, J.et al., Neuroprotective effects of progranulin in ischemic mice. Brain Res (2012), 1436, pp. 130-136; Tenk, H.K., et al., ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neuroscience (2005), 10(11), pp.1449-1457 Van Kampen, J. M.,et al., Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson’s disease. PLoS One (2014), 9(5), e97032; Willnow, T. E.et al., VPS10P-domain receptors - regulators of neuronal viability and function. Nat Rev Neurosci (2008), 9(12), pp. 899-909; Willnow, T.E., et al., Sortilins: new p layers in lipoprotein metabolism. Current Opinion in Lipidology (2011), 22(2), pp. 79-85.

[0400] Wuts, P.G.M. and Greene, T.W, Greene’s Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons, New York (2006); Xu, S.H. et al., Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain, Frotiers in Neuroanatomy (2019), 13(31), pp. 1-27; Yano, H., et al., Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing. J Neurosci (2009), 29(47), pp. 14790-14802; Yin, F., et al., Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med (2010), 207(1), pp. 117-128; Zheng, Y., et al., C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS One (2011), 6(6), e21023; Zhou, X. et al., Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol (2015), 210(6), pp. 991-1002;

[0401] Meneses et al., TDP-43 Pathology in Alzheimer’s Disease, Mol Neurodegeneration (2021), 16, 84; Prudencio et al., Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor, Proc Natl Acad Sci U S A (2012), 109(52): 21510-21515; Beel et al., Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice, Mol Neurodegener. (2018), 13: 55.

[0402] Sequences referenced throughout and forming part of this specification SEQ ID NO: 1 (full length sortilin-isoform 1) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCKAD LGALELWRTS DLGKSFKTIG 301 VKIYSFGLGG RFLFASVMAD KDTTRRIHVS TDQGDTWSMA QLPSVGQEQF 351 YSILAANDDM VFMHVDEPGD TGFGTIFTSD DRGIVYSKSL DRHLYTTTGG 401 ETDFTNVTSL RGVYITSVLS EDNSIQTMIT FDQGGRWTHL RKPENSECDA 451 TAKNKNECSL HIHASYSISQ KLNVPMAPLS EPNAVGIVIA HGSVGDAISV 501 MVPDVYISDD GGYSWTKMLE GPHYYTILDS GGIIVAIEHS SRPINVIKFS 551 TDEGQCWQTY TFTRDPIYFT GLASEPGARS MNISIWGFTE SFLTSQWVSY 601 TIDFKDILER NCEEKDYTIW LAHSTDPEDY EDGCILGYKE QFLRLRKSSM 651 CQNGRDYVVT KQPSICLCSL EDFLCDFGYY RPENDSKCVE QPELKGHDLE 701 FCLYGREEHL TTNGYRKIPG DKCQGGVNPV REVKDLKKKC TSNFLSPEKQ 751 NSKSNSVPII LAIVGLMLVT VVAGVLIVKK YVCGGRFLVH RYSVLQQHAE 801 ANGVDGVDAL DTASHTNKSG YHDDSDEDLL E

[0403] SEQ ID NO: 2 (full length sortilin-isoform 2) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCTDL GALELWRTSD LGKSFKTIGV 301 KIYSFGLGGR FLFASVMADK DTTRRIHVST DQGDTWSMAQ LPSVGQEQFY 351 SILAANDDMV FMHVDEPGDT GFGTIFTSDD RGIVYSKSLD RHLYTTTGGE 401 TDFTNVTSLR GVYITSVLSE DNSIQTMITF DQGGRWTHLR KPENSECDAT 451 AKNKNECSLH IHASYSISQK LNVPMAPLSE PNAVGIVIAH GSVGDAISVM 501 VPDVYISDDG GYSWTKMLEG PHYYTILDSG GIIVAIEHSS RPINVIKFST 551 DEGQCWQTYT FTRDPIYFTG LASEPGARSM NISIWGFTES FLTSQWVSYT 601 IDFKDILERN CEEKDYTIWL AHSTDPEDYE DGCILGYKEQ FLRLRKSSVC 651 QNGRDYVVTK QPSICLCSLE DFLCDFGYYR PENDSKCVEQ PELKGHDLEF 701 CLYGREEHLT TNGYRKIPGD KCQGGVNPVR EVKDLKKKCT SNFLSPEKQN 751 SKSNSVPIIL AIVGLMLVTV VAGVLIVKKY VCGGRFLVHR YSVLQQHAEA 801 NGVDGVDALD TASHTNKSGY HDDSDEDLLE

[0404] SEQ ID NO: 3 (mature sortilin) 1 MTFGQSKLYR SEDYGKNFKD ITDLINNTFI RTEFGMAIGP ENSGKVVLTA 51 EVSGGSRGGR IFRSSDFAKN FVQTDLPFHP LTQMMYSPQN SDYLLALSTE 101 NGLWVSKNFG GKWEEIHKAV CLAKWGSDNT IFFTTYANGS CTDLGALELW 151 RTSDLGKSFK TIGVKIYSFG LGGRFLFASV MADKDTTRRI HVSTDQGDTW 201 SMAQLPSVGQ EQFYSILAAN DDMVFMHVDE PGDTGFGTIF TSDDRGIVYS 251 KSLDRHLYTT TGGETDFTNV TSLRGVYITS VLSEDNSIQT MITFDQGGRW 301 THLRKPENSE CDATAKNKNE CSLHIHASYS ISQKLNVPMA PLSEPNAVGI 361 VIAHGSVGDA ISVMVPDVYI SDDGGYSWTK MLEGPHYYTI LDSGGIIVAI 401 EHSSRPINVI KFSTDEGQCW QTYTFTRDPI YFTGLASEPG ARSMNISIWG 451 FTESFLTSQW VSYTIDFKDI LERNCEEKDY TIWLAHSTDP EDYEDGCILG 501 YKEQFLRLRK SSVCQNGRDY VVTKQPSICL CSLEDFLCDF GYYRPENDSK 551 CVEQPELKGH DLEFCLYGRE EHLTTNGYRK IPGDKCQGGV NPVREVKDLK[[ID=!15]] 601 KKCTSNFLSP EKQNSKSNSV PIILAIVGLM LVTVVAGVLI VKKYVCGGRF 651 LVHRYSVLQQ HAEANGVDGV DALDTASHTN KSGYHDDSDE DLLE

[0405] Sequence number 4 (mouse sortilin) >sp|Q6PHU5|SORT_MOUSE Sortilin OS=Mus musculus OX=10090 GN=Sort1 PE=1 SV=1 MERPRGAADGLLRWPLGLLLLLQLLPPAAVGQDRLDAPPPPAPPLLRWAGPVGVSWGLRA AAPGGPVPRAGRWRRGAPAEDQDCGRLPDFIAKLTNNTHQHVFDDLSGSVSLSWVGDSTG VILVLTTFQVPLVIVSFGQSKLYRSEDYGKNFKDITNLINNTFIRTEFGMAIGPENSGKV ILTAEVSGGSRGGRVFRSSDFAKNFVQTDLPFHPLTQMMYSPQNSDYLLALSTENGLWVS KNFGEKWEEIHKAVCLAKWGPNNIIFFTTHVNGSCKADLGALELWRTSDLGKTFKTIGVK IYSFGLGGRFLFASVMADKDTTRRIHVSTDQGDTWSMAQLPSVGQEQFYSILAANEDMVF MHVDEPGDTGFGTIFTSDDRGIVYSKSLDRHLYTTTGGETDFTNVTSLRGVYITSTLSED NSIQSMITFDQGGRWEHLRKPENSKCDATAKNKNECSLHIHASYSISQKLNVPMAPLSEP NAVGIVIAHGSVGDAISVMVPDVYISDDGGYSWAKMLEGPHYYTILDSGGIIVAIEHSNR PINVIKFSTDEGQCWQSYVFTQEPIYFTGLASEPGARSMNISIWGFTESFITRQWVSYTV DFKDILERNCEEDDYTTWLAHSTDPGDYKDGCILGYKEQFLRLRKSSVCQNGRDYVVAKQ PSVCPCSLEDFLCDFGYFRPENASECVEQPELKGHELEFCLYGKEEHLTTNGYRKIPGDK CQGGMNPAREVKDLKKKCTSNFLNPTKQNSKSNSVPIILAIVGLMLVTVVAGVLIVKKYV CGGRFLVHRYSVLQQHAEADGVEALDSTSHAKSGYHDDSDEDLLE

Claims

1. Equation (I): 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof, During the ceremony, R １ but 【Chemistry 2】 And; X is CR ３ Or N, where R ３ H, Halo, and C １ ~C ３ Selected from the group consisting of alkyl groups; each Y is independently CHR ４ , NR ５ , CR ６ R ６ , C(O), or O, wherein R ４ is independently selected from the group consisting of H, halo, and C １ -C ４ alkyl; R ５ is independently H, halo, C １ -C ４ alkyl, C ２ -C ４ hydroxyalkyl, -(C ２ -C ４ Alkyl)-O-(C １ ~C ４ Alkyl), -C(O)-(C １ ~C ４ Alkyl), and -C(O)O-(C １ ~C ４ Selected from the group consisting of alkyl; and R ６ Halo and C are independent １ ~C ４ Selected from the group consisting of alkyl groups; R ２ H, C １ ~C ４ Alkyl, C ２ ~C ４ Hydroxyalkyl, and C １ ~C ３ Selected from the group consisting of haloalkyls; The aforementioned compound is the following compound: 【Transformation 3】 It is not one of them; Compounds, or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs.

2. R ２ H, CH ３ ,CH ２ F, CHF ２ , and CF ３ A compound according to claim 1, selected from the group consisting of the following.

3. The compound according to claim 2, wherein R2 is selected from the group consisting of H, CH3, CHF2, and CF3.

4. Each Y independently controls the CHR ４ , NR ５ , C(O), or O; and / or, R ３ is H or C １ ~C ３ Alkyl; and / or, Each R ４ H is; and / or, Each R ５ H and C are independent. １ ~C ３ Alkyl, or -C(O)O-(C １ ~C ４ It is alkyl; The compound according to claim 1.

5. The compound according to claim 4, wherein R3 is H or methyl.

6. The compound according to claim 4, wherein each R5 is independently H, methyl, or -C(O)O-(tert-butyl).

7. The compound according to claim 6, wherein each R5 is independently H or methyl.

8. R １ The following is the basis: 【Chemistry 4】 A compound according to claim 1, selected from one of the following.

9. The compound according to claim 8, wherein one or less Y is NR5 or O, and the remaining Y is independently C(O) or CHR4.

10. R １ The following is the basis: 【Transformation 5】 Selected from one of the following, in the formula each Y independently of NR ５ or O; each R ７ These are independently H, Halo, and C １ ~C ４ Selected from the group consisting of alkyl groups, or the R ７ The compound according to claim 8, wherein it forms an oxo group together with the carbon atom to which it is bonded.

11. The compound according to claim 10, wherein each R7 is H, or R7 together with the carbon atom to which it is bonded forms an oxo group.

12. The compound according to claim 11, wherein one R7 is H, or the R7 together with the carbon atom to which it is bonded forms an oxo group, and all other R7 groups are H.

13. R １ The following is the basis: 【Transformation 6】 A compound according to claim 10, selected from one of the following.

14. R １ The following is the basis: 【Transformation 7】 A compound according to claim 13, selected from one of the following.

15. R １ The following is the basis: 【Transformation 8】 A compound according to claim 14, selected from one of the following.

16. (2S)-2-{[(1S)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydronaphthalene-2-yl)methyl]aminohexanoic acid; (2S)-2-[({1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinoline-7-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-7-yl)methyl ]amino-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydroquinoline-3-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydroquinoline-3-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinoline-7-yl)methyl]aminohexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(1-methyl-1,2,3,4-tetrahydroquinoline-7-yl)ethyl]aminohexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)-2,2,2-trifluoroethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-[({5H,6H,7H-cyclopenta[b]pyridine-3-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(2,3-dihydro-1H-inden-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)methyl]aminohexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-[({5H,7H,8H-pyrano[4,3-b]pyridine-3-yl}methyl)aminohexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[({2H,3H,4H-pyrano[2,3-b]pyridine-6-yl}methyl)aminohexanoic acid; (2S)-2-{[(1R)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(5-methyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]aminohexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)methyl]aminohexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7 -ethyl(-yl)amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(1,2,3,4-tetrahydroquinoline-7-yl)ethyl]aminohexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-[({2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-yl}methyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)methyl]aminohexanoic acid; (2S)-2-{[(2,3-dihydro-1-benzofuran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(7-methyl-2,3-dihydro-1H-inden-5-yl)methyl]aminohexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1,3-dihydro-2-benzofuran-4-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(2,3-dihydro-1-benzofuran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-8-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(2H-1,3-benzodioxol-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-6-yl)methyl]aminohexanoic acid; (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinoline-7-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl]aminohexanoic acid; (2S)-2-{[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinoline-6-yl)methyl]aminohexanoic acid; (2S)-2-{[(1R)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydro Isoquinoline-6-yl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-yl)methyl]aminohexanoic acid; (2S)-2-{[(2,3-dihydro-1H-inden-4-yl)methyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinoline-6-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-yl)methyl]aminohexanoic acid; The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

17. Formula (II) 【Chemistry 9】 Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof, During the ceremony, R ８ H, C １ ~C ３ Alkyl and C １ ~C ３ Selected from the group consisting of haloalkyl groups; R ９ is phenyl or pyridine, where phenyl and pyridine are independently 5-membered heterocycloalkyl, triazolyl, -O-phenyl, and -NR １０ R １１ It is substituted with one or more substituents selected from the group consisting of R １０ and R １１ H or C １ ~C ３ Selected from alkyl groups; or, R ８ C １ ~C ３ It is a hydroxyalkyl group; R ９ C at will １ ~C ３ It is a phenyl substituted with an alkoxy. Compounds, or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs.

18. The compound according to claim 17, wherein R8 is selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; R9 is phenyl or pyridine, where phenyl and pyridine are independently substituted with one or more substituents selected from the group consisting of 5-membered heterocycloalkyl, triazolyl, -O-phenyl, and -NR10R11, and R10 and R11 are independently selected from H or C1-C3 alkyl.

19. The compound according to claim 18, wherein R 8 is selected from the group consisting of H, CH 3, CHF 2, and CF 3.

20. The compound according to claim 19, wherein R8 is selected from the group consisting of H and CH3.

21. The compound according to claim 18, wherein R 10 and R 11 are independently selected from H or CH 3.

22. The compound according to claim 21, wherein R10 and R11 are CH3.

23. The compound according to claim 17, wherein R8 is a C1-C3 hydroxyalkyl group and R9 is a phenyl group optionally substituted with a C1-C3 alkoxy group.

24. The compound according to claim 23, wherein R8 is -C2H4-OH.

25. The compound according to claim 23, wherein R9 is optionally substituted with -O-CH3.

26. R ８ H, C １ ~C ３ Alkyl and C １ ~C ３ Selected from the group consisting of haloalkyls, R ９ is pyrrolidinyl, triazolyl, -O-phenyl, or -NR １０ R １１ Phenyl substituted with, or R ９ is a pyridine substituted with -O-phenyl; or, R ８ is C １ -C ３ hydroxyalkyl, and R ９ is phenyl optionally substituted with C １ -C ３ alkoxy; The compound according to claim 17.

27. (2S)-5,5-dimethyl-2-{[(2-phenoxypyridine-4-yl)methyl]amino}hexanoic acid; (2S)-5,5-dimethyl-2-{[(6-phenoxypyridine-3-yl)methyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-({[3-(pyrrolidine-1-yl)phenyl]methyl}aminohexanoic acid; 2-{[(1S)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(1R)-1-(6-phenoxypyridine-3-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(1S)-1-(6-phenoxypyridine-3-yl)ethyl]aminohexanoic acid; (2S)-5,5-dimethyl-2-{[(4-phenoxyphenyl)methyl]amino}hexanoic acid; (2S)-2-({[3-(dimethylamino)phenyl]methyl}amino)-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-{[(3-phenoxyphenyl)methyl]amino}hexanoic acid; (2S)-2-{[(1S)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(1R)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-({[3-(1H-1,2,4-triazole-1-yl)phenyl]methyl}aminohexanoic acid; The compound according to claim 17, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, and a pharmaceutically acceptable carrier, excipient, and / or diluent.

29. The pharmaceutical composition according to claim 28 for the treatment or prevention of a disease characterized by neurodegenerative diseases, mental disorders, inflammatory diseases, cancer, pain, diabetes, retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, hearing loss, or misfolded tau.

30. The pharmaceutical composition according to claim 29, wherein the neurodegenerative disease is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases including Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke.

31. The pharmaceutical composition according to claim 30, wherein the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy.

32. The pharmaceutical composition according to claim 29, wherein the neurodegenerative disease is a neurodegenerative disease characterized by a misfolded TAR DNA-binding protein 43.

33. The pharmaceutical composition according to claim 32, wherein the neurodegenerative disease characterized by the misfolded TAR DNA-binding protein 43 is amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia.

34. The pharmaceutical composition according to claim 29, wherein the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder.

35. The pharmaceutical composition according to claim 29, wherein the inflammatory disease is selected from inflammatory diseases and neuroinflammation.

36. The pharmaceutical composition according to claim 29, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, brain tumor, and colorectal cancer.

37. The pharmaceutical composition according to claim 36, wherein the brain tumor is a glioblastoma.

38. The pharmaceutical composition according to claim 29, wherein the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

39. The pharmaceutical composition according to claim 29, wherein the hearing loss is selected from noise-induced hearing loss, ototoxicity-induced hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

40. The pharmaceutical composition according to claim 29, wherein the retinopathy is diabetic retinopathy.

41. The pharmaceutical composition according to claim 29, wherein the pain is chronic pain.

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