Amino acid-based carbamates and / or ureas for treating sortilin-dependent disorders

Abstract

The present invention relates to compounds of formula (I) that are modulators of sortilin activity, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment or prevention of medical conditions in which modulation of sortilin activity is beneficial.

Description

[Technical field]

[0001] The present invention relates to compounds that bind to and modulate sortilin activity, and pharmaceutical compositions comprising these compounds, and their use in treating or preventing medical conditions in which modulation of sortilin activity is beneficial. [Background technology]

[0002] Sortilin is a type I transmembrane protein that acts as a receptor for several ligands (Petersen et al., 1997). Sortilin is abundantly expressed in neurons and microglia in the nervous system and inner ear, and is involved in metabolic control in several peripheral tissues (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 mediates the sorting of select cargo between the trans-Golgi network at the cell surface and the endosomal pathway (Nykjaer & Willnow, 2012; Willnow, Petersen, & Nykjaer, 2008). Sortilin has a large extracellular domain called VPS10, which defines a family of receptors 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 multiple ligands, including pro-nerve growth factor (proNGF), 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 established that sortilin is the most important clearance receptor for PGRN (Hu et al., 2010). Thus, sortilin negatively regulates extracellular PGRN levels in the periphery and brain. Indeed, deficiency or blockade of this receptor increases plasma PGRN levels in both mice and humans (Carrasquillo et al., 2010; Gass, Prudencio, Stetler, & Petrucelli, 2012; Hu et al., 2010; Lee et al., 2014; Miyakawa et al., 2020; Pottier et al., 2018).

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

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

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

[0007] PGRN requires three amino acids (QLL in human and PLL in mouse) at the C-terminus of PGRN to bind to sortilin, and a peptide derived from the last 24 amino acids of PGRN binds with similar affinity as the full-length protein (Zheng et al., 2011). This binding mode is structurally similar to that of neurotensin (Zheng et al., 2011), i.e., at the NTIS1 binding site of sortilin. Small molecule screens have been successfully performed in collaboration with Aarhus University to identify blockers of neurotensin binding to sortilin (Andersen et al., 2014; Schroder et al., 2014).

[0008] Sortilin not only exists as a full-length receptor with sorting capacity, but can also form multimeric signaling receptor-ligand complexes. Part of sortilin can also be released from the plasma membrane to remove ligands (NT in pain) and regulate their activity. For example, sortilin is involved in synaptic plasticity by controlling the rate of conversion of proBDNF to BDNF. This may also be true for other pro-neurotrophins.

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

[0010] Sortilin binds to a vast number of ligands and membrane receptors, and is therefore involved in functions known to be important in cell signaling and sorting. For example, sortilin is involved in signaling by the following proneurotrophins: the precursor form of nerve growth factor (proNGF), the precursor form of brain-derived neurotrophic factor (proBDNF), and the precursor form of neurotrophin-3 (proNT3). In complex with the p75NTR (p75 neurotrophin receptor) protein, sortilin has been reported in cell and animal models to form a receptor that exerts a pro-neurotrophin-mediated apoptotic effect, leading to degeneration and cell death (Jansen et al., 2007; Tenk et al., 2005; Nykjaer et al., 2004).

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

[0012] Furthermore, it has been reported that plasma sortilin levels are a powerful biomarker for identifying patients with either coronary heart disease or diabetes mellitus (Oh et al., 2017; Moller et al., 2021). Patients who showed elevated sortilin levels in plasma and were therefore identifiable as suffering from the above conditions also showed elevated glucose levels, suggesting that sortilin is a therapeutic target for treating these conditions. Soluble sortilin has also been proposed as a treatment for type II diabetes (WO2021116290(A1), 2021).

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

[0014] TDP-43 controls the splicing of several gene products, including sortilin. In humans, this splicing adds the cryptic exon 17b (between exon 17 and exon 18), which introduces a stop codon in the stalk and may generate a non-membrane-bound fragment (Prudencio et al., 2012). Furthermore, it has been shown that PGRN may decrease insoluble TDP-43 levels and slow axon degeneration (Beel et al., 2018). Sortilin inhibition increases PGRN levels and is therefore beneficial in the treatment of neurodegenerative diseases involving TDP43.

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

[0016] The blood-brain barrier is a highly selective, semipermeable boundary composed of endothelial cells that prevents nonselective passage of solutes from circulating blood into the extracellular fluid of the CNS, where neurons reside, thus limiting the treatment of neurological diseases by restricting the passage of therapeutic agents across the blood-brain barrier.

[0017] Therefore, therapeutic agents for treating CNS diseases must be able to cross the blood-brain barrier, and in addition, they must have sufficient concentrations of unbound drug in the brain, since the free form hypothesis states that only unbound compounds interact and exert their pharmacological effects.

[0018] Test compound (F ub To determine the proportion of unbound β-lactamase, the sample supernatants can be analyzed by methods such as liquid chromatography-tandem mass spectrometry (LC-MS / MS). The proportion of unbound β-lactamase can then be calculated from the peak area ratios obtained for each matrix according to the following formula: F ub =C PBS / C 血漿 In the formula, C PBS and C 血漿 are the analyte concentrations in PBS (receiver) and plasma (donor), respectively.

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

[0020] Values ​​measured in brain homogenates (F ub、測定値 ) to calculate the proportion of unbound IgG in the brain (F), taking into account the dilution factor used in preparing the brain homogenate. ub、脳 ) can be calculated as:

number

[0021] Brain-plasma non-binding partition coefficient (K puu ) can be determined as the ratio between the free compound concentration in plasma and the free compound concentration in the brain:

number

[0022] In the treatment of CNS diseases, K puu It is desirable for K to have a value greater than 0 and as high as possible. A value around 1 indicates that the free fraction of the compound freely crosses the blood-brain barrier; a value greater than 1 suggests the involvement of an active influx transport mechanism at the blood-brain barrier; a value less than 1 indicates that the free fraction of the compound is poorly permeable or recognized by an active efflux mechanism, resulting in reduced exposure in the CNS, while at the same time crossing the blood-brain barrier back into the plasma or CSF. A K of 0 or close to 0 puu The values ​​indicate that the compound has poor permeability or a highly active efflux mechanism, in which case it is highly unlikely that the desired active species would result in significant exposure in the CNS, in any case.

[0023] In view of the above, there is an unmet need for novel compounds that can be used in the treatment and prevention of medical conditions that benefit from modulation of sortilin, including neurodegenerative disorders, psychiatric disorders, inflammatory disorders, lysosomal storage diseases, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, renal disease, psoriasis, inherited eye conditions, hearing loss, or diseases characterized by misfolded tau. The neurodegenerative disorder may be selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; the psychiatric disorder may be selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; the inflammatory disorder may be selected from inflammatory disease and neuroinflammation; the lysosomal storage disease may be selected from the CLN genes CLN1 (ΡΡΤ1), CLN2 (ΤΡΡ1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ΑΑΡ13Α2), CLN13 (CTSF), CLN14 NCL / Batten disease caused by mutations in (KCTD7), CLCN6, and / or SGSH; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysacharidoses (MPS) types I (Fuller disease) / II (Hunter disease) / IIIa (Sanfilippo disease type A) / IIIB (Sanfilippo disease type B) / IIIc (Sanfilippo disease type C) / IIId (Sanfilippo disease type D) / IVA (Morquio A) / IVB / VI / VII (Sly disease) / IX, mucolipisosis types III (I-cell disease) and IV, multiple sulfatase deficiency;Sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, apartylglucosaminuria, fucosidosis, Schindler disease, metachromatic leukodystrophy caused by arylsulfatase A or saposin B deficiency, globoid cell leukodystrophy (Krabbe disease), Farber disease, Wolman disease and cholesterol ester storage disease, pycnodystostosis, cystinosis, Salla disease, Danon disease, Griscelli disease types 1 / 2 / 3, Hermansky-Pudliak syndrome The cancer may be selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; the cardiovascular disease may be selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; the hearing loss may be selected from noise-induced hearing loss, ototoxic hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss;

[0024] Also, a compound capable of crossing the blood-brain barrier and having a K value of greater than 0.1 for use in treating diseases of the central nervous system. puu There is also an unmet need for sortilin modulators that have Summary of the Invention

[0025] The present invention relates to compounds of formula (I), pharmaceutical compositions comprising these compounds, and the use of these compounds and pharmaceutical compositions for use in therapy, which may include the treatment or prevention of medical conditions in which modulation of sortilin activity is beneficial.

[0026] Such medical conditions include neurodegenerative disorders, psychiatric disorders, inflammatory disorders, lysosomal storage diseases, cancer, pain, diabetes mellitus, retinopathy, brain tumors, glaucoma, uveitis, cardiovascular disease, kidney disease, psoriasis, inherited eye conditions, chronic pain, hearing loss, diseases characterized by misfolded tau, or diseases of the central nervous system.

[0027] The compounds according to the invention have a blood-brain K of greater than 0.1. puu and thus are able to cross the blood-brain barrier. Compounds exhibiting this property may be used in the treatment or prevention of diseases of the central nervous system. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows an X-ray derived image of the compound of Example 1 ((2S)-2-[(benzylcarbamoyl)amino]-5,5-dimethylhexanoic acid) bound to h-sortilin. [Diagram 2] FIG. 2 shows an X-ray derived image of the compound of Example 1 ((2S)-2-[(benzylcarbamoyl)amino]-5,5-dimethylhexanoic acid) bound to h-sortilin. [Diagram 3] FIG. 3 shows an X-ray derived image of the compound of Example 2 ((2S)-2-{[benzyl(methyl)carbamoyl]amino}-5,5-dimethylhexanoic acid) bound to h-sortilin. [Figure 4] FIG. 4 shows an X-ray derived image of the compound of Example 2 ((2S)-2-{[benzyl(methyl)carbamoyl]amino}-5,5-dimethylhexanoic acid) bound to h-sortilin. [Diagram 5] FIG. 5 shows an X-ray derived image of the compound of Example 2 ((2S)-2-{[benzyl(methyl)carbamoyl]amino}-5,5-dimethylhexanoic acid) bound to h-sortilin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In a first aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; X is selected from N and O; R 1 , R 2 , and R 3 are each independently selected from the group consisting of halo, H, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C2-C4)alkenyl, and halo-(C2-C4)alkenyl; and, R 4 (C3~C 20 )Aryl, halo-(C3-C 20 )aryl, (C3-C8)heteroaryl, halo-(C3-C 20 )heteroaryl, (C1-C6)-alkylene-(C3-C 20 )-aryl, (C1-C6)-alkylene-(C3-C 20 )-heteroaryl, (C1-C6)-alkylene-(3- to 10-membered heterocycle); (C1-C6)-Alkylene-(C3-C 20 )-aryl, the aryl group in (C1-C6)-alkylene-(C3-C 20 The heteroaryl group in (C1-C6)-heteroaryl, or the heterocycle in (C1-C6)-alkylene-(3- to 8-membered heterocycle) is optionally substituted with one or more substituents independently selected from halo, H, -OH, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C1-C4)alkoxy, and halo-(C1-C4)alkoxy; If X is O, then R 5 does not exist; If X is N, then R 5 is selected from the group consisting of halo, H, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C2-C4)alkenyl, and halo-(C2-C4)alkenyl; or, If X is N; X, R 4 , and R 5 together form a 4- to 20-membered heterocycle; which heterocycle is monocyclic, bicyclic, or tricyclic and is optionally substituted with one or more substituents independently selected from halo, -OH, cyano, carbonyl, (C1-C4)alkyl, halo-(C1-C4)alkyl, acetyl, (C1-C4)alkoxy, and halo-(C1-C4)alkoxy.

[0030] The compounds of formula (I) are sortilin modulators that bind and modulate sortilin and are therefore found to be potentially useful in conditions in which sortilin inhibition is beneficial, including neurodegenerative disorders, psychiatric disorders, inflammatory disorders, lysosomal storage diseases, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, renal disease, psoriasis, inherited eye conditions, hearing loss, or diseases characterized by misfolded tau. The neurodegenerative disorder may be selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; the psychiatric disorder may be selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; the inflammatory disorder may be selected from inflammatory disease and neuroinflammation; the lysosomal storage disease may be selected from the CLN genes CLN1 (ΡΡΤ1), CLN2 (ΤΡΡ1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ΑΑΡ13Α2), CLN13 (CTSF), CLN14 NCL / Batten disease caused by mutations in (KCTD7), CLCN6, and / or SGSH; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysacharidoses (MPS) types I (Fuller disease) / II (Hunter disease) / IIIa (Sanfilippo disease type A) / IIIB (Sanfilippo disease type B) / IIIc (Sanfilippo disease type C) / IIId (Sanfilippo disease type D) / IVA (Morquio A) / IVB / VI / VII (Sly disease) / IX, mucolipisosis types III (I-cell disease) and IV, multiple sulfatase deficiency;Sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, apartylglucosaminuria, fucosidosis, Schindler disease, metachromatic leukodystrophy caused by arylsulfatase A or saposin B deficiency, globoid cell leukodystrophy (Krabbe disease), Farber disease, Wolman disease and cholesterol ester storage disease, pycnodystostosis, cystinosis, Salla disease, Danon disease, Griscelli disease types 1 / 2 / 3, Hermansky-Pudliak syndrome The cancer may be selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; the cardiovascular disease may be selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; the hearing loss may be selected from noise-induced hearing loss, ototoxic hearing loss, age-induced hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss;

[0031] As used herein, the term "Sortilin" may refer to full-length Sortilin (also referred to as immature Sortilin), including the signal peptide, the propeptide, the Vps10p domain, the 10CC domain, the transmembrane domain, and the large cytoplasmic tail. The term "Sortilin" may have the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 as defined in European Patent Application No. 21152638.9. Alternatively, the term may refer to mature Sortilin, including the Vps10p domain, the 10CC domain, the transmembrane domain, and the large cytoplasmic tail, and having the amino acid sequence of SEQ ID NO: 3 as defined in European Patent Application No. 21152638.9, or a naturally occurring fragment, homolog, or variant thereof. The terms "Sortilin" or "Sortilin molecule" are used interchangeably herein. It is understood that Sortilin can interact with a proneurotrophin molecule to form a Sortilin / pro-neurotrophin complex. This sortilin / pro-neurotrophin complex may or may not be able to interact with the p75NTR molecule to form a trimeric complex containing sortilin, proneurotrophin, and p75NTR, which is understood to be involved in deleterious biological responses such as initiating apoptosis in retinal and ganglion cells and regulating growth cone retraction of projecting axons (Jansen et al., 2007; Nykjaer et al., 2004; Santos et al., 2012; Skeldal et al., 2012).

[0032] As used herein, the term "pro-neurotrophin" refers to a larger precursor of a neurotrophin that undergoes proteolytic cleavage to generate the mature form of the neurotrophin. Neurotrophins are a family of proteins, commonly referred to as growth factors, that induce neuronal survival, development, and function. Pro-neurotrophins have biological activity and play different roles than their pro-neurotrophin counterparts, such as inducing apoptosis. Examples of pro-neurotrophins include pro-NGF, pro-BDNF, pro-NT3, and pro-NT4. Pro-neurotrophins may also regulate synaptic plasticity. While mature neurotrophins increase synaptic strength, in their precursor form, neurotrophins may weaken synapses.

[0033] The compounds of the present invention may be inhibitors, binders, modulators, or antagonists of Sortilin. As used herein, the terms "Sortilin antagonist", "Sortilin inhibitor", "Sortilin binder", or "Sortilin modulator" (used interchangeably) refer to substances that interfere with, block, or attenuate the effect of Sortilin protein binding to progranulin, or neurotensin or another extracellular ligand, or pro-neurotrophins (e.g., proNGF, proNT3, proBDNF), or inhibit the formation of a trimeric complex between Sortilin, p75NTR, and pro-neurotrophins. The term "Sortilin antagonist" also encompasses substances or agents that interfere with the formation of a high affinity trimeric complex. In the latter scenario, it is recognized that Sortilin can bind to p75NTR (but not proNGF) and, at the same time, p75NTR can bind to the NGF domain of proNGF, which may result in the formation of a trimeric complex. However, the resulting trimeric complex may have a lower affinity for its receptor and, as a result, a significantly reduced ability to trigger apoptosis via the above mechanisms. Skeldal et al. (2012) showed that the apoptotic function of the trimeric complex is abolished in the absence of sortilin in the intracellular domain. The term "sortilin antagonist" also includes substances or agents that interfere with, block, or attenuate the effect of sortilin protein interacting with p75NTR. This interaction may be completely prevented, in which case the formation of the trimeric complex is prevented, or may be only partially prevented, in which case the trimeric complex may form but with reduced biological efficacy. Skeldal et al. showed that the complex formation between sortilin and p75NTR relies on contact points in the extracellular domain of the receptor and that the interaction is critically dependent on a 23 amino acid sequence in the extracellular juxtamembrane region of p75NTR. Thus, sortilin antagonists may interfere with this 23 amino acid sequence or proximal sequences within the molecule.A "sortilin antagonist" may act as an inhibitor of the cellular uptake of a ligand, where the ligand may be progranulin, neurotensin, or BDNF.

[0034] R 1 , R 2 , and R 3 are preferably each independently selected from the group consisting of halo, (C1-C2)alkyl, and halo-(C1-C2)alkyl.

[0035] The alkyl and haloalkyl groups may be straight-chained or branched.

[0036] In a preferred embodiment of the present invention, R 1 , R 2 , and R 3 are each independently selected from F, CH3, and CF3. Most preferably, R 1 , R 2 , and R 3 For example, in exemplary compounds of the invention, R 1 , R 2 , and R 3 Each may be F, CH3, or CF3.

[0037] In another preferred embodiment of the present invention, R 4 (C4~C 10 )Aryl, halo-(C4-C 10 )aryl, (C3-C8)heteroaryl, halo-(C3-C 20 )heteroaryl, (C1-C4)-alkylene-(C4-C 10 )-aryl, (C1-C4)-alkylene-(C4-C 10 )-heteroaryl, (C1-C4)-alkylene-(3- to 10-membered heterocycle).

[0038] Heteroaryl may contain one, two or more heteroatoms. Preferably, heteroaryl contains one or two heteroatoms. The heteroatoms may be selected from N, S, or O. In groups where more than one heteroatom is present, the heteroatoms may be the same or different.

[0039] The aryl and heteroaryl groups may be monocyclic or bicyclic, preferably monocyclic. Preferably, the aryl and heteroaryl groups have 5 to 8 carbon atoms. The heteroaryl groups may have a ring size of 6 to 12 members, preferably 6 to 8 members.

[0040] The alkylene moieties of alkylene-aryl, alkylene-heteroaryl, and alkylene-(3- to 10-membered heterocycle) may be linear or branched. If desired, the alkylene moieties may be substituted with a halogen group such as F.

[0041] In some preferred embodiments, R 4 teeth, [ka] It is.

[0042] In another preferred embodiment of the invention, X is N and R 5 is selected from the group consisting of H, (C1-C3)-alkyl, and (C1-C3)haloalkyl.

[0043] In another preferred embodiment of the invention, X is N; X, R 4 , and R 5 together form a 5- to 10-membered heterocycle; which heterocycle is monocyclic or bicyclic and optionally substituted with one or more substituents independently selected from halo, -OH, carbonyl, (C1-C3)alkyl, halo-(C1-C3)alkyl, acetyl, and (C1-C3)alkoxy, and halo-(C1-C3)alkoxy.

[0044] The alkyl, haloalkyl, alkoxy, and haloalkoxy substituents may be straight or branched.

[0045] Substituents may be attached to any position of the aryl, heteroaryl, or heterocycle. One or more substituents may be attached to a carbon atom, a heteroatom, or a combination thereof. Preferably, there are no substituents or 1 to 5 substituents.

[0046] A heteroaryl or heterocycle may contain one, two or more heteroatoms. Preferably, a heteroaryl or heterocycle contains one or two heteroatoms. The heteroatoms may be selected from N, S, or O. In groups where more than one heteroatom is present, the heteroatoms may be the same or different.

[0047] The heterocycle may be aliphatic. The heterocycle may be monocyclic, bicyclic, or tricyclic. Preferably, the heterocycle is monocyclic or bicyclic. Preferably, the heterocycle has 5 to 10 members, more preferably 5 to 9 members.

[0048] The aryl and heteroaryl groups may be monocyclic, bicyclic, or tricyclic. Preferably, they are monocyclic or bicyclic. Preferably, the aryl and heteroaryl groups have a ring size of 5 to 10 members.

[0049] In some preferred examples of this embodiment, X is N; X, R 4 , and R 5 Together, [ka] Form.

[0050] Particular compounds of the invention are those listed below. [ka] (2S)-2-[(benzylcarbamoyl)amino]-5,5-dimethylhexanoic acid; [ka] (2S)-2-{[benzyl(methyl)carbamoyl]amino}-5,5-dimethylhexanoic acid; [ka] (2S)-2-{[(benzyloxy)carbonyl]amino}-5,5-dimethylhexanoic acid; [ka] (2S)-5,5-Dimethyl-2-[(morpholine-4-carbonyl)amino]hexanoic acid; or [ka] (2S)-5,5-Dimethyl-2-[(1,4-oxazepane-4-carbonyl)amino]hexanoic acid.

[0051] Preferably, the compound of formula (I) has the following configuration: [ka]

[0052] The inventors have discovered that the above compounds may not only be effective sortilin modulators, but may also be able to cross the blood-brain barrier, providing an opportunity to develop more effective treatments for diseases of the central nervous system.

[0053] The compounds of the present invention have a blood-brain K value of greater than 0.1. puu Such compounds are capable of crossing the blood-brain barrier and are suitable for use in treating disorders of the central nervous system, as described herein.

[0054] The compound has a K of 0.1 to 10, 0.1 to 5, 0.1 to 3, 0.1 to 2, 0.1 to 1, 0.1 to 0.8, 0.1 to 0.6, 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3, or 0.1 to 0.2. puu may have.

[0055] Alternatively, the compounds of the present invention are unable to cross the blood-brain barrier. Thus, the compounds of the present invention have a K puu may have.

[0056] Blood-brain K puu Methods for measuring are known to those skilled in the art and include, for example, the method described in Example 20 of European Patent Application No. 21194937.5.

[0057] In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention and one or more pharma- ceutically acceptable carriers, excipients and / or diluents.

[0058] In a third aspect of the invention there is provided a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use in therapy.

[0059] In a fourth aspect, there is provided a compound or pharmaceutical composition for use in the treatment or prevention of a neurodegenerative disorder, a psychiatric disorder, an inflammatory disorder, cancer, pain, diabetes mellitus, brain tumour, diabetic retinopathy, glaucoma, chronic pain, uveitis, cardiovascular disease, renal disease, psoriasis, an inherited eye condition, hearing loss, a disease characterised by misfolded tau, or a disease of the central nervous system. The disease of the central nervous system may be selected from neurodegenerative disorders including 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; psychiatric disorders including bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorders; hearing loss selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors (e.g., glioblastoma), retinopathies such as diabetic retinopathy, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau.

[0060] Preferably, the neurodegenerative disorder is selected from 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.

[0061] The psychiatric disorder is preferably selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder.

[0062] Preferably, the inflammatory disorder is selected from inflammatory diseases and neuroinflammation.

[0063] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0064] Preferably, the hearing loss is selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0065] Thus, in an embodiment, a compound for use according to the invention may disrupt the interaction between a sortilin molecule and a proneurotrophin molecule, or may disrupt the interaction between a sortilin molecule and a p75NTR molecule. The sortilin molecule may be mature sortilin.

[0066] In one embodiment of the fourth aspect there is provided a compound or pharmaceutical composition for use in the treatment or prevention of a disease of the central nervous system, the compound having a blood-brain K of greater than 0.1. puu has.

[0067] The compound has a K of 0.1 to 10, 0.1 to 5, 0.1 to 3, 0.1 to 2, 0.1 to 1, 0.1 to 0.8, 0.1 to 0.6, 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3, or 0.1 to 0.2. puu may have.

[0068] Preferably, the disease of the central nervous system is selected from: a neurodegenerative disorder selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; a psychiatric disorder selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; hearing loss selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors, retinopathy, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau.

[0069] In a fifth aspect of the invention there is provided the use of a compound according to the first aspect of the invention for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder, a psychiatric disorder, an inflammatory disorder, a lysosomal storage disease, cancer, pain, diabetes mellitus, retinopathies such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular disease, kidney disease, psoriasis, inherited eye conditions, chronic pain, hearing loss, or a disease characterised by misfolded tau. The compound may be used in the treatment or prevention of a disease of the central nervous system.

[0070] 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.

[0071] Preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy.

[0072] The neurodegenerative disorder is preferably characterized by misfolded TAR DNA binding protein 43 (tdp-43).In other words, the neurodegenerative disease is characterized by truncated tdp-43 and inclusions.Examples of such diseases include amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, and frontotemporal dementia.

[0073] Preferably, the psychiatric disorder is selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder.

[0074] Preferably, the inflammatory disorder is selected from inflammatory diseases and neuroinflammation.

[0075] Preferably, the lysosomal disease is NCL / Batten disease caused by mutations in the CLN genes CLN1 (ΡΡΤ1), CLN2 (ΤΡΡ1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ΑΡΡ13Α2), CLN13 (CTSF), CLN14 (KCTD7), CLCN6, and / or SGSH; Peyer's disease, Fabry's disease, Gaucher's disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysacharidoses (MPS) types I (Fuller's disease) / II (Hunter's disease) / IIIa (Sanfilippo disease type A) / IIIB (Sanfilippo disease type B) / IIIc (Sanfilippo disease type C) / II Id (Sanfilippo disease type D) / IVA (Morquio A) / IVB / VI / VII (Sly disease) / IX, mucolipisosis type III (I-cell disease) and type IV, multiple sulfatase deficiency; sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, fucosidosis, Schindler disease, metachromatic leukodystrophy caused by deficiency of either arylsulfatase A or saposin B, globoid cell leukodystrophy (Krabbe disease), Farber disease, Wolman disease and cholesterol ester storage disease, pycnodystostosis, cystinosis, Salla disease, Danon disease, Griscelli disease type 1 / 2 / 3, Hermansky-Pudlak syndrome Pudliak Disease, and Chediak-Higashi Syndrome.

[0076] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0077] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0078] Preferably, the hearing loss is selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0079] In a sixth aspect of the invention there is provided a method for treating or preventing a disease or condition responsive to sortilin modulation comprising administering a therapeutically effective amount of a compound according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

[0080] The compounds of the present invention may include isotopically labeled and / or isotopically enriched forms of the compounds. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds as described herein. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, for example: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Cl, etc.

[0081] The compounds of the present invention may be used as such or, where appropriate, as their pharmacologically acceptable salts (acid or base addition salts). The pharmacologically acceptable addition salts described below are intended to include the therapeutically active non-toxic acid and base addition salt forms that the compounds can form. Compounds that are basic in nature can be converted to pharma-ceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, and the like; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid, and the like. Compounds with acidic properties can be converted into pharmaceutically acceptable base addition salts by treating their acid form with a suitable base.Exemplary base addition salt forms include sodium salts, potassium salts, calcium salts, and salts with pharmaceutically acceptable amines, such as ammonia, alkylamines, benzathine, and amino acids, such as arginine and lysine.The term addition salts, as used herein, also includes the solvates that the compounds and their salts can form, such as hydrates, alcoholates, and the like.

[0082] Throughout this disclosure, a given chemical formula or name is intended to encompass all its pharma- ceutically acceptable salt forms, solvates, hydrates, N-oxides, and / or prodrug forms. It is to be understood that the compounds of the present invention encompass any and all hydrates and / or solvates of the compound formula. It is understood that certain functional groups, such as hydroxyl groups, amino groups, and similar groups, form complexes and / or coordination compounds with water and / or various solvents in the various physical forms of the compounds. Thus, the above formula should be understood to encompass and represent the various hydrates and / or solvates thereof.

[0083] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, with the concomitant transfer of a hydrogen ion. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which hydrogen ions can occupy more than one position of the heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be sterically locked into one form by appropriate substitution.

[0084] The compounds described herein may have asymmetry (e.g., one or more stereocenters). All stereoisomers, including enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, including by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are included in the present invention. Although cis and trans geometric isomers of the compounds of the present invention are described, they may be isolated as a mixture of isomers or as separated isomers.

[0085] In the case of compounds containing asymmetric carbon atoms, the present invention relates to D-form, L-form and D,L mixtures, and also to diastereomeric forms when there are two or more asymmetric carbon atoms. Compounds of the present invention containing asymmetric carbon atoms and generally occurring as racemates can be separated into optically active isomers in known manner, for example with optically active acids. However, it is also possible to use optically active starting materials from the beginning and obtain the corresponding optically active compounds or diastereomeric compounds later as final products.

[0086] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. A prodrug may be inactive when administered to a subject in need of treatment, but is converted to an active compound of the invention in the body. Typically, a prodrug is rapidly converted in the body, for example by hydrolysis in blood, to yield the parent compound of the invention. Prodrug compounds usually offer advantages of solubility, tissue compatibility, or delayed release in mammals (see Silverman, RB, 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, such as hydroxy, amino, or mercapto groups, present in the compounds of the invention such that the modifications are cleaved by routine manipulation or in the body to the parent compound of the invention. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxy functional groups, or phenylcarbamate derivatives of amino functional groups.

[0087] The term "treatment" as used herein may include prevention of the named disorder or condition, or the amelioration or elimination of the disorder once it has been established. The term "prevention" refers to the prevention of the named disorder or condition.

[0088] The methods described herein include those in which a subject has been identified as being in need of a particular treatment. Identification of a subject as being in need of such treatment may be at the discretion of the subject or a medical professional, and may be subjective (e.g., opinion) or objective (e.g., measurable by a laboratory or diagnostic method).

[0089] In other aspects, the methods herein include methods further comprising monitoring the subject's response to the administration of the treatment. Such monitoring may include periodic imaging or sampling of the subject's tissues, bodily fluids, specimens, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as in need of such treatment by assessing relevant markers or indicators of suitability for such treatment.

[0090] The present invention provides a method for monitoring the progress of a treatment. The method includes 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 a compound described herein) in a subject suffering from or susceptible to a disorder or a symptom thereof, and receiving a sufficient therapeutic amount of a compound described herein to treat the disease or a symptom thereof. The level of the marker determined by the method can be compared to known levels of the marker in healthy normal controls or other affected individuals to ascertain the disease status of the subject. In a preferred embodiment, a second level of the marker is determined in the subject at a time later than the time the first level is measured, and the two levels are compared to monitor the progress of the disease or the efficacy of the treatment. In certain preferred embodiments, a pre-treatment level of the marker is determined in the subject before initiating a treatment according to the invention; the efficacy of the treatment can then be determined by comparing the pre-treatment level of the marker to the level of the marker in the subject after treatment has been initiated.

[0091] The marker level or activity in the subject may be determined at least once. Comparison of the marker level with other measurements of the marker level, e.g., obtained earlier or later from the same patient, another patient, or a healthy individual, may be useful in determining whether the treatment of the present invention is having the desired effect, thereby allowing for dosage adjustments, if necessary. Measurement of the marker level may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or body fluid sample is first taken from the subject. Examples of suitable samples include blood samples, urine samples, tissue samples, oral or cheek cell samples, and hair samples including hair roots. Other suitable samples are known to those of skill in the art. Measurement of the protein and / or mRNA levels (e.g., marker levels) in the sample may be performed using any suitable method known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabeling / assay, blotting / chemiluminescence, real-time PCR, and the like.

[0092] In clinical use, the compounds disclosed herein are prepared into pharmaceutical compositions (or formulations) for various modes of administration. It is understood that the compounds of the present invention may be administered together with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein can be administered by any suitable route, preferably oral, rectal, nasal, topical (including ophthalmic, buccal, and sublingual), sublingual, transdermal, intrathecal, transmucosal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal). Other formulations can be conveniently presented as unit dosage forms (e.g., tablets and sustained release capsules), as liposomes, and can be prepared by any method well known in the pharmaceutical arts. Pharmaceutical formulations are usually prepared by mixing the active substance or its pharmaceutical acceptable salt with a conventional pharmaceutical acceptable carrier, diluent, or excipient. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc. Such formulations may contain other pharmacologically active substances and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc. Usually, the content of the active compound is 0.1-95% by weight of the formulation, preferably 0.2-20% by weight in parenteral formulations, and more preferably 1-50% by weight in oral formulations. These formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. These formulations may be prepared in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections in a conventional manner. Liquid preparations may be prepared by dissolving or suspending the active substance in water or other suitable solvents. Tablets and granules may be coated in a conventional manner. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds disclosed herein may be formulated in sustained release formulations.

[0093] The dosage level and frequency of administration of a particular compound will vary depending on a variety of factors, including the potency of the particular compound used, the metabolic stability and length of action of the compound, the age, weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combination, severity of the condition being treated, and the patient undergoing therapy. Daily dosages may range, for example, from about 0.001 mg to about 100 mg per kg of body weight, administered one or more times, for example, in single doses of about 0.01 mg to about 25 mg each. Typically, such dosages are given orally, although parenteral administration may be selected.

[0094] definition "Desired" or "desirably" means that the subsequently described event or circumstance may occur, but need not occur, and that the description encompasses instances where the event or circumstance occurs and instances where it does not occur.

[0095] The term "heteroatom" means O, N, or S.

[0096] The term "(C1-Cn) alkyl" refers to a linear, branched, or cyclic or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3, or n carbon atoms. n For an alkyl group to contain a cyclic moiety, it must be formed from at least three carbon atoms. nFor the range portion "(C1-C6)alkyl," all subgroups are contemplated. For example, the range (C1-C6)alkyl contemplates all subranges such as (C1-C5)alkyl, (C1-C4)alkyl, (C1-C3)alkyl, (C1-C2)alkyl, (C1)alkyl, (C2-C6)alkyl, (C2-C5)alkyl, (C2-C4)alkyl, (C2-C3)alkyl, (C2)alkyl, (C3-C6)alkyl, (C3-C5)alkyl, (C3-C4)alkyl, (C3)alkyl, (C4-C6)alkyl, (C4-C5)alkyl, (C4)alkyl, (C5-C6)alkyl, (C6)alkyl, etc. Examples of "C1-C6 alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, and branched, cyclic or partially cyclic pentyl and hexyl.

[0097] "Hello-(C1~C n The term "alkyl" refers to any C1-C alkyl group as defined above substituted with at least one halogen atom. n alkyl, the halogen atoms being preferably F, Cl, Br and I, more preferably F and Cl, most preferably F.

[0098] Where a term indicates a range (for example, "1 to 6 carbon atoms" in the definition of (C1-C6)alkyl), each integer, i.e., 1, 2, 3, 4, 5, and 6, is considered to be disclosed.

[0099] "(C2~C n The term "(C2-C)alkenyl" refers to a linear, branched, or cyclic or partially cyclic alkyl group having at least one carbon-carbon double bond and having 2 to 6 carbon atoms. The alkenyl group may contain a ring formed from 3 to 6 carbon atoms. nFor the range portion "(C2-C4)alkenyl", all subgroups thereof are contemplated. For example, the range "(C2-C4)alkenyl" includes (C2-C4)alkenyl, (C2-C3)alkenyl, and (C2)alkenyl. Examples of "(C2-C4)alkenyl" include 2-propenyl, 2-butenyl, 3-butenyl, or 2-methyl-2-propenyl.

[0100] The term "(C1-C4)alkoxy" refers to -O-((C1-C4)alkyl), where the (C1-C4)alkyl group is as defined above, attached to the remainder of the compound via an oxygen atom. Examples of "(C1-C4)alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy.

[0101] The term "halo(C1-C4)alkoxy" refers to a (C1-C4)alkoxy as above substituted with a halogen atom, preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0102] The term "halo" refers to a halogen atom, preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0103] The term "3- to 10-membered heterocycle" refers to a non-aromatic ring system having from 3 to 10 ring atoms, with at least one ring atom being a heteroatom.

[0104] An "effective amount" refers to that amount of a compound of the present invention that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0105] As used herein, the term "administration" or "administering" refers to a route of administration of the compounds disclosed herein. Exemplary routes of administration include, but are not limited to, oral administration, intraocular administration, intravenous administration, intraperitoneal administration, intraarterial administration, and intramuscular administration. The preferred route of administration may vary depending on a variety of factors, such as the components of a pharmaceutical composition that includes a compound disclosed herein, the site of potential or actual disease, and the severity of the disease.

[0106] The terms "subject" and "patient" are used interchangeably herein. The terms refer to a human or another mammal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that may be suffering from or susceptible to a disease or disorder, but may or may not have the disease or disorder. Preferably, the subject is a human.

[0107] As defined herein, a "lysosomal storage disease" (LSD) is any disorder characterized by impaired lysosomal function and the accumulation of intracellular stores of polymeric substrates. In some embodiments, the lysosomal storage disease is an inherited / genetic disorder. The lysosomal storage disease can be a disorder with a primary lysosomal origin. Lysosomal storage diseases include a number of rare genetic disorders, which are most often inherited in a recessive manner. In all of these cases, restoring lysosomal integrity and function has the potential to ameliorate a range of cellular and systemic pathologies.

[0108] As defined herein, neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of LSDs characterized by accumulation of autofluorescent storage material (ASM) in lysosomes, neuroinflammation and neurodegeneration, neurological symptoms, and early death. NCL is caused by mutations in one of 13 genes and is typically inherited in an autosomal recessive manner.

[0109] The compounds of the invention may be disclosed by their name or by their chemical structure. If a discrepancy exists between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0110] The present invention will now be further described by the following non-limiting examples. The following specific examples are to be construed as merely illustrative, and not limiting to the remainder of the disclosure in any way. Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent based on the description herein. All references and publications cited herein are hereby incorporated by reference in their entirety.

[0111] Preparation of the Compounds of the Invention The compounds of the present invention can be prepared according to the following general synthetic method Scheme 1 by methods well known and well understood in the art. Suitable reaction conditions are well known in the art, and appropriate substitution of solvents and co-reagents is within the common general knowledge of one of ordinary skill in the art. Similarly, one of ordinary skill in the art will understand that synthetic intermediates may be isolated and / or purified by various well-known techniques, as necessary or desired, and often various intermediates can be used directly in subsequent synthetic steps with little or no purification. Furthermore, one of ordinary skill in the art will understand that in some cases the order in which each moiety is introduced is not critical. As will be well understood by one of ordinary skill in the art, the particular order of steps required to produce a compound of formula (I) will depend on the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties. All substituents are as defined above unless otherwise indicated, and all reagents are well known and well understood in the art. [ka]

[0112] General synthesis, Scheme 1 Suitable starting materials are optically active and protected amino acids of general formula AA-1, either as single enantiomers or as racemic mixtures, which may be commercially available or prepared by various methods. For example, as shown in the general synthesis scheme 1, the carboxylic acid function of appropriately substituted amino acids of general formula AA-1 may be used as the free acid (PG=H) or may be protected as a suitable derivative, for example as a methyl ester. The introduction of a substituent on the primary amine present in AA-1 may be carried out in various ways, and for illustrative purposes may be carried out by a condensation step using a suitable acyl reagent (such as, but not limited to, carbonyldiimidazole, phosgene, or triphosgene) and the starting material AA-1 or a suitably substituted amine A-1 in a suitable solvent, such as, but not limited to, dichloromethane. It will be understood by those skilled in the art that the urea-forming reaction or the carbamate-forming reaction may be carried out in a single step, or in successive steps in the same reactor, or in separate successive steps.

[0113] General synthesis method The compounds of general formula (I) may be prepared in a variety of ways, some of which are described below. The products of each step may be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.

[0114] Compounds of general formula (I) contain one or more stereocenters. These stereocenters can be introduced from starting materials of the AA-1 type, which are available as single enantiomers, with optical activity. The integrity of existing stereocenters can be confirmed by analytical techniques well known to those skilled in the art, such as chiral-supported high-pressure chromatography. Alternatively, it will be understood that when racemic starting materials are used, single isomeric products can be obtained as single enantiomers or as single diastereoisomers, if desired, by known techniques such as preparative chiral-supported high-pressure chromatography.

[0115] It is also understood by those skilled in the art that not all of the substituents in the compound of formula (I) are tolerant of a particular reaction condition employed to synthesize the compound. As is well known in the art, these moieties may be introduced at any convenient time during synthesis, or may be protected and subsequently deprotected as necessary or desired. It is also understood by those skilled in the art that these protecting groups may be removed at any convenient time during the synthesis of the compound 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). EXAMPLES

[0116] Abbreviation approx: approximately; aq: aqueous solution; br: broad; ca.: approximately; CDI: 1,1'-carbonyldiimidazole; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl; h: time; min: minute; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V); HPLC: high performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: mole, molecular ion; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: quartet; rt: room temperature (approximately 20°C); R T: residence time; s: singlet, solid; SPPS: solid phase peptide synthesis; t: triplet; TBAF: tetrabutyl ammonium fluoride; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra-performance liquid chromatography; UV: ultraviolet.

[0117] Other abbreviations are intended to convey the generally accepted meaning.

[0118] Normal experimental conditions All starting materials and solvents were obtained from commercial sources or prepared from literature references. Unless otherwise noted, reaction mixtures were magnetically stirred and each reaction was carried out at room temperature (approximately 20° C.).

[0119] Unless otherwise stated, column chromatography was carried out using prepacked silica (40 μm) cartridges on an automated flash chromatography system such as a CombiFlash Rf system.

[0120] 1 H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane unless otherwise stated. The following abbreviations or combinations of abbreviations are used for the multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0121] Example 1 [ka]

[0122] Synthesis of (S)-2-(3-benzylureido)-5,5-dimethylhexanoic acid Benzyl isocyanate (0.058 mL, 0.471 mmol) was added to a mixture of (S)-2-amino-5,5-dimethylhexanoic acid (50 mg, 0.314 mmol) and DIPEA (0.165 mL, 0.942 mmol) in N,N-dimethylformamide (anhydrous) (1 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by acidic prep (Method 2). The fractions containing the product were combined and lyophilized. This gave (S)-2-(3-benzylureido)-5,5-dimethylhexanoic acid (57 mg, 0.195 mmol, 62% yield) as a white solid. LCMS (Method 1, 0.930 min; M+H=293.1; calculated 293.1). 1 H-NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.36 - 7.18 (m, 5H), 6.47 (t, J = 6.1 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 4.20 (d, J = 6.0 Hz, 2H), 4.14 - 4.04 (m, 1H), 1.70 - 1.58 (m, 1H), 1.58 - 1.45 (m, 1H), 1.22 - 1.13 (m, 2H), 0.85 (s, 9H).

[0123] Example 2 [ka]

[0124] Synthesis of (S)-2-(3-benzyl-3-methylureido)-5,5-dimethylhexanoic acid Phenyl chloroformate (0.073 ml, 0.577 mmol) was added to a mixture of (S)-methyl 2-amino-5,5-dimethylhexanoate hydrochloride (100 mg, 0.477 mmol) and DIPEA (0.302 ml, 1.732 mmol) in acetonitrile (anhydrous) (1 ml). The mixture was stirred for 4 h. N-methylbenzylamine (0.112 ml, 0.866 mmol) was added. The mixture was stirred for 2 days. LiOH (75 mg, 3.13 mmol) and water (1 mL) were added. The mixture was stirred at 50° C. overnight. 1M HCl was added and the mixture was extracted with EtOAc. The solvent was evaporated and the product was purified by the preparation under acidic conditions (Method 2). The product-containing fractions were combined and lyophilized to give (S)-2-(3-benzyl-3-methylureido)-5,5-dimethylhexanoic acid (68.7 mg, 0.224 mmol, 46% yield). LCMS (Method 1, 0.985 min; M+H=307.2; calculated 307.2). 1 H-NMR (400 MHz, DMSO) δ12.36 (s, 1H), 7.35 - 7.29 (m, 2H), 7.27 - 7.23 (m, 1H), 7.23 - 7.19 (m, 2H), 6.41 (d, J = 7.9 Hz, 1H), 4.44 (dd, J = 22.2, 15.7 Hz, 2H), 4.00 (td, J = 8.7, 5.4 Hz, 1H), 2.77 (s, 3H), 1.75 - 1.53 (m, 2H), 1.26 (td, J = 12.6, 4.8 Hz, 1H), 1.14 (td, J = 12.5, 5.0 Hz, 1H), 0.85 (s, 9H).

[0125] Example 3 [ka]

[0126] Synthesis of (S)-2-(((benzyloxy)carbonyl)amino)-5,5-dimethylhexanoic acid Benzyl chloroformate (0.082 ml, 0.577 mmol) was added to a mixture of (S)-methyl 2-amino-5,5-dimethylhexanoate hydrochloride (100 mg, 0.477 mmol) and DIPEA (0.302 ml, 1.732 mmol) in acetonitrile (anhydrous) (1 ml). The mixture was stirred at room temperature overnight. 1 mL of water and lithium hydroxide (75.0 mg, 3.13 mmol) were added and the mixture was stirred at 40° C. overnight. The crude mixture was purified by preparation under acidic conditions (Method 2). The product-containing fractions were combined and lyophilized to give (S)-2-(((benzyloxy)carbonyl)amino)-5,5-dimethylhexanoic acid (42.1 mg, 0.138 mmol, 28% yield). LCMS (Method 1, 1.025 min; M+H=294.2; calculated 294.2; M+H-CO2=250.2; calculated 250.2). 1 H-NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.39 - 7.28 (m, 5H), 5.03 (s, 2H), 3.87 (td, J = 8.7, 4.6 Hz, 1H), 1.72 - 1.61 (m, 1H), 1.61 - 1.48 (m, 1H), 1.31 - 1.11 (m, 2H), 0.84 (s, 9H).

[0127] Example 4 [ka]

[0128] Synthesis of (S)-5,5-dimethyl-2-(morpholine-4-carboxamido)hexanoic acid Morpholine-4-carbonyl chloride (178 mg, 1.19 mmol) was added to a solution of (S)-methyl 2-amino-5,5-dimethylhexanoate hydrochloride (100 mg, 0.477 mmol) and DIPEA (0.291 mL, 1.67 mmol) in dichloromethane (1 mL). The solvent was removed. The product was dissolved in 2 mL of acetonitrile:water (1:1). Lithium hydroxide (57.1 mg, 2.38 mmol) was added and the mixture was stirred at 40° C. overnight. This crude mixture was purified by preparation under acidic conditions (Method 2). The product-containing fractions were combined and lyophilized to give (S)-5,5-dimethyl-2-(morpholine-4-carboxamido)hexanoic acid (97.3 mg, 0.357 mmol, 74% yield). LCMS (Method 1, 0.742 min; M+H=273.2; calcd. 273.2). 1 H-NMR (400 MHz, DMSO) δ 7.57-6.55 (br, 1H), 6.39 (d, J = 6.8 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.54 (t, J = 4.9 Hz, 4H), 3.26 - 3.16 (m, 5H), 1.71 - 1.57 (m, 1H), 1.57 - 1.46 (m, 1H), 1.23 - 1.07 (m, 2H), 0.82 (s, 9H).

[0129] Example 5 [ka]

[0130] Synthesis of (S)-5,5-dimethyl-2-(1,4-oxazepane-4-carboxamido)hexanoic acid Phenyl chloroformate (0.060 mL, 0.477 mmol) was added to a solution of (S)-methyl 2-amino-5,5-dimethylhexanoate hydrochloride (100 mg, 0.477 mmol) and DIPEA (0.333 mL, 1.907 mmol) in dichloromethane (1 mL). The mixture was stirred for 1 h. Homomorpholine hydrochloride (131 mg, 0.954 mmol) was added and the mixture was stirred overnight. The solvent was removed. The product was dissolved in 2 mL of acetonitrile:water (1:1). Lithium hydroxide (57.1 mg, 2.38 mmol) was added and the mixture was stirred overnight at 40° C. The crude mixture was purified by the preparation under acidic conditions (Method 2). The product-containing fractions were combined and lyophilized to give (S)-5,5-dimethyl-2-(1,4-oxazepane-4-carboxamido)hexanoic acid (74.7 mg, 0.261 mmol, 54% yield). LCMS (Method 1, 0.752 min; M+H=287.2; calculated 287.2). 1 H-NMR (400 MHz, DMSO) δ 7.67- 6.50 (br, 1H), 6.17 (d, J = 6.8 Hz, 1H), 3.84 (q, J = 6.6 Hz, 1H), 3.67 - 3.51 (m, 4H), 3.43 (q, J = 4.7 Hz, 4H), 1.85 - 1.71 (m, 2H), 1.69 - 1.58 (m, 1H), 1.59 - 1.46 (m, 1H), 1.20 - 1.07 (m, 2H), 0.83 (s, 9H).

[0131] Method information Method 1: Method 1: UPLC_AN_BASE, Instrument: Waters IClass; Binary Pump: UPIBSM, SM: UPISMFTN, 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 × 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, Post time: 0.3 min, Eluent A: 10 mM ammonium bicarbonate aqueous solution (pH = 9.5), Eluent B: acetonitrile.

[0132] Method 2: Instrument: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 Prep LC; Column: Waters XSelect CSH (C18, 100×30 mm, 10μ); Flow rate: 55 ml / min; Column temperature: room temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; Detection: DAD (220-320 nm); Detection: MSD (ESI positive / negative) Mass range: 100-1000; Fraction collection based on MS and DAD.

[0133] Biological Data Neurotensin scintillation proximity assay Exemplary compounds of the invention were tested in the Neurotensin (NTS) Scintillation Proximity Assay (SPA). IC 50 The data are shown in Table 1 below. NTS is a 13 amino acid neuropeptide and a ligand for sortilin. IC 50 IC is a measure of the amount of compound required to inhibit 50% of NTS binding to sortilin. 50 It will be appreciated by those of skill in the art that the lower the value, the less compound is needed to achieve the desired effect, thereby reducing the chance of unwanted off-target effects.

[0134] The affinity of the compound to bind to h-sortilin in the SPA format [ 3 H]-neurotensin displacement was measured in a total volume of 40 μl in 50 mM HEPES (pH 7.4) assay buffer containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween-20. Compounds were preincubated with 150 nM 6his-sortilin for 30 min at room temperature, followed by addition of 5 nM [3H]-neurotensin and Ni-chelating imaging beads (PerkinElmer), and plates were read 6 h later on a ViewLux with a 360 s exposure time. Dose-response evaluation of compounds was performed using eight drug concentrations (spanning three decades of concentrations). IC 50 Values ​​were calculated by nonlinear regression with sigmoidal concentration-response (variable slope) using CDD Vault software. All values ​​reported are the average of at least two determinations.

[0135] The data in Table 1 below demonstrate that the compounds disclosed herein are sortilin inhibitors. [Table 1]

[0136] X-ray data Materials and Methods The luminal domain of sortilin, sSortilin, was obtained as previously reported (Andersen et al., Acta Cryst. D, 2017). Prior to crystallization, 12 μl of 4 mg / ml sSortilin in 50 mM Tris-HCl (pH 8.0), 150 mM NaCl was mixed with 1.2 μl of two compounds (Example 1 and Example 2) dissolved in DMSO at concentrations of 15.1 mM and 18.8 mM, respectively.

[0137] Sitting drops were set up by adding 2 μL of the sortilin-ligand mixture to 2 μL of reservoir solution consisting of 100 mM Hepes pH 7.3, 400 mM malonic acid (pH 7.3), 8% v / v glycerol, and 22.5% w / v PEG3350. The sitting drop was left to equilibrate by vapor diffusion with 500 μL of reservoir solution. Crystals were mounted in litho loops without further cryoprotection and flash frozen in liquid nitrogen. Diffraction data were collected at beamline P13 EMBL / DESY (Hamburg) and processed using the XDS package (Kabsch, W., Acta Cryst. D, 2010).

[0138] The phases of the structure factors were obtained by molecular replacement using the Phaser program implemented in the Phenix software package (Afonine et al., Acta Cryst. D, 2012) using the known structure of sortilin (PDB entry: 3F6K) as a search model. Refined models were obtained by several model building cycles in Coot (Emsley P. et al., Acta Cryst. D, 2010) and maximum likelihood refinement using Phenix. The resulting X-ray derived images of the compounds of Examples 1 and 2 bound to h-sortilin are shown in Figures 1 and 2, respectively.

[0139] The refinement statistics and the agreement of these models with the standard geometries of the compounds of Examples 1 and 2 are shown in Tables 2 and 3, respectively. [Table 2] 1 and 2 show X-ray derived images of the compound of Example 1 bound to h-Sortilin. [Table 3]

[0140] Figures 3, 4 and 5 show X-ray derived images of the compound of Example 2 bound to h-Sortilin.

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Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; During the ceremony, X is selected from N and O; R １ , R ２ , and R ３ are each independently halo, H, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkenyl, and halo-(C ２ ~C ４ ) alkenyl; and, R ４ (C ３ ~C ２０ ) aryl, halo-(C ３ ~C ２０ ) aryl, (C ３ ~C ８ ) heteroaryl, halo-(C ３ ~C ２０ ) heteroaryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-aryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-heteroaryl, (C １ ~C ６ )-alkylene-(3- to 10-membered heterocycle); (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-aryl, an aryl group in (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-heteroaryl group in the heteroaryl, or (C １ ~C ６ The heterocycle in the -alkylene-(3- to 8-membered heterocycle) is optionally selected from halo, H, —OH, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, and halo-(C １ ~C ４ ) alkoxy; When X is O, R ５ does not exist; When X is N, R ５ is halo, H, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkenyl, and halo-(C ２ ~C ４ ) alkenyl; or, When X is N, X, R ４ , and R ５ taken together form a 4- to 20-membered heterocycle; the heterocycle may be monocyclic, bicyclic, or tricyclic, and may optionally include halo, —OH, cyano, carbonyl, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, acetyl, (C １ ~C ４ ) alkoxy, and halo-(C １ ~C ４ ) alkoxy; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

2. R １ , R ２ , and R ３ are each independently halo, (C １ ~C ２ ) alkyl, and halo-(C １ ~C ２ 2. The compound of claim 1, wherein said alkyl is selected from the group consisting of:

3. R １ , R ２ , and R ３ are each independently F, CH ３ , and C.F. ３ 3. The compound according to claim 1 or claim 2, selected from:

4. R ４ But (C ４ ~C １０ ) aryl, halo-(C ４ ~C １０ ) aryl, (C ３ ~C ８ ) heteroaryl, halo-(C ３ ~C ２０ ) heteroaryl, (C １ ~C ４ )-alkylene-(C ４ ~C １０ )-aryl, (C １ ~C ４ )-alkylene-(C ４ ~C １０ )-heteroaryl, and (C １ ~C ４ 4. The compound according to claim 1, wherein the aryl group is selected from the group consisting of aryl, aryl- ...

5. R ４ but, 【Chemistry 2】 The compound according to any one of claims 1 to 4,

6. X is N and R ５ H, (C １ ~C ３ )-alkyl, and (C １ ~C ３ 6. The compound according to claim 1, wherein the compound is selected from the group consisting of haloalkyl.

7. X is N; X, R ４ , and R ５ taken together form a 5- to 10-membered heterocycle; said heterocycle is monocyclic or bicyclic and optionally contains halo, —OH, carbonyl, (C １ ~C ３ ) alkyl, halo-(C １ ~C ３ ) alkyl, acetyl, and (C １ ~C ３ ) alkoxy, and halo-(C １ ~C ３ 4. The compound according to claim 1, substituted with one or more substituents independently selected from: aryl, aryloxy, arylsulfate, arylsulfuric acid ...

8. X is N; X, R ４ , and R ５ Together, 【Chemistry 3】 8. The compound of claim 7, wherein

9. The compound of formula (I) (2S)-2-[(benzylcarbamoyl)amino]-5,5-dimethylhexanoic acid; (2S)-2-{[benzyl(methyl)carbamoyl]amino}-5,5-dimethylhexanoic acid; (2S)-2-{[(benzyloxy)carbonyl]amino}-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[(morpholine-4-carbonyl)amino]hexanoic acid; or (2S)-5,5-Dimethyl-2-[(1,4-oxazepane-4-carbonyl)amino]hexanoic acid The compound according to any one of claims 1 to 8,

10. Blood-brain K exceeding 0.1 ｐｕｕ The compound according to any one of claims 1 to 9, having the formula:

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and one or more pharma- ceutically acceptable carriers, excipients and / or diluents.

12. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in therapy.

13. 12. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in the treatment or prevention of a neurodegenerative disorder, a psychiatric disorder, an inflammatory disorder, a lysosomal storage disorder, cancer, pain, diabetes mellitus, retinopathies such as diabetic retinopathy, brain tumours, glaucoma, chronic pain, uveitis, cardiovascular disease, kidney disease, psoriasis, inherited eye conditions, hearing loss, a disease characterised by misfolded tau, or a disease of the central nervous system.

14. The neurodegenerative disorder is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke, preferably the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy; preferably the neurodegenerative disorder is characterized by misfolded TAR DNA binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia; the psychiatric disorder is selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; The lysosomal storage disease is NCL / Batten disease caused by mutations in the CLN genes CLN1 (ΡΡΤ1), CLN2 (ΤΡΡ1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ΑΡΡ13A2), CLN13 (CTSF), CLN14 (KCTD7), CLCN6, and / or SGSH; Pompe disease, Fasciopathy, and the like. Brie disease, Gaucher disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysaccharidoses (MPS) types I (Fuller disease), II (Hunter disease), IIIa (Sanfilippo disease type A), IIIB (Sanfilippo disease type B), IIIc (Sanfilippo disease type C), IIId (Sanfilippo disease type C), IIIe (Sanfilippo disease type D), IIIf (Sanfilippo disease type F), IIIg (Sanfilippo disease type G), IIIh (Sanfilippo disease type H), IIIi (Sanfilippo disease type I), IIIj ... Ilippo disease type D) / IVA (Morquio disease type A) / VB / VI / VII (Sly disease) / IX, mucolipidosis type III (I-cell disease) and type IV, multiple sulfatase deficiency; sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, fucosidosis , Schindler's disease, metachromatic leukodystrophy caused by deficiency of either arylsulfatase A or saposin B, globoid cell leukodystrophy (Krabbe's disease), Farber's disease, Wolman's disease and cholesterol ester storage disease, pycnodystostosis, cystinosis, Salla's disease, Danon's disease, Griscelli disease types 1 / 2 / 3, Hermansky Pudliak Disease, and Chediak-Higashi syndrome; the inflammatory disorder is selected from an inflammatory disease and neuroinflammation; the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; The cardiovascular disease is preferably selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; The hearing loss is selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; 14. A compound or pharmaceutical composition for use according to claim 13.

15. The compound has a blood-brain K of greater than 0.1 ｐｕｕ having the compound or pharmaceutical composition is for use in the treatment or prevention of a disease of the central nervous system; Preferably, the disease of the central nervous system is selected from 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; psychiatric disorders selected from bipolar disorder, major depression, post-traumatic stress disorder, and anxiety disorder; hearing loss selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors, retinopathy, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau.

15. A compound or pharmaceutical composition for use according to claim 13 or claim 14.

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