Sorting protein modulators

Abstract

The present invention relates to compounds of formulae (I) and (II) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides and / or prodrugs thereof. The 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 sorteins is beneficial.

Description

Field of the Invention

[0001] The present invention relates to compounds of formula (I) or (II), which surprisingly have been found to modulate the activity of sortilin. The invention also relates to pharmaceutical compositions comprising these compounds, and their use in the treatment or prevention of medical conditions in which modulation of sortilin activity is beneficial. Specifically, the compounds of the invention can cross the blood-brain barrier and can thus be particularly useful for treating diseases of the central nervous system. Background Art

[0002] Sortilin is a type I transmembrane protein that acts as a receptor for a variety of ligands (Petersen et al., 1997). Sortilin is highly expressed in neurons and microglia in the nervous system, the inner ear, and some peripheral tissues involved in metabolic control (Tauris et al., 2020; Goettsch et al., 2017; Willnow et al., 2011; Kjolby et al., 2010). In addition to acting as a receptor involved in signal transduction, sortilin also mediates the sorting of selected cargo between the cell surface trans-Golgi network 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 called sortilin or VS10p domain receptors. The VPS10P domain in sortilin is homologous to yeast VPS10P and consists of a 10-bladed β-propeller structure and a cysteine-rich 10CC module (Nykjaer & Willnow, 2012; Zheng, Brady, Meng, Mao, & Hu, 2011).

[0003] Sortilin binds to a variety of ligands, including pro-nerve growth factor (pro-NGF), pro-brain-derived neurotrophic factor (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). In addition, sortilin binds to progranulin (PGRN), a secreted protein involved in many cellular functions, including ensuring lysosomal processes, anti-inflammatory responses, and neurotrophic stimulation (Galimberti, Fenoglio, & Scarpini, 2018). Sortilin targets PGRN for rapid endocytosis and degradation, and 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 levels of PGRN in the periphery and the brain. Indeed, the lack or blockade of this receptor increases plasma PGRN levels in 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, and haploinsufficiency of the PGRN gene accounts for up to 25% of all cases (Gijselinck, Van Broeckhoven, & Cruts, 2008). Extracellular protein levels are reduced by >50% in patients with PGRN loss-of-function heterozygous mutations and invariably develop into FTD, making PGRN a disease-causing gene for this disorder (Baker et al., 2006; Carecchio et al., 2011; Cruts & Van Broeckhoven, 2008; Galimberti et al., 2010). In addition, PGRN mutant alleles have been found in patients with Alzheimer's disease (AD) (Brouwers et al., 2008; Sheng, Su, Xu, & Chen, 2014), and high levels of extracellular PGRN have protective effects 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, PGRN does not require sortilin to elicit its function. Thus, neurons lacking sortilin expression are equally responsive to PGRN-induced neuronal growth (De Muynck et al., 2013; Gass, Lee, et al., 2012). In addition, PGRN is successfully delivered to neuronal lysosomes in sortilin-deficient cells, indicating the existence of alternative transport pathways. Indeed, PGRN can bind to the lysosomal protein, prosaposin (PSAP). When PSAP binds to its cognate receptors (cation-independent mannose-6-phosphate receptor and LRP1), it delivers PGRN to lysosomes (Zhou et al., 2015). Finally, in a phase II clinical trial of monoclonal anti-sortilin antibodies, markers for lysosomal integrity were normal (NCT03987295).

[0006] Functional PGRN receptors remain to be identified. However, studies have shown that PGRN promotes neuronal survival, reduces inflammation, and increases microglial phagocytosis of Aβ (Martens et al., 2012; Pickford et al., 2011; Yin et al., 2010).

[0007] The binding of PGRN to sortilin requires three amino acids at the C-terminus of PGRN (QLL in humans, PLL in mice), and a peptide derived from the last 24 amino acids of PGRN binds with an affinity similar to that of the full-length protein (Zheng et al., 2011). It has been proposed that this binding mode is structurally similar to that of neurotensin binding (Zheng et al., 2011), i.e., binding in the NTIS1 binding site of sortilin. A successful small molecule screen was completed in collaboration with Aarhus University, which identified blockers of neurotensin binding to sortilin (Andersen et al., 2014; Schroder et al., 2014).

[0008] Sortilin exists as a full-length and sorting-capable receptor, but is also able to form multimeric signaling receptor-ligands. Portions of sortilin can also be released from the plasma membrane to scavenge ligands (NT in pain) and control ligand activity. For example, sortilin is involved in synaptic plasticity by controlling the conversion rate of proBDNF to BDNF. This may also apply to other proneurotrophins.

[0009] Finally, the propeptide of sortilin (also known as spadin, which is a ligand for the receptor) has been shown to control the activity of the membrane transporter TREK-1, which is a target in diseases such as major depression. Structurally, sortilin has the amino acid sequence according to 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 tail region. The luminal domain of sortilin has 6 potential N-linked glycosylation sites, while the cytoplasmic tail region is able to recruit various adaptor proteins.

[0010] Sortilin binds to a large number of ligands and membrane receptors and is thus involved in functions known to be important in cell signaling and sorting. For example, sortilin is involved in the signaling of proneurotrophins, which are the precursor forms of nerve growth factor (NGF precursor), brain-derived neurotrophic factor (BDNF precursor), and neurotrophin-3 (NT3 precursor), respectively. Sortilin has been reported to form a receptor for proneurotrophin-mediated apoptotic effects when complexed with the protein p75NTR (p75 neurotrophin receptor), leading to degeneration and cell death in cell and animal models (Jansen et al., 2007; Tenk et al., 2005; Nykjaer et al., 2004).

[0011] Previous work has shown that sorting nexin plays a role in cellular sorting and signaling associated with diseases such as diabetes and obesity (Huang et al., 2013). Sorting nexin promotes the translocation of GLUT4 to the plasma membrane and protects it from degradation in lysosomes (Pan et al., 2017). Sorting nexin levels have been shown to be regulated by the levels of inflammation associated with these diseases. The pro-inflammatory cytokine TNFα reduces the mRNA and protein levels of sorting nexin in cultured mouse and human adipocytes and when injected into mice (Kaddai et al., 2009). Sorting nexin can also affect the secretion of cytokines: targeting sorting nexin in immune cells has been proposed to reduce inflammation and the progression of atherosclerotic diseases (Mortensen et al., 2014). In addition, US2016 / 0331746 describes various scaffolds of small molecules capable of binding to the active site of sorting nexin. Sorting nexin is involved in the regulation of glucose uptake (Shi & Kandror, 2005) and the development of lipid disorder diseases (Gao et al., 2017).

[0012] In addition, plasma sorting nexin levels have been reported to be potential biomarkers for identifying patients with coronary heart disease or diabetes (Oh et al., 2017; et al., 2021). Patients showing elevated sorting nexin levels in their plasma and thus identifiable as suffering from the abovementioned conditions also show elevated glucose levels, indicating that sorting nexin is a therapeutic target for treating these conditions. Soluble sorting nexin has also been proposed as a treatment for type II diabetes (WO 2021116290A1, 2021).

[0013] TAR DNA-binding protein 43 (TDP-43) is associated with multiple 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 sorting nexin. In humans, splicing involves the inclusion of cryptic exon 17b (between exons 17 and 18), which introduces a stop codon in the stem and may produce a non-membrane-bound fragment (Prudencio et al., 2012). In addition, it has been shown that PGRN can reduce the levels of insoluble TDP-43 and slow axonal degeneration (Beel et al., 2018). Inhibition of sorting nexin increases PGRN levels and thus is beneficial for treating neurodegenerative diseases involving TDP43.

[0015] Sorting nexin is associated with a variety of disorders that affect the central nervous system (CNS). Some studies have shown that circulating sorting nexin plays a role in patients with mental disorders such as depression, which may be related to alterations in neurotrophic factor activity (Buttenshon et al., 2015); and it has also been reported that sorting nexin plays 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 reach the CNS is a major challenge.

[0016] The blood-brain barrier is a highly selective semipermeable boundary of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the CNS where neurons are located. Therefore, due to the limited permeability of therapeutic agents across the blood-brain barrier, the treatment of nervous system diseases is also limited.

[0017] Therefore, therapeutic agents for treating CNS diseases must be able to cross the blood-brain barrier. In addition to this, they must also have a sufficient concentration of unbound drug in the brain because the free drug hypothesis states that only unbound compounds can interact and elicit a pharmacological effect.

[0018] To determine the unbound fraction (F ub ) of a test compound, the sample supernatant can be analyzed by methods such as liquid chromatography with tandem mass spectrometry (LC-MS / MS). Then the unbound fraction can be calculated from the peak area ratio obtained from each matrix according to the following formula:

[0019] F ub =C PBS / C 血浆

[0020] where C PBS and C 血浆 are the analyte concentrations in PBS (receptor) and plasma (donor), respectively.

[0021] Recovery samples can be prepared under each condition without dialysis, and the following formula can be used to evaluate the recovery rate of the dialysis experiment:

[0022] % recovery rate=100×(V PBS ×C PBS +V 血浆 ×C 血浆 ) / V 血浆 ×C 回收

[0023] where V PBS is the volume of the receptor side (PBS) of the dialysis device, and V 血浆 is the volume of the donor side (plasma). C 回收is the analyte concentration measured from the recycled samples. Compounds such as propranolol or fluoxetine can be included as controls in the experiment.

[0024] The unbound fraction (F ub,脑 ) in the brain can be calculated based on the measurement in the brain homogenate (F ub,测量 ) and considering the dilution factor used in preparing the brain homogenate:

[0025]

[0026] where D = dilution factor.

[0027] The brain / plasma unbound partition coefficient (K puu ) can be determined as the ratio between the free compound concentrations in plasma and brain:

[0028]

[0029] where C u,脑 = the unbound concentration in the brain (C x F ub,脑 ); where

[0030] C = the steady-state concentration; and

[0031] C ub,血浆 = the unbound concentration in plasma (C x F ub ).

[0032] Alternatively, the ratio of AUCs can be used to determine K puu . A known concentration of the target compound is administered to the relevant target species by oral or intravenous route. The time course of the compound concentration in plasma and cerebrospinal fluid (CSF) is measured. The plasma concentration is corrected to account for the unbound fraction of the compound. The area under the CSF concentration curve and the free portion of the plasma concentration curve are calculated by known methods and the ratio is determined to give:

[0033] K puu = AUC0-infcsf / (AUC0-inf plasma x (%Fu plasma / 100))

[0034] For the treatment of CNS diseases, it is desirable for K puu to have as high a value as possible, greater than 0. A value around 1 indicates that the free fraction of the compound freely penetrates the blood-brain barrier; a value greater than 1 indicates the involvement of an active influx transport mechanism at the blood-brain barrier; and a value less than 1 indicates poor permeability of the free fraction of the compound or recognition by an active efflux mechanism, reducing exposure in the CNS while returning to plasma or CSF across the blood-brain barrier. A K of 0 or close to 0 puuValues represent compounds with poor permeability or highly active efflux mechanisms that are highly unlikely to achieve a meaningful exposure of the desired active substance in the CNS under any circumstances.

[0035] 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 sorting proteins is beneficial. In particular, there is an unmet need for sorting protein modulators that can cross the blood-brain barrier and can thus be used to treat central nervous system diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is a graph depicting the levels of Example 3 in microdialysis samples of the hippocampus of adult male Sprague Dawley rats after oral administration of the compound, corrected for a 69.8% probe recovery.

[0037] Figure 2 is a graph depicting the levels of Example 3 in the plasma of adult male Sprague Dawley rats after oral administration of the compound.

[0038] Figure 3 is a graph depicting the relative pharmacodynamic response of PGRN in the hippocampal microdialysate of adult male Sprague Dawley rats after oral administration of the vehicle or Example 3.

[0039] Figure 4 is a graph depicting the levels of PGRN in the plasma of adult male Sprague Dawley rats after oral administration of Example 3. DETAILED DESCRIPTION

[0040] Surprisingly, it has been found that the compounds of formula (I) and (II) modulate the activity of sorting proteins and can thus be used to treat or prevent conditions in which modulation of sorting proteins is beneficial. In addition, the compounds can cross the blood-brain barrier and can thus be particularly useful for treating diseases of the central nervous system.

[0041] In a first aspect of the invention, there is provided a compound of formula (I):

[0042]

[0043] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide and / or prodrug thereof; wherein

[0044] R 1 is

[0045] X is CR 3 or N, wherein, R 3 is selected from the group consisting of H, halogen and C 1 -C3 a group consisting of alkyls;

[0046] 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, halogen, and C 1 -C 4 alkyl; R 5 is independently selected from the group consisting of H, halogen, 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 alkyl); and R 6 is independently selected from the group consisting of halogen and C 1 -C 4 alkyl;

[0047] R 2 is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, and C 1 -C 3 haloalkyl;

[0048] wherein the compound is not one of the following compounds:

[0049]

[0050] Preferably, the compound of formula (I) is not one of the following compounds:

[0051]

[0052] R 2 is preferably selected from the group consisting of H, CH 3 , CH 2 F, CHF 2 and CF 3 , more preferably R 2 is selected from the group consisting of H, CH 3 , CHF 2 and CF 3 .

[0053] R 3 Preferably H or C 1 -C 3 alkyl, more preferably H or methyl.

[0054] Each R 4 Preferably is H.

[0055] Each R 5 Preferably independently is H, C 1 -C 3 alkyl or -C(O)O-(C 1 -C 4 alkyl), more preferably H, methyl or -C(O)O-(tert-butyl), more preferably H or methyl, most preferably H.

[0056] As defined above, each Y is independently CHR 4 , NR 5 , CR 6 R 6 , C(O) or O. In one aspect of the present invention, each Y can independently be CHR 4 , NR 5 , CR 6 R 6 or O.

[0057] As defined above, R 1 is a partially saturated fused bicyclic system. The ring system can be attached to the rest of the molecule at any suitable position on the aromatic ring. However, in a particularly preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0058]

[0059] R 1 The partially saturated ring of the group may include one or more heteroatoms. However, preferably no more than two atoms in the partially saturated ring are heteroatoms. Thus, no more than one or two Y are preferably NR 5 or O, and the remaining Y are preferably C(O), CHR 4 or CR 6 R 6 .

[0060] R 1 The carbon atoms in the partially saturated ring of the group can be substituted with one or two substituents as defined above. However, preferably any carbon atom in the partially saturated ring is substituted with no more than 1 substituent. Thus, if the ring atoms in the partially saturated ring are carbon, then preferably C(O) or CHR 4 .

[0061] Thus, in a particularly preferred aspect of the present invention, no more than two Ys are NR 5 or O, and the remaining Ys are independently C(O) or CHR 4 .

[0062] R 1 Preferred examples of the group include:

[0063]

[0064] In the above-mentioned preferred R 1 groups, each Y is independently NR 5 or O. However, when the partially saturated ring includes two Y atoms, preferably one Y is O and the other Y is O or N.

[0065] Each R 7 is independently selected from the group consisting of H, halogen, and C 1 -C 4 alkyl, or R 7 together with the carbon atom to which it is attached forms a carbonyl group.

[0066] It is also preferred that only one carbon atom in the partially saturated ring is substituted by a substituent. Thus, one R 7 group is preferably selected from the group consisting of H, halogen, and C 1 -C 4 alkyl, or R 7 together with the carbon atom to which it is attached forms a carbonylidene group, and any other R 7 groups are all H. More preferably, one R 7 group is H or R 7 together with the carbon atom to which it is attached forms a carbonyl group, and any other R 7 groups are all H.

[0067] In the compound of formula (I), when the R 1 group is attached to the rest of the molecule at the ortho position of the saturated ring, X can be CH and Y can be O.

[0068] In a more preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0069]

[0070] More preferably, R 1 is selected from one of the following groups:

[0071]

[0072] Most preferably, R 1 is selected from one of the following groups:

[0073]

[0074]

[0075] In another preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0076]

[0077] In another preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0078]

[0079]

[0080] In another preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0081]

[0082]

[0083] In another preferred aspect of the present invention, R 1 is selected from one of the following groups:

[0084]

[0085]

[0086] The specific compounds of the first aspect of the present invention are listed below.

[0087] · (2S)-2-{[(1S)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0088]

[0089] · (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid:

[0090]

[0091] · (2S)-5,5-dimethyl-2-{[(1R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid:

[0092]

[0093] · (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydronaphthalen-2-yl)methyl]amino}hexanoic acid:

[0094]

[0095] · (2S)-2-[({1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinolin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid:

[0096]

[0097] · (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0098]

[0099] · (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydroquinolin-3-yl)ethyl]amino}hexanoic acid:

[0100]

[0101] · (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydroquinolin-3-yl)methyl]amino}hexanoic acid:

[0102]

[0103] · (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid:

[0104]

[0105] · (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid:

[0106]

[0107] · (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0108]

[0109] · (2S)-5,5-Dimethyl-2-{[(1R)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid:

[0110]

[0111] · (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)-2,2,2-trifluoroethyl]amino}-5,5-dimethylhexanoic acid:

[0112]

[0113] · (2S)-2-{[(1R)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0114]

[0115] · (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0116]

[0117] · (2S)-2-[({5H,6H,7H-cyclopenta[b]pyridin-3-yl}methyl)amino]-5,5-dimethylhexanoic acid:

[0118]

[0119] · (2S)-2-{[(2,3-dihydro-1H-inden-5-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0120]

[0121] · (2S)-5,5-Dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid:

[0122]

[0123] · (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0124]

[0125] · (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid:

[0126]

[0127] · (2S)-5,5-dimethyl-2-[({5H,7H,8H-pyrano[4,3-b]pyridin-3-yl}methyl)amino]hexanoic acid:

[0128]

[0129] · (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0130]

[0131] · (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0132]

[0133] · (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0134]

[0135] · (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0136]

[0137] · (2S)-5,5-dimethyl-2-[({2H,3H,4H-pyrano[2,3-b]pyridin-6-yl}methyl)amino]hexanoic acid:

[0138]

[0139] · (2S)-2-{[(1R)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0140]

[0141] · (2S)-5,5-dimethyl-2-{[(5-methyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}hexanoic acid:

[0142]

[0143] · (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid:

[0144]

[0145] · (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid:

[0146]

[0147] · (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0148]

[0149] · (2S)-5,5-dimethyl-2-{[(1S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid:

[0150]

[0151] · (2S)-5,5-dimethyl-2-{[(1R)-1-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid:

[0152]

[0153] · (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0154]

[0155] · (2S)-2-[({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid;

[0156]

[0157] · (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0158]

[0159] · (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid:

[0160]

[0161] · (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid:

[0162]

[0163] · (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid:

[0164]

[0165] · (2S)-2-{[(2,3-dihydro-1-benzofuran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0166]

[0167] · (2S)-5,5-dimethyl-2-{[(7-methyl-2,3-dihydro-1H-inden-5-yl)methyl]amino}hexanoic acid:

[0168]

[0169] · (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0170]

[0171] · (2S)-2-{[(1R)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0172]

[0173] · (2S)-2-{[(1,3-dihydro-2-benzofuran-4-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0174]

[0175] · (2S)-2-{[(2,3-dihydro-1-benzofuran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid

[0176]

[0177] · (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-8-yl)methyl]amino}-5,5-dimethylhexanoic acid

[0178]

[0179] · (2S)-2-{[(2H-1,3-benzodioxol-5-yl)methyl]amino}-5,5-dimethylhexanoic acid

[0180]

[0181] · (2S)-5,5-dimethyl-2-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}hexanoic acid

[0182]

[0183] · (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid

[0184]

[0185] · (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid

[0186]

[0187] · (2S)-5,5-dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid

[0188]

[0189] · (2S)-2-{[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid

[0190]

[0191] · (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid:

[0192]

[0193] · (2S)-2-{[(1R)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0194]

[0195] · (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0196]

[0197] · (2S)-5,5-dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid:

[0198]

[0199] · (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0200]

[0201] · (2S)-5,5-dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid:

[0202]

[0203] · (2S)-2-{[(2,3-dihydro-1H-inden-4-yl)methyl]amino}-5,5-dimethylhexanoic acid:

[0204]

[0205] · (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid:

[0206]

[0207] · (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid:

[0208]

[0209] · (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid:

[0210]

[0211] · (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid:

[0212]

[0213] · (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid:

[0214]

[0215] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug of the above compound.

[0216] In a second aspect of the present invention, a compound of formula (II) is provided:

[0217]

[0218] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0219] In one embodiment, R 8 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, and R 9 is phenyl or pyridine, wherein the phenyl and pyridine are independently substituted with one or more substituents selected from the group consisting of 5-membered heteroalkyl, triazolyl, -O-phenyl, and -NR 10 R 11 .

[0220] R 10 and R 11 are independently selected from H or C 1 -C 3 alkyl, preferably H or CH 3 , more preferably CH 3 .

[0221] Preferably, R 8 is selected from the group consisting of: H, CH 3 , CHF 2 and CF 3 , more preferably H and CH 3 .

[0222] Preferably, R 9 is phenyl substituted by pyrrolidinyl, triazolyl, -O-phenyl or -NR 10 R 11 ; or R 9 is pyridine substituted by -O-phenyl.

[0223] More preferably, R 9 is selected from one of the following groups:

[0224]

[0225] wherein the phenyl and pyridine are substituted as defined above.

[0226] Most preferably, R 9 is selected from one of the following groups:

[0227]

[0228] In an alternative embodiment of the second aspect of the present invention, R 8 is C 1 -C 3 hydroxyalkyl and R 9 is phenyl optionally substituted by C 1 -C 3 alkoxy.

[0229] Preferably, R 8 is -(C 2 H 4 )-OH.

[0230] Preferably, R 9 is phenyl optionally substituted by -O-CH 3 .

[0231] More preferably, R 9 is The specific compounds of the second aspect of the present invention are listed below.

[0232] · (2S)-5,5-dimethyl-2-{[(2-phenoxypyridin-4-yl)methyl]amino}hexanoic acid:

[0233]

[0234] · (2S)-5,5-dimethyl-2-{[(6-phenoxypyridin-3-yl)methyl]amino}hexanoic acid:

[0235]

[0236] · (2S)-5,5-dimethyl-2-({[3-(pyrrolidin-1-yl)phenyl]methyl}amino)hexanoic acid:

[0237]

[0238] · 2-{[(1S)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid:

[0239]

[0240] · (2S)-5,5-dimethyl-2-{[(1R)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid:

[0241]

[0242] · (2S)-5,5-dimethyl-2-{[(1S)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid:

[0243]

[0244] · (2S)-5,5-dimethyl-2-{[(4-phenoxyphenyl)methyl]amino}hexanoic acid:

[0245]

[0246] · (2S)-2-({[3-(dimethylamino)phenyl]methyl}amino)-5,5-dimethylhexanoic acid:

[0247]

[0248] · (2S)-2-{[(1R)-3-hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid:

[0249]

[0250] · (2S)-5,5-dimethyl-2-{[(3-phenoxyphenyl)methyl]amino}hexanoic acid:

[0251]

[0252] · (2S)-2-{[(1S)-3-Hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid:

[0253]

[0254] · (2S)-2-{[(1R)-3-Hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid:

[0255]

[0256] · (2S)-5,5-Dimethyl-2-({[3-(1H-1,2,4-triazol-1-yl)phenyl]methyl}amino)hexanoic acid:

[0257]

[0258] Or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide and / or prodrug of the above compounds.

[0259] According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier, excipient and / or diluent.

[0260] According to a fourth aspect of the present invention, there is provided a compound or pharmaceutical composition according to the present invention for use in therapy.

[0261] According to a fifth aspect of the present invention, there is provided a compound or pharmaceutical composition according to the present invention for use in the treatment or prevention of neurodegenerative disorders, mental disorders, inflammatory disorders, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye disorders, hearing loss or diseases characterized by misfolded tau.

[0262] Preferably, the neurodegenerative disorder is selected from motor neuron diseases, 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 wherein the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis and progressive muscular atrophy.

[0263] The neurodegenerative disorder is preferably a neurodegenerative disorder characterized by misfolded TAR DNA-binding protein 43 (tdp-43). In other words, 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.

[0264] Preferably, the mental disorder is selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder.

[0265] Preferably, the inflammatory disorder can be selected from inflammatory diseases and neuroinflammation.

[0266] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0267] Preferably, the cardiovascular disease is preferably selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0268] 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.

[0269] According to a sixth aspect of the present invention, there is provided the use of a compound according to the present invention in the preparation of a medicament for the treatment or prevention of the following: neurodegenerative disorders, mental disorders, inflammatory disorders, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye disorders, hearing loss, or diseases characterized by misfolded tau.

[0270] 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 sorting protein modulation, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0271] The compounds of the present invention may 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 atoms constituting such compounds. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.

[0272] The compounds of the present invention can be used in their own form or, where appropriate, in the form of their pharmaceutically acceptable salts (acid or base addition salts). The pharmaceutically acceptable addition salts mentioned below are intended to include the non-toxic acid and base addition salt forms that the compounds are capable of forming. Compounds having basic properties can be converted into their pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, glyoxylic 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, para-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid, etc. Compounds having acidic properties can be converted into their pharmaceutically acceptable base addition salts by treatment with an appropriate base. Exemplary base addition salt forms are sodium salts, potassium salts, calcium salts and salts formed with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine amines and amino acids such as, for example, arginine and lysine. The term addition salt as used herein also includes solvates, such as, for example, hydrates, alcoholates, etc., that the compounds and their salts are capable of forming.

[0273] Throughout this disclosure, a given chemical formula or name should also cover all of its pharmaceutically acceptable salts, solvates, hydrates, N-oxides and / or prodrug forms. It should be understood that the compounds of the present invention include any and all hydrates and / or solvates of the compound formula. It should be understood that certain functional groups, such as hydroxyl, amino and other groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Accordingly, the above formula should be understood to include and represent those various hydrates and / or solvates.

[0274] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imino pairs, lactam-lactim pairs, amide-imino pairs, enamine-imine pairs and cyclic forms in which the proton can occupy two or more positions in a heterocyclic 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 can be in equilibrium or sterically locked in one form by appropriate substitution.

[0275] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the invention containing an asymmetrically substituted carbon atom can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the invention are described and can be isolated as mixtures of isomers or in separated isomer forms.

[0276] In the case of compounds containing an asymmetric carbon atom, the invention relates to the D-form, L-form, and D,L mixtures, and when there is more than one asymmetric carbon atom, also to diastereoisomeric forms. Those compounds of the invention which contain an asymmetric carbon atom and are usually produced as racemates can be separated into optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use optically active starting materials from the outset and then obtain the corresponding optically active or diastereoisomeric compounds as the final product.

[0277] Preferably, the compounds of formula (I) and (II) are the compounds of formula (Ia) and (IIa) respectively:

[0278]

[0279] The term "prodrug" refers to a compound that can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. When administered to a subject in need thereof, the prodrug can be inactive but is converted in vivo into the active compound of the invention. Prodrugs are generally rapidly converted in vivo, for example by hydrolysis in the blood, to yield the parent compound of the invention. Prodrug compounds generally have the advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see Silverman, R.B., The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), pages 498 to 549). Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in the compounds of the invention, such as hydroxyl, amino, or mercapto groups, in such a way that the modification is cleaved to the parent compound of the invention in a conventional operation or in vivo. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxyl functional groups or phenylcarbamate derivatives of amino functional groups.

[0280] The compounds of the present invention can be sortilin inhibitors, binders, modulators or antagonists. 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 to progranulin, or neurotensin or other extracellular ligands or neurotrophic factor precursors (e.g., NGF precursor, NT3 precursor, BDNF precursor), or prevent the formation of a trimeric complex between sortilin, p75NTR and a neurotrophic factor precursor. The term "sortilin antagonist" also includes substances or agents that interfere with the formation of a high-affinity trimeric complex. In the latter case, it is recognized that a trimeric complex may form because sortilin can bind to p75NTR (but not to the NGF precursor) and p75NTR can simultaneously bind to the NGF domain of the NGF precursor. However, the resulting trimeric complex may have a lower affinity for its receptor, and thus its ability to stimulate apoptosis through the above mechanism is significantly reduced. Skeldal et al. (2012) demonstrated that when the intracellular domain of sortilin is deleted, the apoptotic function of the trimeric complex is lost. The term "sortilin antagonist" also includes substances or agents that interfere with, block or otherwise attenuate the interaction between sortilin and p75NTR. This interaction can be completely blocked, in which case the trimeric complex is prevented from forming, or only partially blocked, in which case the trimeric complex can form, but may have reduced biological potency. Skeldal et al. showed that the complex formation between sortilin and p75NTR depends on contact points in the extracellular domain of the receptor, and the interaction critically depends on the 23 amino acid sequence in the extracellular juxtamembrane region of p75NTR. Thus, a sortilin antagonist may interfere with this 23 amino acid sequence or adjacent sequences in the molecule. A "sortilin antagonist" can act as an inhibitor of ligand cellular uptake, where the ligand can be progranulin, neurotensin, BDNF, etc.

[0281] The compounds of the present invention can cross the blood-brain barrier and can thus be particularly useful for treating or preventing central nervous system diseases, including neurodegenerative disorders selected from motor neuron diseases, 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; mental disorders selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorders; 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.

[0282] The compounds of the present invention may have a K puu greater than 0.1, such as between 0.1 and 10, between 0.1 and 5, between 0.1 and 3, between 0.1 and 2, between 0.1 and 1, between 0.1 and 0.8, between 0.1 and 0.6, between 0.1 and 0.5, between 0.1 and 0.4, between 0.1 and 0.3, or between 0.1 and 0.2.

[0283] As used herein, the term "treatment" can include the prevention of a specified disorder or condition, or, once the disorder has occurred, the amelioration or elimination of the disorder. The term "prevention" refers to the prevention of a specified disorder or condition.

[0284] The methods described herein include those in which a subject is identified as in need of a specific prescribed treatment. Identifying a subject in need of such treatment can be based on the judgment of the subject or a healthcare professional and can be subjective (e.g., an opinion) or objective (e.g., measurable by a test or diagnostic method).

[0285] In other aspects, the methods herein include those that further include monitoring a subject's response to treatment administration. Such monitoring can include periodically imaging or sampling a subject's tissue, fluid, sample, cell, protein, chemical marker, genetic material, etc. that serves as a marker or indicator of the treatment regimen. In other methods, a subject is pre-screened or identified as in need of such treatment by evaluating relevant markers or indicators suitable for such treatment.

[0286] The present invention provides a method for monitoring the progress of treatment. The method includes the step of determining the level or diagnostic measurement (e.g., screening, assay) of a diagnostic marker (Marker) (e.g., any target or cell type described herein that is modulated by the compounds of the present invention) in a subject having or susceptible to a disorder or its symptoms described herein, wherein a therapeutically effective amount of the compounds of the present invention has been administered to the subject. The marker level determined in the method can be compared with the known marker level in a healthy normal control or other diseased patients to determine the disease state of the subject. In a preferred embodiment, a second level of the marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of the disease or the efficacy of the treatment. In certain preferred embodiments, a pre-treatment level of the marker in the subject is determined before starting treatment according to the present invention; then the pre-treatment level of the marker can be compared with the marker level in the subject after the start of treatment to determine the efficacy of the treatment.

[0287] The level of a marker or marker activity in a subject can be determined at least once. Comparison of the marker levels, e.g., with another measurement of the marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, can be used to determine whether the treatment according to the present invention has the desired effect, thereby allowing appropriate adjustment of the dosage level. The determination of the marker level can be carried out using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from the subject. Examples of suitable samples include blood, urine, tissue, oral or buccal cells, and hair samples containing roots. Other suitable samples are known to those skilled in the art. Any suitable technique known in the art can be used to determine the protein level and / or mRNA level (e.g., marker level) in the sample, including but not limited to enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence methods, real-time PCR, etc.

[0288] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It should be understood that the compounds of the present invention can be administered together with a physiologically acceptable carrier, excipient, and / or diluent (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein can be administered by any suitable route, preferably orally, rectally, nasally, topically (including ophthalmic, buccal, and sublingual), sublingually, transdermally, intrathecally, transmucosally, or parenterally (including subcutaneous, intramuscular, intravenous, and intradermal). Other formulations can conveniently be in unit dosage form, such as tablets and sustained release capsules, and in liposomes, and can be prepared by any method well known in the pharmaceutical art. Pharmaceutical formulations are generally prepared by mixing the active substance or its pharmaceutically acceptable salt with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, dicalcium phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc. Such formulations may also contain other pharmacologically active agents and conventional additives, such as stabilizers, wetting agents, emulsifying agents, flavoring agents, buffering agents, etc. Generally, the amount of the active compound is between 0.1 - 95% by weight of the formulation, preferably between 0.2 - 20% by weight in formulations for parenteral use, and more preferably between 1 - 50% by weight in oral formulations. The formulations can also be prepared by known methods such as granulation, tableting, microencapsulation, spray coating, etc. The formulations can be prepared into dosage forms such as tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections by conventional methods. Liquid formulations can be prepared by dissolving or suspending the active substance in water or other suitable negative carriers. Tablets and granules can be coated in a conventional manner. In order to maintain a therapeutically effective plasma concentration for a long time, the compounds disclosed herein can be incorporated into sustained release formulations.

[0289] The dosage levels and frequencies of administration of the specific compounds will vary depending on a variety of factors, including the potency of the specific compound used, the metabolic stability and duration of action of the compound, the age, weight, general health status, gender, diet, mode and time of administration, excretion rate, drug combination, the severity of the condition to be treated, and the patient being treated. The daily dose can be, for example, in the range of about 0.001 mg to about 100 mg per kilogram of body weight, administered in single or multiple doses, such as about 0.01 mg to about 25 mg per dose. Generally, such a dose is administered orally, but parenteral administration can also be selected.

[0290] Definitions

[0291] As used herein, the term "sortilin" can refer to full-length sortilin (also referred to as immature sortilin), which comprises a signal peptide, a propeptide, a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail, having the amino acid sequence according to SEQ ID NO:1 or SEQ ID NO:2, or it can refer to mature sortilin, which includes a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail, having the amino acid sequence according to SEQ ID NO:3, or a naturally occurring fragment, homolog, or variant thereof. The terms "sortilin" or "sortilin molecule" are used interchangeably herein. It should be understood that sortilin is capable of interacting with a neurotrophin precursor molecule to form a sortilin / neurotrophin precursor complex. This sortilin / neurotrophin precursor complex may or may not be capable of interacting with a p75NTR molecule to form a trimeric complex comprising sortilin, a neurotrophin precursor, and p75NTR. It is understood that such a trimeric complex may lead to adverse biological responses, such as stimulating apoptosis of retinal and ganglion cells, and controlling growth cone retraction of projecting axons (Jansen et al., 2007; Nykjaer et al., 2004; Santos et al., 2012; Skeldal et al., 2012).

[0292] As used herein, the term "neurotrophin precursor" refers to a larger precursor of a neurotrophin, which undergoes proteolytic cleavage to produce the mature form of the neurotrophin. Neurotrophins are a family of proteins that induce neuronal survival, development, and function, and are commonly referred to as growth factors. Neurotrophin precursors are biologically active and have different effects compared to their neurotrophin counterparts, such as inducing apoptosis. Examples of neurotrophin precursors include NGF precursor, BDNF precursor, NT3 precursor, and NT4 precursor. Neurotrophin precursors can also control synaptic plasticity. While mature neurotrophins induce synaptic strength, their original forms may weaken synapses.

[0293] "Optional" or "optionally" means that the subsequent described event or circumstance may but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur.

[0294] The term "heteroatom" means O, N, or S.

[0295] The term "(C 1 -C n )alkyl" represents a straight-chain, branched-chain, cyclic, or partially cyclic alkyl group having from 1 to n carbon atoms, i.e., 1, 2, 3,..., or n carbon atoms. For "(C 1 -C n) "alkyl" group, which should be formed by at least three carbon atoms. For the part within the range of "(C 1 -C n ) alkyl", all subgroups are considered. For example, within the range of (C 1 -C 6 ) alkyl, all subgroups such as (C 1 -C 5 ) alkyl, (C 1 -C 4 ) alkyl, (C 1 -C 3 ) alkyl, (C 1 -C 2 ) alkyl, (C 1 ) alkyl, (C 2 -C 6 ) alkyl, (C 2 -C 5 ) alkyl, (C 2 -C 4 ) alkyl, (C 2 -C 3 ) alkyl, (C 2 ) alkyl, (C 3 -C 6 ) alkyl, (C 3 -C 5 ) alkyl, (C 3 -C 4 ) alkyl, (C 3 ) alkyl, (C 4 -C 6 ) alkyl, (C 4 -C 5 ) alkyl, (C 4 ) alkyl, (C 5 -C 6 ) alkyl, (C 6 ) alkyl. Examples of "C 1 -C 6 alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, branched or cyclic or partially cyclic pentyl and hexyl, etc.

[0296] The term "(C 1 -C n ) haloalkyl" means the C 1 -C n alkyl as described above that is substituted by at least one halogen atom, and the halogen atom is preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0297] The term "(C 1 -C n) "Hydroxyalkyl" means a C as described above substituted by at least one -OH group 1 -C n alkyl.

[0298] The term "(C 1 -C n ) alkoxy" means -O-((C 1 -C n ) alkyl), where (C 1 -C n ) the alkyl group is as defined above and is attached to the remainder of the compound through an oxygen atom.

[0299] When the term represents a range, such as "1 to 6 carbon atoms" in the definition of (C 1 -C 6 ) alkyl, each integer is considered to be disclosed, namely 1, 2, 3, 4, 5, and 6.

[0300] The term "halogen" means a halogen atom, and is preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0301] The term "5-membered heteroalkyl" means a non-aromatic ring having 5 ring atoms, wherein at least one ring atom is a heteroatom. Preferably, each heteroatom is independently selected from N, S, or O, more preferably N. Preferably, no more than 2 ring atoms are heteroatoms. More preferably, only one ring atom is a heteroatom.

[0302] "Effective amount" means the amount of the compound of the present invention that confers a therapeutic effect on the subject being treated. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the effect or feels the effect).

[0303] As used herein, the terms "administration" or "administering" refer to the route of administration of the compounds disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intraocular, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration can vary depending on a variety of factors, such as the components of the pharmaceutical composition containing the compounds disclosed herein, the location of the potential or actual disease, and the severity of the disease.

[0304] The terms "subject" and "patient" are used interchangeably herein. They refer to a human or other mammal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that may have or be susceptible to a disease or disorder but may or may not have the disease or disorder. Preferably, the subject is human.

[0305] The compounds of the present invention may be disclosed by name or chemical structure. If there is a difference between the compound name and its related chemical structure, the chemical structure shall prevail.

[0306] The present invention will now be further illustrated by the following non-limiting examples. The following specific examples should be construed as illustrative only and not limiting in any way the remainder of the disclosure. 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 references and publications cited herein are hereby incorporated by reference in their entirety.

[0307] Preparation of the Compounds of the Present Invention

[0308] 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 co-reagents is within the common general knowledge of those skilled in the art. Similarly, those skilled in the art should understand that synthetic intermediates can be separated and / or purified by various well-known techniques as needed or desired, and various intermediates can be used directly in subsequent synthetic steps with little or no purification. In addition, those skilled in the art will understand that in some cases, the order of introduction of moieties is not important. The specific order of steps required for the compounds of formula (I) or (II) depends on the particular compound being synthesized, the starting compounds, and the relative propensities of the substituent moieties, as is well known to those of ordinary skill in the art. Unless otherwise specified, all substituents are as previously defined, and all reagents are well known and understood in the art.

[0309] Suitable starting materials with optical activity, either as single enantiomers or as racemic mixtures, and protected amino acids of general formula AA-1 can be commercially available or can be prepared by a variety of methods. For example, as shown in the general synthetic procedure Scheme 1, the carboxylic acid functional group of a suitably substituted amino acid of general formula AA-1 can be used as the free acid, PG = H, or can be protected as a suitable derivative, such as a methyl ester. The insertion of substituents on the primary amine present in AA-1 can be accomplished by a variety of methods, and for illustrative purposes, by a reductive amination step involving a suitable substituted carbonyl compound Int-1, aldehyde or 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 substituents on the primary amine present in AA-1, as shown in the general synthetic procedure Scheme, uses an alkylation step between a suitable protected AA-1 and a reagent of type Int-2. In the latter, LG represents a reactive leaving group, such as a bromine atom, which can be selectively replaced by the 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 illustrates a complementary general synthetic strategy which can be advantageous when, for example, 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 purchased or synthesized from commercial sources by methods known to those skilled in the art.

[0310] General synthetic procedure

[0311]

[0312] 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, etc.

[0313] Compounds of general formula (I) or (II) can contain one or more stereocenters. These can be introduced from available single enantiomers, optically active starting materials of type AA-1. The integrity of existing stereocenters can be confirmed by analytical techniques well known to those skilled in the art, such as chiral support high-pressure chromatography. Alternatively, when using racemic starting materials, it should be understood that if desired, single isomer products can be obtained in the form of single enantiomers or single diastereomers by known techniques such as preparative chiral support high-pressure chromatography.

[0314] Those skilled in the art should also understand that not all substituents in the compounds of formula (I) or (II) can tolerate certain reaction conditions used for the synthesis of the compounds. These moieties can be introduced at a convenient point in the synthesis, or can be protected and then deprotected as needed or desired, as is well known in the art. Those skilled in the art will understand that protecting groups can be removed at any convenient point in the synthesis of the compounds of the present invention. Methods for introducing or removing the protecting groups used in the present invention 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).

[0315] Examples

[0316] Abbreviations

[0317] approx: about; aq: aqueous solution; br: broad; ca.: about; CDI: 1,1'-carbonyldiimidazole; d: doublet; DCM: dichloromethane; DIC: N,N′-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et 3 N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethyloxycarbonyl; Boc: tert-butoxycarbonyl; h: hour; min: minute: HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V); HPLC: high performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: mole, molecular ion; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: quartet; rt: room temperature (about 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 light.

[0318] Other abbreviations are intended to convey their generally accepted meanings.

[0319] General Experimental Conditions

[0320] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. Unless otherwise stated, the reaction mixtures were stirred magnetically and the reactions were carried out at room temperature (about 20 °C).

[0321] Unless otherwise stated, column chromatography was performed on a pre-packed silica gel (40 μm) column using an automated flash chromatography system such as the CombiFlash Rf system.

[0322] 1 1H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. Unless otherwise stated, chemical shift values are reported in ppm relative to tetramethylsilane. The following abbreviations or combinations thereof are used to denote the multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0323] Analytical methods

[0324] 1 1H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 instrument or a Bruker Avance AV-II-400 instrument. Unless otherwise stated, chemical shift values are reported in ppm relative to tetramethylsilane. The following abbreviations or combinations thereof are used to denote the multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0325] Method 1: UPLC_AN_BASE, Equipment: Waters Iclass; Binary Pump (Bin.Pump): UPIBSM, SM: UPISMFTN with 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 rate: 0.6 mL / min, Gradient: t0 = 5% B, t2.0 min = 98% B, t2.7 min = 98% B, Posttime: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (pH = 9.5), Eluent B: acetonitrile.

[0326] Method 2: PREP_ACID-AS4A, Equipment: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100x30mm, 10μ); Flow rate: 55 mL / min; Column temperature: RT; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile Linear (lin.) 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 positive / negative) Mass range: 100–1000; Fraction collection based on MS and DAD.

[0327] Method 3: UPLC_AN_ACID, Equipment: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN with 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, 50x2.1mm, 2.5μm, Temperature: 40°C, Flow rate: 0.6 mL / min, Gradient: t0 = 5% B, t2.0 min = 98% B, t2.7 min = 98% B, Post-run time: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile.

[0328] Method 4: Equipment: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100x30mm, 10μ); Flow rate: 55 mL / min; Column temperature: RT; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; Detection: DAD (220 - 320 nm); Detection: MSD (ESI positive / negative) Mass range: 100–1000; Fraction collection based on MS and DAD.

[0329] Method 5: Equipment: ACQ-SQD2; HPLC instrument type: Waters modular preparative HPLC system; Column: Waters XSelect (C18, 100x30 mm, 10 μm); Flow rate: 55 ml / min for the preparative pump; Column temperature: RT; Eluent A: 10 mM ammonium bicarbonate in water with pH = 9.5, Eluent B: 100% acetonitrile; Detection: DAD (220 - 320 nm); Detection: MSD (ESI positive / negative) mass range: 100–800; Fraction collection based on MS and DAD.

[0330] Method 6: Instrument: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210 - 320 nm, SQD: MS: QDA ESI, positive / negative 100 - 800; Column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 μm, Temperature: 25 °C, Flow rate: 0.6 mL / min, Gradient: t0 = 5% B, t1.3 min = 98% B, t1.7 min = 98% B, Post-run time: 0.3 min, Eluent A: 10 mM ammonium bicarbonate in water (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 rate: 80 L / Hr; Desolvation gas flow: 1000 L / Hr; Full MS scan: MS range 100 - 800 (positive and negative modes); Scan: 0.4 seconds.

[0331] 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 (positive) 100 - 800 (negative), Column: XSelect CSH C18 XP (50x2.1 mm 2.5 μm) Flow rate: 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.

[0332] Method 8: MS instrument type: Agilent Technologies G6120AA Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Atlantis T3 (C18, 150x19mm, 10μ); flow rate: 25 mL / min; column temperature: RT; eluent A: 0.1% formic acid in water; eluent B: 100% acetonitrile; copy the linear gradient from the gradient method here; detection: DAD (220 - 320nm); detection: MSD (ESI positive / negative) mass range: 100–1000; fraction collection based on MS and DAD.

[0333] Method #acid3min - UPLC acidic method

[0334] Instrument: Waters HClass; binary solvent pump, SM - FTN, CMA, PDA, QDa

[0335] Column: Waters ACQUITY CSH C18, 1.7μm, 2.1x 30mm, 40℃

[0336] Detection: UV at 210 - 400nm unless otherwise stated, MS by electrospray ionization

[0337] Solvents: A: 0.1% formic acid in water, B: MeCN

[0338] Gradient:

[0339] Time ％A ％B Flow rate (ml / min) 0.00 98 2 0.77 2.50 0 100 0.77 3.00 0 100 0.77

[0340] Method #basic3min - UPLC basic method

[0341] Instrument: Waters HClass; binary solvent pump, SM - FTN, CMA, PDA, QDa

[0342] Column: Waters ACQUITY BEH C18, 1.7μm, 2.1x 30mm, 40℃

[0343] Detection: UV at 210 - 400nm unless otherwise stated, MS by electrospray ionization

[0344] Solvents: A: 0.2% ammonia in water, B: MeCN

[0345] Gradient:

[0346] Time ％A ％B Flow rate (ml / min) 0.00 98 2 0.77 2.50 0 100 0.77 3.00 0 100 0.77

[0347] Method #acid3minb

[0348] Instrument: Agilent 1260; quaternary pump, HiP injector, column oven, DAD:, G6150 MSD

[0349] Column: Waters Cortecs C18, 30x 2.1mm, 2.7μm, 40 °C

[0350] Detection: UV at 260 nm + / - 90 nm, MS by electrospray ionization, unless otherwise specified

[0351] Solvents: A: 0.1% formic acid in water, B: MeCN

[0352] Gradient:

[0353] Time ％A ％B Flow rate (ml / min) 0.00 98 2 1.35 2.50 0 100 1.35 3.00 0 100 1.35

[0354] Method #basic3minb

[0355] Instrument: Agilent 1260; quaternary pump, HiP injector, column oven, DAD:, G6150 MSD

[0356] Column: Phenomenex Evo C18, 30x 2.1mm, 2.6μm, 40 °C

[0357] Detection: UV at 260 nm + / - 90 nm, MS by electrospray ionization, unless otherwise specified

[0358] Solvents: A: 0.2% ammonia in water, B: MeCN

[0359] Gradient:

[0360] Time ％A ％B Flow rate (ml / min) 0.00 98 2 1.35 2.50 0 100 1.35 3.00 0 100 1.35

[0361] Intermediate

[0362] Intermediate 1

[0363]

[0364] Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde

[0365] 7-Bromo-2-dimethyl-1,2,3,4-tetrahydroisoquinoline (250 mg, 1 Eq, 1.11 mmol), PdCl 2 (dppf).CH 2 Cl 2(80 mg, 0.089 Eq, 98 μmol), Et 3 A solution of N (336 mg, 0.46 mL, 3 Eq, 3.32 mmol) and triethylsilane (386 mg, 0.53 mL, 3 Eq, 3.32 mmol) in DMF (5 mL) was degassed under N 2 flow for 5 min and then sealed. Then it was purged with N 2 (x3), after which CO (1.5 bar) was charged, and then the reaction mixture was heated to 90 °C for 2.5 h. The reaction mixture was dissolved in EtOAc (40 mL), and then washed with saturated aqueous NH 4 Cl (40 mL), water:brine (2 x 1:1, 40 mL), and brine (40 mL). The organic phase was dried over MgSO 4 , filtered, and concentrated on silica (~1 g). The crude product was purified by silica gel chromatography (12 g column, 0 - 5% (1% Et 3 N / MeOH) / DCM)) to give 2-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde (219 mg, 1.0 mmol, 90%, 80% purity) as a brown oil. LCMS (method #basic3minb, 1.25 min; [M+H]+ = 176.2. 1H NMR (500 MHz, DMSO) δ 9.93 (s, 1H), 7.66 (dd, J = 7.9, 1.7 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 3.58 (s, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.37 (s, 3H).

[0366] The following intermediates were prepared in a similar manner to Intermediate 1 starting from their corresponding aryl bromides.

[0367]

[0368]

[0369]

[0370] Example

[0371] Example 1

[0372]

[0373] Synthesis of (S)-2-((isochroman-6-ylmethyl)amino)-5,5-dimethylhexanoic acid hydrochloride

[0374] 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, then 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, reproted with aqueous 1M HCl, and concentrated to afford (S)-2-((isochroman-6-ylmethyl)amino)-5,5-dimethylhexanoic acid hydrochloride (123.7 mg, 0.362 mmol, 57.6% yield) as a white solid.

[0375] LCMS (method 1, 0.906 min; M+H = 306.5; calcd 306.2). 1 1H-NMR (400 MHz, DMSO) δ 14.02 (br, 1H), 9.37 (s, 2H), 7.31–7.27 (m, 2H), 7.10 (d, J = 7.9 Hz, 1H), 4.69 (s, 2H), 4.10 (s, 2H), 3.98–3.78 (m, 3H), 2.79 (t, J = 5.7 Hz, 2H), 1.99–1.70 (m, 2H), 1.33 (td, J = 13.1, 4.8 Hz, 1H), 1.11 (td, J = 12.9, 4.4 Hz, 1H), 0.86 (s, 9H).

[0376] The following examples were prepared in a similar manner to Example 1 starting from their corresponding aldehydes.

[0377]

[0378] Example 3

[0379]

[0380] Synthesis of (S)-2-((isochroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid methanesulfonate

[0381] Chroman-7-carbaldehyde (2.26 g, 13.93 mmol; 1.0 eq) 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 eq) in methanol (20 mL). The mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (6.61 g, 31.2 mmol; 2.0 eq) was added. The mixture was stirred at room temperature for 16 h. The product precipitated and was collected by filtration. The residue was washed with methanol (5 mL) to afford (S)-2-((chroman-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 dissolved in EtOAc and washed with water (2x) and brine. The product was precipitated from the organic layer and collected by filtration. The residue was washed with a small amount of EtOAc and dried in vacuo to afford (S)-2-((chroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid (1.04 g, 3.41 mmol, 24% yield). (S)-2-((chroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid (1.37 g, 4.48 mmol) was dissolved in methanesulfonic acid (0.1 M in MeCN) (44.8 mL, 4.48 mmol; 1 eq). 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 afford (S)-2-((chroman-7-ylmethyl)amino)-5,5-dimethylhexanoic acid compound 7 with methanesulfonic acid (1.638 g, 4.08 mmol, 29% yield).

[0382] LCMS (method 1, 0.902 min; M+H = 306.1; calcd 306.2). 1H-NMR (400 MHz, DMSO) δ 10.03 (br, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 4.68 (s, 2H), 4.11–3.99 (m, 2H), 3.88 (t, J = 5.7 Hz, 2H), 3.75–3.67 (m, 1H), 2.79 (t, J = 5.8 Hz, 2H), 2.30 (s, 3H), 1.86–1.67 (m, 2H), 1.30 (td, J = 12.9, 4.9 Hz, 1H), 1.13 (td, J = 12.7, 4.7 Hz, 1H), 0.85 (s, 9H).

[0383] The following examples were prepared in a similar manner to Example 3 starting from their corresponding aldehydes.

[0384]

[0385]

[0386] Example 7

[0387]

[0388] Synthesis of (S)-5,5-dimethyl-2-(((5,6,7,8-tetrahydroquinolin-3-yl)methyl)amino)hexanoic acid - methanesulfonic acid

[0389] 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) with triethylamine (148 μl, 1.061 mmol, 3.25 equiv) was added 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). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated by blowing dry with nitrogen. 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 h. 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 compound with methanesulfonic acid (13.1 mg, 0.033 mmol, 10.02% yield). LCMS (method 7, 0.900 min; M+H - MsO - = 305.2; calculated 305.2). 1 1H-NMR (400 MHz, DMSO) δ 8.35 (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).

[0390] The following examples were prepared in a similar manner to Example 7 starting from the corresponding amines.

[0391]

[0392] Example 10

[0393]

[0394] Synthesis of (S)-5,5-dimethyl-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, methanesulfonic acid

[0395] A solution of 6-bromo-2-dimethyl-1,2,3,4-tetrahydroisoquinoline (129 mg, 1 Eq, 570 μmol), triethylamine (173 mg, 239 μL, 3 Eq, 1.71 mmol), triethylsilane (199 mg, 273 μL, 3 Eq, 1.71 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 (30 mg, 0.064 Eq, 37 μmol) in DMF (3.5 mL) was degassed under N 2 flow for 5 min and then sealed. Then purged with N 2 (x3), after which CO (1.5 bar) was charged, and then the reaction mixture was heated to 90 °C for 6 h. The reaction mixture was dissolved in EtOAc (30 mL), and then washed with saturated NH 4 Cl aqueous solution (20 mL), water:brine (2x1:1, 20 mL) and brine (20 mL). The organic phase was dried over MgSO 4 and filtered and concentrated on silica (~1 g). The crude product was purified by silica gel chromatography (12 g column, 0-5% (1% Et 3 N 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.

[0396] A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (49 mg, 1 Eq, 0.31 mmol), 2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (54 mg, 1 Eq, 0.31 mmol), and triethylamine (31 mg, 43 μL, 1 Eq, 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, after which sodium borohydride (12 mg, 1 Eq, 0.31 mmol) was added and stirring was continued for 1 h at rt. AcOH (0.1 mL) was added and the reaction mixture was concentrated onto silica gel (~1 g). The crude product was purified by chromatography on RP Flash C18 (12 g column, 10 - 50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)). The isolated fractions were dissolved in 2M NaOH (0.5 mL) and the crude product was repurified by chromatography on RP Flash C18 (12 g column, 15 - 50% MeCN / 10 mM ammonium bicarbonate) to give the free base. The free base was treated with MeOH (1 mL) and 0.1M MsOH in MeCN (1 eq) was added, after which it was concentrated to dryness to give (S)-5,5-dimethyl-2-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, methanesulfonate (19 mg, 39 μmol, 13%, 85% purity) as a colorless solid.

[0397] UPLC (method #basic3min, 0.72 min, M+H = 319.3. 1H NMR (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), no 3x exchangeable Hs were observed.

[0398] Example 11

[0399]

[0400] (R)-2-Hydroxy-5,5-dimethylhexanoic acid synthesis

[0401] 1 M aqueous sulfuric acid solution (226 mL, 226 mmol, 3.0 equiv) was added to (R)-2-amino-5,5-dimethylhexanoic acid (12 g, 75 mmol, 1.0 equiv) in water (220 mL). 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, keeping the temperature below 0 °C. After addition, the mixture was warmed to room temperature and stirred for 16 h.

[0402] Extract the mixture with Et 2 O (4 x 200 mL), wash the combined organic layers with brine (300 mL), dry over Na 2 SO 4 , filter and concentrate in vacuo to give (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 74.4% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) 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).

[0403] Synthesis of methyl (R)-2-hydroxy-5,5-dimethylhexanoate

[0404] At 0 °C, SOCl 2 (12 mL, 164 mmol, 2.93 equiv) was added to (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 1 equiv) in methanol (120 mL). After addition, the mixture was warmed to room temperature and stirred for 16 h. The mixture was basified to pH 9 by addition of saturated NaHCO 3 aqueous solution and extracted with Et 2 O (2 x 400 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford methyl (R)-2-hydroxy-5,5-dimethylhexanoate (10.01 g, 55.0 mmol, 98% yield) as a yellow oil. Contained 4.2% (w / w) MeOH. 1H-NMR (400 MHz, CDCl 3 ) δ 4.18 (dd, J = 7.2, 4.2 Hz, 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).

[0405] (R)-Methyl 5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate Synthesis

[0406] At 0 °C, trifluoromethanesulfonic anhydride (4.65 mL, 27.5 mmol, 1.10 equiv) was added dropwise to a solution of (R)-methyl 2-hydroxy-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). After addition, the mixture was warmed to room temperature and stirred for 16 h. Water (100 mL) was added, and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford (R)-methyl 5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (7.14 g, 23.31 mmol, 49% corrected yield) 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).

[0407] (S)-Methyl 5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexane-1-sulfonate Synthesis

[0408] (R)-Methyl 5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (70 mg, 0.229 mmol, 1.0 eq.) 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 eq.) in dichloromethane (1 mL). The dichloromethane was removed and the residue was dissolved in acetonitrile:water (2 mL, 1:1). Lithium hydroxide (27.4 mg, 1.143 mmol, 5.0 eq.) was added and the mixture was stirred for 16 h. The mixture was subjected to acidic preparative HPLC (method 2) to afford (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 eq.) was added. The mixture was lyophilized to afford (S)-5,5-dimethyl-2-(((R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)hexanoic acid - methanesulfonate (20.5 mg, 0.050 mmol, 21.7% yield).

[0409] LCMS (method 1, 1.239 min; M+H - MsO - = 318.5; calcd 318.4). 1 1H-NMR (400 MHz, DMSO) δ 7.18 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 4.26 (d, J = 6.9 Hz, 1H), 3.54–3.40 (m, 2H), 2.71 (d, J = 5.7 Hz, 4H), 2.30 (s, 3H), 1.74 (h, J = 3.8 Hz, 4H), 1.52 (d, J = 6.7 Hz, 3H), 1.27 (td, J = 13.0, 4.7 Hz, 1H), 1.03 (td, J = 12.8, 3.9 Hz, 1H), 0.85 (s, 9H).

[0410] The following examples were prepared in a similar manner to Example 11 starting from the corresponding enantiomeric secondary amines.

[0411]

[0412] Example 15

[0413]

[0414] Synthesis of (S)-2-((3,4-dimethylbenzyl)amino)-5,5-dimethylhexanoic acid, methanesulfonate

[0415] A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (61 mg, 1.0 Eq, 0.38 mmol), tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 1 Eq, 383 μmol), and Et 3 N (40 mg, 55 μL, 1.0 Eq, 0.39 mmol) in MeOH (3 mL) was heated at 40 °C for 2 h, then cooled with an ice bath and treated with NaBH 4 (15 mg, 1.0 Eq, 0.40 mmol). The mixture was warmed to rt, then concentrated to dryness and suspended in water (5 mL). Acetic acid (42 mg, 40 μL, 1.8 Eq, 0.70 mmol) was added, then filtered. The starting material was suspended in water (10 mL) and acetone (2 mL), then heated at 60 °C for 30 min. After cooling to rt, the Boc-protected free base (112 mg, 0.28 mmol, 74% yield) was collected by filtration.

[0416] The free base sample (61 mg, 0.15 mmol) was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at rt for 1 h, then diluted with MeOH (4 mL) and loaded onto SCX (∼1 g). It was washed with MeOH and eluted with 7 M NH 3 (5 column volumes) in MeOH to give the desired starting material, which was concentrated. It was then dissolved in MeOH (2 mL), and 0.1 M MsOH in MeCN (1 equivalent) was added, then the starting material was concentrated to dryness to give (S)-5,5-dimethyl-2-(((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)amino)hexanoic acid, methanesulfonate (67 mg, 0.16 mmol, 43%, 98% purity) as a colorless solid.

[0417] LCMS (method #acid3minb, 0.13 min, M+H = 305.2. 1H NMR (500 MHz, DMSO) δ 9.01 (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), and no 1x exchangeable H was observed.

[0418] The following examples were prepared in a similar manner to Example 15 starting from their corresponding aldehydes.

[0419]

[0420]

[0421] Example 19

[0422]

[0423] Synthesis of (S)-5,5-dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid, methanesulfonate

[0424] A suspension of (S)-2-amino-5,5-dimethylhexanoic acid (112 mg, 1 Eq, 705 μmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (125 mg, 1 Eq, 705 μmol) and Et 3 N (71.9 mg, 99.0 μL, 1.01 Eq, 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 4 (27.0 mg, 1.01 Eq, 714 μmol). The mixture was then warmed to rt and stirred for 2.5 h, then the reaction mixture was filtered. The solvent was removed in vacuo from the filtrate. The solid was triturated with water (3 mL), then filtered and washed with MeCN (5 mL) to give a white solid. The crude was purified by chromatography on RP Flash C18 (4 g column, 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 an off-white solid.

[0425] LCMS (method #acid3minb, 1.34 min, M+H = 320.2. 1H NMR (500 MHz, MeOD) δ 0.92 (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 = 6.0 Hz, 1H), 3.95 (d, J = 13.0 Hz, 1H), 4.08 (d, J = 12.9 Hz, 1H), 4.26–4.31 (m, 2H), 6.74 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 2.1, 8.2 Hz, 1H).

[0426] (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 Eq, 86.0 μmol) was stirred in MeOH (2.50 mL), and then methanesulfonic acid (0.1 M, in MeCN) (8.26 mg, 860 μL, 0.10 mol, 1 Eq, 86.0 μmol) was added. The resulting solution was stirred at 25 °C for 30 min and then concentrated in vacuo to give the product, which was dried in a vacuum desiccator at 25 ℃ for 15 h. (S)-5,5-Dimethyl-2-(((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)amino)hexanoic acid, methanesulfonate (27.0 mg, 64 μmol, 75%, 99% purity) was obtained as a green / yellow solid.

[0427] LCMS (method #acid3minb, 0.97 min, M+H = 320.5. 1H NMR (500 MHz, DMSO) δ 14.00 (bs, 1H), 9.07 (bs, 1H), 8.99 (bs, 1H), 6.85 (dd, J = 8.2, 2.1 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.25–4.20 (m, 2H), 4.00–3.97 (m, 2H), 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, 4.7 Hz, 1H), 1.09 (td, J = 13.0, 4.3 Hz, 1H), 0.85 (s, 9H).

[0428] The following examples were prepared in a similar manner to Example 19 starting from the corresponding aldehyde.

[0429]

[0430]

[0431]

[0432]

[0433] The following examples were prepared in a similar manner to other examples starting from their corresponding ketones, aldehydes or esters.

[0434]

[0435]

[0436]

[0437]

[0438] 1 Remake using HCl instead of 1 equivalent of MsOH

[0439] 2 React using a racemic triflate

[0440] The following examples were synthesized in a similar manner to other examples.

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450] Biological data

[0451] Neurotensin scintillation proximity assay

[0452] Exemplary compounds of the invention were tested in a neurotensin (NTS) scintillation proximity assay (SPA). IC 50 Data are shown in the table below. NTS is a 13 - amino acid neuropeptide and is a sortilin ligand. IC 50 is a measure of the amount of compound required to inhibit 50% of the binding of NTS to sortilin. One of ordinary skill in the art will recognize that the lower the IC 50 value, the less compound is required to achieve the desired effect and, as a result, the chance of undesired off - target effects is reduced.

[0453] Compound affinity was determined by measuring the displacement of 3 [3H] - neurotensin binding to h - sortilin in SPA format. A 50 mM HEPES pH 7.4 assay buffer with a total volume of 40 μl containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween - 20 was used. Compounds were pre - incubated with 150 nM of 6his - sortilin for 30 minutes at room temperature, then 5 nM [3H] - neurotensin and Ni - chelate imaging beads (Perkin Elmer) were added. After 6 hours, the plate was read on a ViewLux with an exposure time of 360 s. A dose - response evaluation of the compound was performed using 8 concentrations of the drug (covering 3 decimal orders). Using CDD Vault software, the IC 50 value was calculated by non - linear regression using a sigmoidal concentration - response (variable slope). All values reported are the average of at least 2 determinations.

[0454] The data in the table below demonstrate that the compounds of the invention are sortilin inhibitors.

[0455]

[0456]

[0457]

[0458] Creoptix (GCI) method - using SEQ ID NO.4 (mouse sortilin)

[0459] The GCI assay is based on a known surface plasmon resonance methodology that has been specifically enhanced for detecting the binding of small entities to proteins. The protein bound to the surface is immersed in a solution containing a potential ligand, generating binding kinetics, which results in K on and K off rates as well as K d . This methodology does not require the use of additional tracers and can be used with or without competition with a known ligand.

[0460] Reagents:

[0461] Reagent Part number Supplier DMSO D8418 Sigma Borate B BELU-50 Xantec Bioanalytics EDTA E7889-100ML Merck Life Science UK HBS-N BR-1006-70 Cytiva 4PCH wave chip 4PCH Creoptix AG rhSortilin 3154-ST-050 Bio-Techne Ltd rmSortilin 2934-ST-050 Bio-Techne Ltd EDC BR100050 Cytiva NHS BR100050 Cytiva Acetate pH 5.0 BR100351 Cytiva Trizma / Tris 93352-1KG Merck Life Science UK

[0462] All the buffers described above were filtered using a 0.2 μm filter (product number: 10300461, Nalgene) and degassed for 15 minutes before use.

[0463] The temperature of the flow cell used throughout the experiment was 25 °C.

[0464] Chip conditioning and immobilization

[0465] Using the preset conditioning wizard (WAVE control software), the 4PCH chips in all flow cells were conditioned using a 0.2X concentration running buffer (running buffer composition: 1X HBS-N, pH 7.4, 3.4 mM EDTA, 1% DMSO), injected with: 0.1 M borate, 1 M NaCl (pH 9), and then the injection of 0.2X running buffer was started three times.

[0466] Buffer replacement was performed and 1x running buffer (1X HBS-N, pH 7.4, 3.4 mM EDTA, 1% DMSO) was used in the immobilization procedure:

[0467] An initial injection of EDC / NHS (mixed in a 1:1 ratio) was performed in all 4 flow cells to activate the surface for amine coupling of the ligand.

[0468] Manually thaw the recombinant sorting protein aliquots quickly and centrifuge at 13,300 rpm for 10 minutes. Then prepare a 10 μg / ml protein solution in acetate at pH 5.0 and inject it once each on flow cells 2, 3, and 4 for human, human (flow cells 2 & 3), and mouse sorting proteins for 20 minutes, followed by a 60-second dissociation period.

[0469] Finally, a 7-minute passivation injection with 50 mM tris was performed in all flow cells.

[0470] All conditioning and immobilization cycles were performed at a flow rate of 10 μl / min.

[0471] Fast kinetics: Intermediate binder

[0472] Using the built-in "Intermediate binder" to screen compounds at 1 μM: 100 ul / min, 45 s baseline, 25 s association, 300 s dissociation, use a blank for every 5 samples, and perform DMSO correction (1.5% DMSO at the start and end of the experiment and every 20 cycles). The entire experiment was performed at a collection rate of 10 Hz.

[0473] Screen the compounds to a final assay concentration of 1 μM and a final DMSO concentration of 1%. To this end, dilute the compounds in DMSO from a 10 mM stock solution to 100 μM (100x the final assay concentration), and then dilute 1:100 in running buffer without DMSO to establish a final assay concentration of 1 μM compound and a final DMSO concentration of 1% [DMSO].

[0474] Using a Bioshake instrument, mix the compounds and DMSO by shaking the plate at 1000 rpm for 60 seconds.

[0475] The flow rate used throughout the experiment was 100 μl / min.

[0476] Data evaluation:

[0477] Evaluate the data using the RAPID kinetic analysis tool in the GCI WAVE_control software and fit the data using a standard 1:1 kinetic biomodel.

[0478] The results for the compounds of the present invention are shown in the table below.

[0479]

[0480]

[0481] For the compounds of the present invention, it is advantageous to have a K of less than 1.00E-4. d The generated K d data demonstrate that the examples of the present invention directly bind to sorting proteins and bind in a generally similar manner in both human and murine sorting proteins, which is advantageous for the development of non-human pharmacokinetics and disease models.

[0482] Blood-brain barrier permeability

[0483] To determine whether the compounds of the present invention can cross the blood-brain barrier, the K of Example 3 and Comparative Example 1 was calculated puu , and Comparative Example 1 is a sorting protein modulator not according to the present invention and having the following structure:

[0484]

[0485] Study the plasma protein binding and brain homogenate binding of the compounds in mice, dogs, and rats by rapid equilibrium dialysis

[0486] Administer the compound of Comparative Example 1 to mice, and the compound of Example 3 to rats and dogs, and then withdraw plasma and brain at specific time points to analyze the compound concentration. Separately, measure the fraction of the compound bound to plasma protein or brain homogenate to allow assessment of the free fraction.

[0487] The free drug hypothesis states that only the unbound compound can penetrate through biological membranes, interact with the biological membranes and elicit a pharmacological effect. Therefore, the compound needs to have a high free brain concentration. However, only the free unbound drug fraction is affected by the clearance mechanisms.

[0488] In practice, in vitro rapid equilibrium dialysis is used to evaluate the unbound fractions in plasma and brain tissue. In vivo pharmacokinetic studies are conducted separately, in which a certain dose of the target compound is administered at T = 0 hours, and the total concentrations of the target compound in plasma and brain samples are analyzed at subsequent time points (e.g., 0.5, 1, and 4 hours). These total concentrations can then be adjusted with the unbound fraction to give the unbound concentrations in plasma and brain. Then the unbound partition coefficient (K puu ) is determined as the ratio between the free compound concentrations in the target compartment (here the brain / CNS) and plasma.

[0489] Rapid equilibrium dialysis

[0490] The test compound is incubated in triplicate at 5 μM in a RED device with inserts (8K MWCO, Thermo Scientific) in plasma and brain homogenates from the relevant species at 37 ℃ for 4 hours. 350 μL of 150 mM phosphate buffered saline (PBS, pH 7.4) is used as the receptor side solution. Samples are collected from both sides after 4 hours of equilibration time, and similar matrices are prepared by diluting the donor side samples with blank PBS and the receptor side samples with blank plasma / phosphate buffered saline. After incubation, aliquots of the donor side matrix are diluted with an equal volume of the blank receptor side matrix, and aliquots of the receptor side matrix are diluted with an equal volume of the blank donor side matrix. All samples are subjected to protein precipitation by adding twice the volume of acetonitrile containing 100 nM repaglinide as the internal standard. After centrifugation at 13 200 rpm for 10 minutes, the sample supernatants are analyzed by LC-MS / MS to obtain the unbound fraction (F ub ) of the test compound. The unbound fraction is calculated based on the obtained peak area ratios for each matrix:

[0491] F ub = C PBS / C 血浆 ;

[0492] where C PBS and C 血浆 are the analyte concentrations in PBS (receptor) and plasma (donor), respectively.

[0493] Undialyzed recovered samples were prepared under each condition, and the following formula was used to evaluate the recovery rate of the dialysis experiment:

[0494] % Recovery = 100 × (V PBS × C PBS + V 血浆 × C 血浆 ) / V 血浆 × C 回收

[0495] where V PBS is the volume of the receptor side (PBS) of the dialysis device, and V 血浆 is the volume of the donor side (plasma). C 回收 is the analyte concentration measured from the recovered sample.

[0496] Propranolol (1 μM) and fluoxetine (5 μM) were included in the experiment as control compounds.

[0497] The unbound fraction (F ub,脑 ) in the brain was calculated based on the measurement in the brain homogenate (F ub,测量 ), considering the dilution factor used in preparing the brain homogenate:

[0498]

[0499] where D = dilution factor (here it is 5).

[0500] Analytical method

[0501] Instrument: Waters Acquity UPLC + Waters Xevo TQ-XS triple quadrupole MS Column: Waters Acquity HSS T3 (2.1x50mm, 1.8μm) column with a pre-column filter Gradient elution; A = 0.1% formic acid, B = acetonitrile

[0502] Time (min) Flow A％ B％ Curve 0.000 0.500ml / min 95 5 - 0.500 0.500ml / min 95 5 6 2.500 0.500ml / min 25 75 6 3.500 0.500ml / min 2 98 1 4.500 0.500ml / min 95 5 1

[0503] Temperature: 40 ℃

[0504] Injection volume: 1.5 μl

[0505] Ion source: ESI+

[0506] Capillary voltage: 2400 V

[0507] Source temperature: 150 °C

[0508] Desolvation temperature: 650 °C

[0509] Cone gas flow rate: 240 L / hr

[0510] Desolvation gas flow rate: 1200 L / hr

[0511] Nebulizer gas flow rate: 7 bar

[0512] Collision gas flow rate: 0.15 mL / min

[0513] Software: MassLynx 4.2

[0514]

[0515] *MRM trace used for quantification

[0516] Results of equilibrium dialysis

[0517] The following table shows the unbound fractions of the compounds of Example 3 and Comparative Example 1 in plasma and brain homogenates for mouse plasma, mouse brain, rat brain, and dog plasma.

[0518]

[0519] Blood-brain barrier permeability of the test compound in mice after IV administration

[0520] At T = 0 h, the compound was administered to the animals in a suitable vehicle. At 0.5 h after administration, plasma and brain were taken out separately, and the total compound concentration was prepared and analyzed.

[0521] General sample handling procedure (plasma):

[0522] Protein precipitation (PPT) using 96-well plates

[0523] 1). Aliquots of 5 μL of unknown samples, calibration standards, quality control samples, and diluted quality control samples (if any), single blanks, and double blanks were added to 96-well plates respectively;

[0524] 2). Each sample (except double blanks) was quenched with 200 μL of IS1 (6-in-1 internal standard in MeOH (100 ng / mL each of Labetalol, tolbutamide, Verapamil, dexamethasone, glyburide, and Celecoxib)), and then the mixture was vortexed at 800 rpm for 10 min and centrifuged at 3220×g for 15 min at 4 °C; (double blank samples were quenched with 200 μL of MeOH);

[0525] 3). Transfer an aliquot of 60 μL of the supernatant to another clean 96-well plate, centrifuge at 3220×g for 5 min at 4 °C, and then directly inject the supernatant for LC-MS / MS analysis.

[0526] Dilution procedure description:

[0527] 1) The dilution factor is 10: Add an aliquot of 2 μL of the unknown sample to 18 μL of blank matrix;

[0528] General sample processing procedure (brain homogenate):

[0529] Use a 96-well plate for protein precipitation (PPT)

[0530] 1). Add aliquots of 20 μL of the unknown sample, calibration standards, quality control samples, and diluted quality control samples (if any), single blanks, and double blanks to a 96-well plate, respectively;

[0531] 2). Quench each sample (except for double blanks) with 800 μL of IS1 (double blank samples are quenched with 800 μL of MeOH), and then vortex the mixture at 800 rpm for 10 min and centrifuge at 3220×g for 15 min at 4 °C; 3). Transfer an aliquot of 60 μL of the supernatant to another clean 96-well plate, centrifuge at 3220×g for 5 min at 4 °C, and then directly inject the supernatant for LC-MS / MS analysis.

[0532] Analysis method

[0533] Instrument: LC-MS / MS - CB_Triple Quad 6500plus Column: Waters ACQUITY UPLC HSS T3 1.8 μm 2.1×50 mm

[0534] Gradient elution; A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile

[0535] Time (min) Flow rate A(％) B(％) 0 0.6mL / min 95 5 1 0.6mL / min 30 70 1.2 0.6mL / min 0 100 1.5 0.6mL / min 0 100 1.51 0.6mL / min 95 5 1.6 0.6mL / min 95 5

[0536] Temperature: 45 °C

[0537] Injection volume: Brain 1.5 μl, Plasma 4 μl

[0538] Ion source: ESI+, SRM detection

[0539] Compound MRM transition Retention time Example 3 306>147 0.82 Verapamil 455>165 0.97

[0540] Results

[0541] Example 3 and Comparative Example 1 were formulated into a clear solution of 1.50 mg / mL in 10% DMSO, 5% Tween 80, 40% Pg, 45% saline at pH = approximately 7 (measured with pH test strips) and administered intravenously to male CD1 (ICR)-fed mice at 3 mg / kg.

[0542] The results are shown in the table below. Example 3 returned a plasma concentration of 292 ng / mL and a brain concentration of 61.2 ng / g at 0.5 hours after dosing. This means that a brain-to-plasma concentration of 21% was observed. In contrast, Comparative Example 1 returned a plasma concentration of 3087 ng / ml and a brain concentration of 5 ng / g at 0.5 hours. This means that the brain-to-plasma ratio was less than 1%.

[0543] For the treatment of CNS diseases, it is advantageous to have a brain-to-plasma ratio value greater than 1% and preferably greater than 10% and 20%. Therefore, Example 3 is particularly useful for the treatment of CNS diseases.

[0544]

[0545] The unbound partition coefficient (K puu ) was determined as the ratio between the free compound concentrations in plasma and brain:

[0546]

[0547] where C u,脑 = the unbound concentration in the brain (C x F ub,脑 ); where

[0548] C = the steady-state concentration; and

[0549] C ub,血浆 = the unbound concentration in plasma (C x F ub ).

[0550] Therefore, the K puu of Comparative Example 1 was calculated to be < 0.1. This indicates that Comparative Example 1 did not effectively penetrate the blood-brain barrier.

[0551] Determination of K puu in dogs

[0552] Example 3 was formulated as a solid (batch number C2210502) and placed into enteric-coated capsules (0#). Approximately 30 minutes before dosing the test compound, pentagastrin (0.25 mg / mL and 0.024 mL / kg) was administered to fasted male beagle dogs by intramuscular (IM) injection at 6 μg / kg. Capsules containing 20 mg / kg of Example 3 were administered orally, and plasma and CSF samples were collected before dosing and at 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing, and the concentration of Example 3 was analyzed in a manner similar to the above study.

[0553] Results

[0554]

[0555] *BQL: Below quantification level

[0556] Analytical data

[0557] <![CDATA[AUC 0-inf (ng.h / mL)]]> % Fu plasma Plasma 23816 55 CSF 6414

[0558] The unbound partition coefficient (K puu ) was determined as the ratio between the areas under the curve corrected for the free compound concentration in plasma and CSF.

[0559] K puu = AUC0-infcsf / (AUC0-inf plasma x (%Fu plasma / 100))

[0560] K puu = 6414 / (23816 x (55.5 / 100)) = 6414 / 13218 = 0.49

[0561] Therefore, the K of Example 3 puu is greater than 0.1, indicating that a portion of the unbound compound in plasma penetrates the blood-brain barrier. Therefore, the compound is particularly useful for treating CNS diseases.

[0562] The K of the rat in Comparative Example 2 puu

[0563] Comparative Example 2 is not a sorting protein regulator according to the present invention and has the following structure:

[0564]

[0565] The K of Comparative Example 2 in rats puu was determined as follows.

[0566] The compound of Comparative Example 2 was administered orally or intravenously to animals as a single dose. Blood samples were collected from the animals via the saphenous vein (sv) or vena cava (vc) at specific time points. The final samples were collected under isoflurane anesthesia. A total of one or two blood samples were collected from each animal.

[0567] Within 30 min after sampling, the blood samples were centrifuged for plasma separation (10 min, 2700G, RT). The samples were transferred to pre-labeled plastic tubes and frozen and stored at -80 °C until analysis.

[0568] Blank blood was collected from animals not administered the compound of Comparative Example 2 via cardiac puncture into K 2 EDTA syringes under isoflurane anesthesia. The blood was centrifuged for plasma separation (2700G, 10 min, RT). The blank plasma was frozen and stored at -80 °C until analysis.

[0569] Brains were collected from selected animals at specific time points. The animals were dissected under terminal anesthesia and the final blood samples were collected via the vc. For perfusion, the heart was exposed and the major veins leading to the right atrium were cut. Then a blunt needle was inserted into the left ventricle of the heart and approximately 30 - 50 ml of chilled saline was injected to clear any residual blood. Tissue samples were then immediately collected, frozen in liquid nitrogen and stored at -80 °C until analysis. Blank brain material was collected from animals not administered the compound of Comparative Example 2 in the same manner.

[0570] Rat brain samples were homogenized using an Omni Bead Ruptor 24, using 4 volumes of 150 mM phosphate buffered saline (PBS, pH 7.4) per 1 part of tissue (e.g., 100 mg of brain tissue + 400 μl of PBS).

[0571] Samples were prepared by protein precipitation by mixing 1 part of the sample (rat plasma or brain homogenate) with 3 parts of a mixture of 1% formic acid and internal standard in acetonitrile (e.g., 30 μl of plasma was mixed with 90 μl of the solution). The samples were mixed on a tabletop shaker for 3 minutes and then centrifuged at 2272 x g for 20 minutes. The supernatant was transferred to an analysis plate, diluted 1:1 with ultrapure water and analyzed.

[0572] Standard samples were prepared by spiking blank rat plasma and brain homogenate (5 μl of standard + 45 μl of blank plasma) with analytes at concentrations ranging from 0.1 ng / ml to 20000 ng / ml.

[0573] Quality control (QC) samples were prepared by spiking blank rat plasma and brain homogenate (5 μl of QC + 45 μl of blank matrix) with analytes at concentrations of 0.3, 3, 30, 300 and 3000 ng / ml (in triplicate).

[0574] Prepare standards and quality control products for analysis in the same manner as the samples.

[0575] Analyze brain and plasma samples by tandem ultra - performance liquid chromatography (UPLC) and mass spectrometry (MS) to determine the concentration of the compound of Comparative Example 2. Then calculate K puu .

[0576] The results of intravenous and oral administration of the compound are shown in the table below. The data in the table are the average results of samples collected from two or three animals.

[0577] The data show that the K of Comparative Example 2 puu < 0.1, and thus the compound cannot effectively penetrate the blood - brain barrier.

[0578] Intravenous administration

[0579]

[0580] Oral administration

[0581]

[0582]

[0583] Microdialysis study

[0584] Perform the following experiment using the compound of Example 3 as the mesylate salt.

[0585] Materials and methods

[0586] In vitro experiment

[0587] Perform in vitro experiments using a MetaQuant microdialysis probe with a 4 - mm exposed ethylene - vinyl alcohol (EC20) membrane (CRL Groningen, Netherlands) to determine the recovery of the compound of Example 3. For this purpose, place the probe in a beaker containing 10 nM of the compound of Example 3 in artificial CSF (aCSF: containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl 2 in ultrapure H 2 O, 1.2 mM MgCl 2 ). Continuously stir the contents of the beaker and maintain at a constant temperature of 37 °C. Perfuse the probe with slow - flowing aCSF at a flow rate of 0.12 μL / min and with ultrapure H 2O was perfused with a flow rate of 0.8 μL / min. After pre-stabilization for 2 hours, five consecutive microdialysis samples were collected at 30-minute intervals. Samples of the beaker contents were collected at the start and end of the microdialysis experiment. All samples were collected into 0.5 mL LoBind Eppendorf tubes (Eppendorf SE, Germany; 0030108035) and stored at -80 °C until analysis.

[0588] In vivo experiments

[0589] Thirteen adult male Sprague Dawley rats were used for the experiment. A guide device with a 4 mm exposed polyethersulfone (PES200) membrane (CRL Groningen, Netherlands) and a push-pull microdialysis probe were placed in the left hippocampus of the rats. For animals receiving the test compound, a guide device and a MetaQuant microdialysis probe with a 4 mm exposed ethylene vinyl alcohol (EC20) membrane (CRL Groningen, Netherlands) were placed in the right hippocampus. The coordinates of the probe tip were: AP = -5.3 mm (relative to bregma), lateral coordinates ±4.8 mm (relative to the midline), and vertical coordinate -8.0 mm (relative to the dura mater). The incisor bar was set at -3.3 mm. All coordinates were 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.

[0590] For animals receiving the test compound, an indwelling cannula (35–42 mm) was placed in the jugular vein and brought out through an incision in the top of the skull for blood sampling. The end of each cannula was fixed in place with dental cement and attached to the skull with stainless steel screws.

[0591] The compound of Example 3 was formulated at a concentration of 20 mg / mL in 20% sulfobutyl ether-β-cyclodextrin (SBE-β-CD) in deionized water and used for oral gavage at a volume of 5 mL / kg for 100 mg / kg.

[0592] The experiment was started one day after probe implantation. The push-pull and MetaQuant microdialysis probes were connected to a microperfusion pump (Harvard Apparatus, USA) via flexible PEEK tubing (Western Analytical Products Inc., USA; PK005-020). The probes were perfused with artificial CSF (aCSF: containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl 2 and 1.2 mM MgCl 2) Perfuse at a flow rate of 0.5 μL / min (push-pull probe), or perfuse with slowly flowing aCSF at a flow rate of 0.12 μL / min and with ultra-purified H 2 O carrier at a flow rate of 0.8 μL / min (MetaQuant probe). After pre-stabilization for two hours, microdialysis samples were collected at 60-minute intervals. Three basal samples were collected. Food was removed at t = -120 minutes, and then the compound was administered at t = 0 minutes, and the compound was administered again at t = 180 and 360 minutes. Food was returned after the third administration of the compound. Microdialysate samples were collected within 720 minutes after the first administration of the compound. Samples were collected into 0.5 mL LoBind Eppendorf tubes. All samples were stored at -80 °C until analysis.

[0593] During the experiment, blood samples were collected via a jugular vein catheter. Blood samples were collected into K2-EDTA collection bottles, and after centrifugation, the resulting plasma samples were aliquoted into two portions using low-binding pipette tips and placed into 0.5 mL LoBind Eppendorf tubes. All samples were stored at -80 °C until analysis.

[0594] At the end of the experiment, the animals were sacrificed and terminal brain tissues were collected to verify the probe position.

[0595] The concentration of the compound of Example 3 was determined by HPLC detected by tandem mass spectrometry (MS / MS). The microdialysis samples were mixed with acetonitrile, formic acid, ultra-pure H 2 O and internal standard (labetalol). The plasma samples were mixed with acetonitrile, formic acid and internal standard, and then centrifuged. The resulting supernatant was mixed with acetonitrile and formic acid in ultra-pure H 2 O and then used for HPLC-MS analysis. An aliquot of each analytical sample was injected onto an HPLC column by an autosampler (Shimadzu, Japan). Chromatographic separation was performed using a Kinetex XB-C18 column (50 x 2.1 mm, 2.6 μm) maintained at a temperature of 35 °C. The mobile phase consisted of: A: 0.1% formic acid in ultra-pure H 2 O and B: 0.1% formic acid in acetonitrile. The compounds were eluted using a linear gradient of phase A and phase B at a total flow rate of 0.4 mL / min.

[0596] MS analysis was performed using an API 4000 MS / MS system consisting of an API 4000 MS / MS detector and a Turbo Ion Spray interface (both from Applied Biosystems, Netherlands). The acquisition was performed in positive ionization mode and optimized settings were made for the analytes. The instrument was operated in multiple reaction monitoring (MRM) mode.

[0597] Use weighted (1 / x) regression to fit appropriate in-run calibration curves and use these calibration curves to determine the sample concentrations. Accuracy is verified by quality control samples after each sample series. Use Analyst TM Data System (Applied Biosystems) to calibrate and quantify the data. The MRM transitions of the analyte are shown in the following table.

[0598] Analyte Q1 Q3 Labetalol 329.5 162.1 Example 3 306.3 117.1

[0599] Use weighted (1 / x) regression to fit appropriate in-run calibration curves and use these calibration curves to determine the sample concentrations. Accuracy is verified by quality control samples after each sample series. Use Analyst TM Data System (Applied Biosystems) to calibrate and quantify the data.

[0600] To quantify rat PGRN in the study samples, a commercially available ELISA kit (AG-45A-0043YEK-KI01, AdipoGen, Switzerland) was used. Based on the previous research key 2819, the study samples were added to the plate at a certain dilution. Plasma samples were analyzed in duplicate. Samples beyond the detection limit were re-analyzed at a more appropriate dilution on another plate. Additionally, samples with a %CV higher than 30% for replicate samples were re-analyzed on different plates. Absorbance at 450 nm was measured using a Multiskan FC (ThermoFischer Scientific, USA).

[0601] Data was processed using Microsoft Excel and plotted in Prism 9 for Windows, version 9.3.1 (GraphPad Software, Inc., 1992 - 2021).

[0602] To evaluate the pharmacodynamic microdialysis data, the average of three pre-dose samples was set as 100%. Samples with a relative basal sample concentration < 50% or > 150% were considered outliers and not used for baseline calculation. All post-dose samples were expressed as a percentage of the basal level within the same subject. Before performing statistical analysis, outlier analysis was conducted: values deviating from the relative mean by more than two standard deviations at a single time point within the same dose group were excluded by single iteration.

[0603] Statistical analysis of the relevant data was performed using SigmaPlot 12.5 (Systat Software, Inc., 2011). Two-way ANOVA with repeated measures was used, followed by Bonferroni post hoc tests, to compare the treatment and time effects between the treatment groups. Treatment and time were the main factors. The main effects were evaluated only when there was no statistically significant interaction between the two main factors. If there was a significant interaction between the two factors, the main effects were not considered. In this case, the evaluation of the interaction effect was as follows:

[0604] · The change over time for each dose was evaluated compared to the level at time point t = 0 minutes;

[0605] · The differences in levels after different treatments at each individual time point were compared.

[0606] The statistical significance level was predefined as p < 0.05.

[0607] The reported microdialysate concentrations were corrected for dilution. Where applicable, correction for probe recovery was indicated in the text.

[0608] Results

[0609] In vitro recovery of Example 3

[0610] For the MetaQuant microdialysis probe with a 4 mm exposed EC20 membrane using aCSF as the perfusion fluid, the relative in vitro recovery of Example 3 was on average 69.8 ± 3.40%.

[0611] In study key 2819B, the in vitro recovery of PGRN using a push-pull microdialysis probe with a 4 mm exposed PES 200 membrane perfused with aCSF had previously been determined to be 26.9 ± 0.86%.

[0612] Histological verification

[0613] Visual assessment of the brain showed that all probes were in the correct position.

[0614] Pharmacokinetics

[0615] Figure 1Shows the levels 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 (as indicated by the arrows, at t = 0, 180, and 360 min). At t = -120, -60, and 0 min, the levels of Example 3 were below the lower limit of quantification (LLOQ) of 7.31 ng / mL in the microdialysate. Data are represented as mean + SEM (n = 7). The data have been corrected to account for a probe recovery of 69.8% measured in vitro.

[0616] Figure 2 Shows the levels of Example 3 in the plasma of adult male Sprague Dawley rats after oral administration of 100 mg / kg of Example 3 (as indicated by the arrows, at t = 0, 180, and 360 min). At t = -120 min, the plasma level of Example 3 was < 50.0 ng / mL LLOQ. Data are represented as mean + SEM (n = 7).

[0617] The following table shows the basal levels of PGRN in hippocampal microdialysate and plasma.

[0618]

[0619] Figure 3 Shows the relative pharmacodynamic responses of PGRN in hippocampal microdialysate from adult male Sprague Dawley rats after oral administration of vehicle or 100 mg / kg of Example 3 (as indicated by the arrows, at t = 0, 180, and 360 min). Data are represented as mean + SEM (n = 5 - 6 / group).

[0620] Pharmacodynamics

[0621] Relative PGRN data from the hippocampus of animals treated with Example 3 were statistically evaluated by two-way ANOVA with repeated measures, demonstrating a significant interaction between treatment and time (p < 0.001). Post hoc evaluation showed that PGRN levels in animals treated with Example 3 were elevated at t = 540 - 720 min compared to t = 0 min. Treatment over the observation time showed that PGRN levels in animals treated with Example 3 were significantly higher than the vehicle group at t = 540 - 720 min. The details of the statistical analysis are shown in the following table.

[0622] Source of variation DF SS MS F P Treatment 1 69690.402 69690.402 7.220 0.025 Animal (treatment) 9 89633.628 9959.292 Time 12 89764.733 7480.394 5.332 <0.001 Treatment x Time 12 54438.021 4536.502 3.234 <0.001 Residual 92 129064.821 1402.878 Total 126 422586.580 3353.862

[0623] Figure 4Shows the levels of PGRN in the plasma of adult male Sprague Dawley rats after oral administration of 100 mg / kg of Example 3 (as indicated by the arrows, at t = 0, 180, and 360 min). Data are represented as mean + SEM (n = 7).

[0624] Conclusion

[0625] The above data indicate that the compound of the present invention (Example 3) can cross the blood-brain barrier after oral delivery. This surprising finding suggests that the compound of the present invention can be used to treat disorders of the central nervous system. The data also show that the compound of Example 3 increases the level of PGRN in the rat brain. This further surprising finding indicates that the compound of the present invention may have the ability to treat conditions where an increase in brain PGRN may be useful. For example, the compound of the present invention can be used to treat frontotemporal dementia, which is characterized by depletion of PGRN levels. Patients with depleted brain PGRN levels have a statistically much higher likelihood of developing frontotemporal dementia, and thus the data provided herein suggest that the compound of the present invention can be used to prevent and treat frontotemporal dementia and related disorders.

[0626] Embodiments of the present invention

[0627] Embodiment 1. A compound of formula (I)

[0628]

[0629] (I)

[0630] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; wherein

[0631] R 1 is

[0632] X is CR 3 or N, wherein R 3 is selected from the group consisting of H, halogen, and C 1 -C 3 alkyl;

[0633] Each Y is independently CHR 4 、NR 5 、CR 6 R 6 or O, wherein R 4 is independently selected from the group consisting of H, halogen, carbonyl, and C 1 -C 4 alkyl; R 5 is independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, C2 -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 alkyl); and R 6 is independently selected from the group consisting of halogen and C 1 -C 4 alkyl;

[0634] R 2 is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, and C 1 -C 3 haloalkyl;

[0635] wherein the compound is not one of the following compounds:

[0636]

[0637] Embodiment 2. The compound according to Embodiment 1, wherein R 2 is selected from the group consisting of H, CH 3 , CH 2 F, CHF 2 and CF 3 ; preferably, wherein R 2 is selected from the group consisting of H, CH 3 , CHF 2 and CF 3 .

[0638] Embodiment 3. The compound according to Embodiment 1 or 2, wherein each Y is independently CHR 4 , NR 5 , or O; and / or

[0639] wherein R 3 is H or C 1 -C 3 alkyl, preferably H or methyl; and / or

[0640] wherein each R 4 is independently H or carbonyl; and / or

[0641] wherein each R 5 is independently H, C 1 -C3 alkyl or -C(O)O-(C 1 -C 4 -alkyl), preferably H, methyl or -C(O)O-(tert-butyl), more preferably H or methyl.

[0642] Embodiment 4. A compound according to any one of the foregoing embodiments, wherein R 1 is selected from one of the following groups:

[0643]

[0644] Preferably, wherein no more than one or two Ys are NR 5 or O and the remaining Ys are CHR 4 .

[0645] Embodiment 5. A compound according to Embodiment 4, wherein R 1 is selected from one of the following

[0646]

[0647] wherein each Y is independently NR 5 or O, preferably, wherein one R 4 group is H or carbonyl and the other R 4 groups are all H.

[0648] Embodiment 6. A compound according to Embodiment 5, wherein R 1 is selected from one of the following groups:

[0650]

[0651]

[0652] Embodiment 7. A compound according to Embodiment 6, wherein R 1 is selected from one of the following groups:

[0654]

[0655]

[0656] Embodiment 8. A compound according to Embodiment 7, wherein R 1 is selected from one of the following groups:

[0657]

[0658]

[0659] Embodiment 9. The compound according to any one of the foregoing embodiments, wherein the compound is

[0660] (2S)-2-{[(1S)-2,2-difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0661] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid;

[0662] (2S)-5,5-dimethyl-2-{[(1R)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid;

[0663] (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydronaphthalen-2-yl)methyl]amino}hexanoic acid;

[0664] (2S)-2-[({1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinolin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid;

[0665] (2S)-2-{[(3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0666] (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydroquinolin-3-yl)ethyl]amino}hexanoic acid;

[0667] (2S)-5,5-dimethyl-2-{[(5,6,7,8-tetrahydroquinolin-3-yl)methyl]amino}hexanoic acid;

[0668] (2S)-5,5-dimethyl-2-{[(1S)-2,2,2-trifluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid;

[0669] (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid;

[0670] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0671] (2S)-5,5-dimethyl-2-{[(1R)-1-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid;

[0672] (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)-2,2,2-trifluoroethyl]amino}-5,5-dimethylhexanoic acid;

[0673] (2S)-2-{[(1R)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0674] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0675] (2S)-2-[({5H,6H,7H-cyclopenta[b]pyridin-3-yl}methyl)amino]-5,5-dimethylhexanoic acid;

[0676] (2S)-2-{[(2,3-dihydro-1H-inden-5-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0677] (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid;

[0678] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0679] (2S)-5,5-dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid;

[0680] (2S)-5,5-dimethyl-2-[({5H,7H,8H-pyrano[4,3-b]pyridin-3-yl}methyl)amino]hexanoic acid;

[0681] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-7-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0682] (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0683] (2S)-2-{[(1S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0684] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0685] (2S)-5,5-dimethyl-2-[({2H,3H,4H-pyrano[2,3-b]pyridin-6-yl}methyl)amino]hexanoic acid;

[0686] (2S)-2-{[(1R)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0687] (2S)-5,5-dimethyl-2-{[(5-methyl-3,4-dihydro-2H-1-benzopyran-7-yl)methyl]amino}hexanoic acid;

[0688] (2S)-2-{[(1R)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)-2,2-difluoroethyl]amino}-5,5-dimethylhexanoic acid;

[0689] (2S)-5,5-dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]amino}hexanoic acid;

[0690] (2S)-2-{[(1S)-1-(3,4-dihydro-2H-1-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0691] (2S)-5,5-dimethyl-2-{[(1S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}hexanoic acid;

[0692] (2S)-5,5-dimethyl-2-{[(1R)-1-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]amino}hexanoic acid;

[0693] (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0694] (2S)-2-[({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}methyl)amino]-5,5-dimethylhexanoic acid;

[0695] (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0696] (2S)-5,5-Dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methyl]amino}hexanoic acid;

[0697] (2S)-5,5-Dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid;

[0698] (2S)-5,5-Dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid;

[0699] (2S)-2-{[(2,3-dihydro-1-benzofuran-6-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0700] (2S)-5,5-Dimethyl-2-{[(7-methyl-2,3-dihydro-1H-inden-5-yl)methyl]amino}hexanoic acid;

[0701] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0702] (2S)-2-{[(1R)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0703] (2S)-2-{[(1,3-dihydro-2-benzofuran-4-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0704] (2S)-2-{[(2,3-dihydro-1-benzofuran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0705] (2S)-2-{[(3,4-dihydro-1H-2-benzopyran-8-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0706] (2S)-2-{[(2H-1,3-benzodioxol-5-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0707] (2S)-5,5-Dimethyl-2-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}hexanoic acid;

[0708] (2S)-2-{[(1S)-1-(3,4-dihydro-1H-2-benzopyran-7-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0709] (2S)-5,5-Dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-7-yl)methyl]amino}hexanoic acid;

[0710] (2S)-5,5-Dimethyl-2-{[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid;

[0711] (2S)-2-{[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0712] (2S)-5,5-Dimethyl-2-{[(1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid;

[0713] (2S)-2-{[(1R)-2,2-Difluoro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0714] (2S)-2-{[(3,4-Dihydro-2H-1-benzopyran-5-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0715] (2S)-5,5-Dimethyl-2-{[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid;

[0716] (2S)-2-{[(1S)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0717] (2S)-5,5-Dimethyl-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid;

[0718] (2S)-2-{[(2,3-Dihydro-1H-inden-4-yl)methyl]amino}-5,5-dimethylhexanoic acid;

[0719] (2S)-2-{[(1R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}-5,5-dimethylhexanoic acid;

[0720] (2S)-5,5-Dimethyl-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid;

[0721] (2S)-5,5-Dimethyl-2-{[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl]amino}hexanoic acid;

[0722] (2S)-5,5-dimethyl-2-{[(1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]amino}hexanoic acid;

[0723] (2S)-5,5-dimethyl-2-{[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}hexanoic acid;

[0724] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0725] Embodiment 10. A compound of formula (II)

[0726]

[0727] (II)

[0728] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; wherein

[0729] R 7 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, preferably H, CH 3 , CHF 2 , and CF 3 , preferably H and CH 3 ; and R 8 is phenyl or pyridine, wherein the phenyl and pyridine are independently substituted with one or more substituents selected from the group consisting of 5-membered heteroalkyl, triazolyl, -O-phenyl, and -NR 9 R 10 , and R 9 and R 10 are independently selected from H or C 1 -C 3 alkyl, preferably H or CH 3 , more preferably CH 3 ; or

[0730] R 7 is C 1 -C 3 hydroxyalkyl, preferably –(C 2 H 4 )-OH; and R 8 is phenyl optionally substituted with C 1 -C 3 alkoxy, preferably phenyl optionally substituted with -O-CH 3 .

[0731] Embodiment 11. The compound according to Embodiment 10, wherein R 7 is selected from the group consisting of H, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, and R 8 is pyrrolidinyl, triazolyl, -O-phenyl, or -NR 9 R 10 substituted phenyl, or R 8 is pyridine substituted with -O-phenyl; or

[0732] wherein R 7 is C 1 -C 3 hydroxyalkyl and R 8 is phenyl optionally substituted with C 1 -C 3 alkoxy.

[0733] Embodiment 12. The compound according to Embodiment 10 or 11, wherein the compound is

[0734] (2S)-5,5-dimethyl-2-{[(2-phenoxypyridin-4-yl)methyl]amino}hexanoic acid;

[0735] (2S)-5,5-dimethyl-2-{[(6-phenoxypyridin-3-yl)methyl]amino}hexanoic acid;

[0736] (2S)-5,5-dimethyl-2-({[3-(pyrrolidin-1-yl)phenyl]methyl}amino)hexanoic acid;

[0737] 2-{[(1S)-3-hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid;

[0738] (2S)-5,5-dimethyl-2-{[(1R)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid;

[0739] (2S)-5,5-dimethyl-2-{[(1S)-1-(6-phenoxypyridin-3-yl)ethyl]amino}hexanoic acid;

[0740] (2S)-5,5-dimethyl-2-{[(4-phenoxyphenyl)methyl]amino}hexanoic acid;

[0741] (2S)-2-({[3-(dimethylamino)phenyl]methyl}amino)-5,5-dimethylhexanoic acid;

[0742] (2S)-2-{[(1R)-3-Hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid;

[0743] (2S)-5,5-Dimethyl-2-{[(3-phenoxyphenyl)methyl]amino}hexanoic acid;

[0744] (2S)-2-{[(1S)-3-Hydroxy-1-(3-methoxyphenyl)propyl]amino}-5,5-dimethylhexanoic acid;

[0745] (2S)-2-{[(1R)-3-Hydroxy-1-phenylpropyl]amino}-5,5-dimethylhexanoic acid;

[0746] (2S)-5,5-Dimethyl-2-({[3-(1H-1,2,4-triazol-1-yl)phenyl]methyl}amino)hexanoic acid;

[0747] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

[0748] Embodiment 13. A pharmaceutical composition comprising a compound according to any one of the foregoing embodiments and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0749] 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.

[0750] Embodiment 15. 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 neurodegenerative disorders, mental disorders, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye disorders, hearing loss, or diseases characterized by misfolded tau;

[0751] wherein the neurodegenerative disorder is preferably selected from motor neuron diseases, 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 wherein the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy;

[0752] wherein the neurodegenerative disorder is preferably a neurodegenerative disorder characterized by misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia;

[0753] Among them, the mental disorders are preferably selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorders;

[0754] Among them, the inflammatory disorders are preferably selected from inflammatory diseases and neuroinflammation;

[0755] Among them, the cancers are preferably selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer;

[0756] Among them, the cardiovascular diseases are preferably selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; and

[0757] Among them, the hearing losses are preferably selected from noise-induced hearing loss, ototoxicity-induced hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0758] References

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[0783] Martens, L. et al., Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest (2012), 122(11), pp. 3955 - 3959;

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[0811] 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;

[0812] Zhou, X. et al., Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol (2015), 210(6), pp. 991-1002;

[0813] Meneses et al., TDP-43 Pathology in Alzheimer’s Disease, Mol Neurodegeneration (2021), 16, 84;

[0814] Prudencio et al., Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor, Proc Natl Acad Sci U SA (2012), 109(52):21510–21515;

[0815] 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.

[0816] The sequences are cited throughout the specification and form part of the description

[0817] SEQ ID NO: 1 (Full-length sortilin - isoform 1)

[0818]

[0819] SEQ ID NO: 2 (Full-length sortilin - isoform 2)

[0820]

[0821] SEQ ID NO: 3 (Mature sortilin)

[0822]

[0823] SEQ ID NO: 4 (Mouse sortilin)

[0824]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide and / or prodrug thereof; wherein R 1 is X is CR 3 or N, wherein R 3 selected from the group consisting of H, halogen, and C 1 -C 3 alkyl groups; Each Y is independently CHR 4 , NR 5 , CR 6 R 6 , C(O) or O, where R 4 is independently selected from the group consisting of H, halogen and C 1 -C 4 alkyl; R 5 is independently selected from the group consisting of H, halogen, 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 alkyl); and R 6 is independently selected from the group consisting of halogen and C 1 -C 4 alkyl; R 2 selected from the group consisting of H, C 1 -C 4 alkyl and C 2 -C 4 hydroxyalkyl and C 1 -C 3 haloalkyl; wherein the compound is not one of the following compounds:

2. The compound according to claim 1, wherein R 2 selected from the group consisting of H, CH 3 , CH 2 F, CHF 2 and CF 3 ; preferably wherein, R 2 selected from the group consisting of H, CH 3 , CHF 2 , and CF 3 ; 3. The compound according to claim 1 or 2, wherein Each Y is independently CHR 4 , NR 5 , C(O) or O; and / or wherein, R 3 is H or C 1 -C 3 alkyl, preferably H or methyl; and / or wherein, each R 4 is H; and / or Wherein, each R 5 is independently H, C 1 -C 3 alkyl or -C(O)O-(C 1 -C 4 alkyl), preferably H, methyl or -C(O)O-(tert-butyl), more preferably H or methyl.

4. The compound according to any one of the preceding claims, wherein R 1 selected from one of the following groups: Preferably, no more than one or two Ys are NR 5 or O and the remaining Ys are independently C(O) or CHR 4 .

5. The compound according to claim 4, wherein R 1 selected from one of the following groups: Wherein each Y is independently NR 5 or O, and each R 7 is independently selected from the group consisting of H, halogen, and C 1 -C 4 alkyl, or said R 7 together with the carbon atom to which it is attached forms a carbonyl group, preferably wherein each R 7 is H or said R 7 together with the carbon atom to which it is attached forms a carbonyl group, more preferably wherein one R 7 group is H or said R 7 group together with the carbon atom to which it is attached forms an oxo group, and the other R 7 groups are each H.

6. The compound according to claim 5, wherein R 1 selected from one of the following groups:

7. The compound according to claim 6, wherein R 1 selected from one of the following groups:

8. The compound according to claim 7, wherein R 1 selected from one of the following groups:

9. The compound according to any one of the preceding claims, wherein the compound is (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; (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; (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; (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; (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.

10. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide and / or prodrug thereof; wherein R 8 selected from the group consisting of H, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, preferably H, CH 3 , CHF 2 and CF 3 , preferably H and CH 3 ; and R 9 is phenyl or pyridine, wherein, The phenyl and pyridine are independently substituted by one or more substituents selected from the group consisting of 5-membered heteroalkyl, triazolyl, -O-phenyl, and -NR 10 R 11 , and R 10 and R 11 are independently selected from H or C 1 -C 3 alkyl, preferably H or CH 3 , more preferably CH 3 ; or R 8 is C 1 -C 3 hydroxyalkyl, preferably –(C 2 H 4 )-OH; and R 9 is phenyl optionally substituted by C 1 -C 3 alkoxy, preferably phenyl optionally substituted by -O-CH 3 .

11. The compound according to claim 10, wherein, R 8 selected from the group consisting of H, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, and R 9 is pyrrolidinyl, triazolyl, -O-phenyl, or -NR 10 R 11 substituted phenyl, or R 9 is pyridine substituted by -O-phenyl; or wherein, R 8 is C 1 -C 3 hydroxyalkyl and R 9 is optionally phenyl substituted by C 1 -C 3 alkoxy.

12. The compound according to claim 10 or 11, wherein, the compound is (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.

13. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier, excipient, and / or diluent.

14. The compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13, for use in therapy.

15. The compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13, for use in the treatment or prevention of neurodegenerative disorders, mental disorders, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary ocular disorders, hearing loss, or diseases characterized by misfolded tau; wherein, the neurodegenerative disorders are preferably selected from motor neuron diseases, 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 wherein, the motor neuron diseases are selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy; wherein, the neurodegenerative disorder is preferably a neurodegenerative disorder characterized by misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia; wherein, the mental disorders are preferably selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorders; wherein, the inflammatory disorders are preferably selected from inflammatory diseases and neuroinflammation; wherein, the cancer is preferably selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; Among them, the cardiovascular disease is preferably selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure and ischemic heart disease; and Among them, 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.

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