Sortiline modulators

Abstract

The present invention relates to compounds of formula (I) 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 selected proteins is beneficial.

Description

Technical Field

[0001] This invention relates to compounds of formula (I), which have been unexpectedly found to regulate 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 regulation of sortilin activity is beneficial. In particular, the compounds of the invention can cross the blood-brain barrier and are therefore particularly useful for the treatment of diseases of the central nervous system. The compounds of the invention may also have an enhanced half-life in vivo. Background Technology

[0002] Selectin is a type I transmembrane protein that acts as a receptor for several ligands (Petersen et al., 1997). Selectin is highly expressed in neurons and microglia of 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 its role as a receptor involved in signal transduction, selectin also mediates the sorting of selected carriers between the cell surface, the trans-Golgi network, and the endosome pathway (Nykjaer & Willnow, 2012; Willnow, Petersen, & Nykjaer, 2008). Selectin contains a large extracellular domain called VPS10, which defines a family of receptors known as selectin or VS10p domain receptors. The VPS10P domain in the selected protein is homologous to yeast VPS10P and consists of a 10-lobed β-propeller-like structure and a cysteine-rich 10CC module (Nykjaer & Willnow, 2012; Zheng, Brady, Meng, Mao, & Hu, 2011).

[0003] Selectin binds to a variety of ligands, including pro-nerve growth factor (pro-NGF), pro-BDNF, proneurotrophin-3, neurotensin, and ApoB (Chen et al., 2005; Kjolby et al., 2010; Mazella et al., 1998; Nykjaer et al., 2004; Quistgaard et al., 2009; Yano, Torkin, Martin, Chao, & Teng, 2009). Furthermore, selectin binds to progranulin precursor (PGRN), a secreted protein involved in numerous cellular functions, including lysosomal fixation, anti-inflammatory responses, and neurotrophic stimulation (Galimberti, Fenoglio, & Scarpini, 2018). Selectin targets PGRN for rapid endocytosis and degradation, and it is now widely recognized as the most important clearance receptor for PGRN (Hu et al., 2010). Therefore, the select protein negatively regulates the extracellular levels of PGRN in the periphery and brain. In fact, the absence or blockage 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, and haploinous insufficiency of the PGRN gene accounts for up to 25% of all cases (Gijselinck, Van Broeckhoven, & Cruts, 2008). Patients with heterozygous loss-of-function mutations in PGRN have >50% reduced extracellular levels of this protein and will always develop FTD, making PGRN a pathogenic 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 (Brouwerset et al., 2008; Sheng, Su, Xu, & Chen, 2014), and high levels of extracellular PGRN have a protective effect 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 selectin expression to trigger its function. Therefore, neurons lacking selectin expression also respond to PGRN-induced neuronal outgrowth (De Muynck et al., 2013; Gass, Lee, et al., 2012). Furthermore, PGRN was successfully delivered to neuronal lysosomes in selectin-deficient cells, indicating the existence of alternative transport pathways. In fact, PGRN can bind to the lysosomal protein prosaponin (PSAP). When PSAP binds to its homologous receptors, namely the cation-independent mannose-6-phosphate receptor and LRP1, it carries PGRN to the lysosome (Zhou et al., 2015). Finally, in a phase II clinical trial using a monoclonal anti-selectin antibody, markers of 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 enhances Aβ endocytosis in microglia (Martens et al., 2012; Pickford et al., 2011; Yin et al., 2010).

[0007] The binding of PGRN to the selectin requires three amino acids from the C-terminus of PGRN (QLL in humans and PLL in mice), and peptides derived from the last 24 amino acids of PGRN bind with similar affinity to the full-length protein (Zheng et al., 2011). This binding mode is structurally similar to neurotensin binding (Zheng et al., 2011), i.e., binding at the NTIS1 binding site of the selectin. Small molecule screening has been successfully completed in collaboration with Aarhus University, identifying inhibitors of neurotensin-selectin binding (Andersen et al., 2014; Schroder et al., 2014).

[0008] Selectins exist as full-length, sorting receptors, but can also form multimeric signal transduction receptor-ligand complexes. A portion of selectins can also be released from the plasma membrane to clear ligands (NTs in pain) and control ligand activity. For example, selectins participate in synaptic plasticity by controlling the rate of conversion of pro-BDNF to BDNF. This may also apply to other proneurotrophic proteins.

[0009] Finally, the selectin's propeptide, also known as spatin, is a ligand for the receptor of the membrane transporter TREK-1, which has been shown to control the activity of this protein and is a target of diseases such as major depressive disorder. Structurally, the selectin has the amino acid sequence according to SEQ ID NO:1 and comprises a signal peptide, a propeptide, a Vps10p domain, a 10cc domain (10CCa+10CCb), a transmembrane domain, and a cytoplasmic tail. The selectin's luminal domain has six potential N-linked glycosylation sites, while the cytoplasmic tail can recruit a variety of adaptor proteins.

[0010] Selectin binds to a large number of ligands and membrane receptors, and thus participates in functions known to be important in cell signaling and sorting. For example, selectin is involved in signal transduction via pro-neurotrophins: namely, the precursors of nerve growth factor (pro-NGF), brain-derived neurotrophic factor (pro-BDNF), and neurotrophin-3 (proNT3). Selectin complexes with the protein p75NTR (p75 neurotrophin receptor) to form a receptor for pro-neurotrophin-mediated apoptosis, leading to degeneration and cell death in cell and animal models (Jansenet et al., 2007; Tenket et al., 2005; Nykjaer et al., 2004).

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

[0012] In addition, plasma selectin levels have been reported as a potential biomarker for identifying patients with coronary heart disease or diabetes (Oh et al., 2017). (et al., 2021). Patients with elevated selectin levels in their plasma, thus identifiable as having the above conditions, also showed enhanced glucose levels, suggesting selectin as a therapeutic target for these conditions. Soluble selectin has also been proposed as a treatment for type 2 diabetes (WO2021116290 A1, 2021).

[0013] TAR DNA-binding protein 43 (TDP-43) is associated with a variety of neurodegenerative diseases. For example, TDP-43 inclusion bodies have been found in cases of amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD), and Alzheimer's disease (AD) (Meneses et al., 2021).

[0014] TDP-43 regulates the splicing of several gene products, including selectin. In humans, splicing involves the inclusion of cryptic exon 17b (between exons 17 and 18), which introduces a stop codon in the stem, potentially producing a non-membrane-bound fragment (Prudencio et al., 2012). Furthermore, PGRN has been shown to reduce levels of insoluble TDP-43 and slow axonal degeneration (Beelet et al., 2018). Selectin inhibition increases PGRN levels and may therefore be beneficial for the treatment of neurodegenerative diseases involving TDP-43.

[0015] Selectins are associated with a variety of conditions affecting the central nervous system (CNS). Some studies have shown the role of circulating selectins in patients with mental disorders such as depression, which may be related to altered neurotrophic factor activity (Buttenshon et al., 2015); and selectins have also been reported to play a role in brain aging, Alzheimer's disease, and frontotemporal dementia (Xu et al., 2019). However, delivering therapeutics capable of crossing the blood-brain barrier to the CNS presents significant challenges.

[0016] The blood-brain barrier is a highly selective semi-permeable boundary of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the CNS, where neurons reside. Therefore, the treatment of neurological diseases is limited due to the restricted penetration of therapeutic agents across the blood-brain barrier.

[0017] Therefore, therapeutic agents used to treat CNS diseases must be able to cross the blood-brain barrier. In addition, they must have sufficient unbound drug concentrations in the brain, because the free drug hypothesis states that only unbound compounds can interact and cause pharmacological effects.

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

[0019] F ub =C PBS / C 血浆

[0020] Where C PBS and C 血浆 The concentrations of the analyte in PBS (acceptor) and plasma (donor), respectively.

[0021] Recovery samples can be prepared under each condition (but without dialysis), and they can be used to evaluate the recovery from dialysis experiments using the following formula:

[0022] % recovery rate = 100 × (V PBS ×C PBS +V 血浆 ×C 血浆 ) / V 血浆 C 回收率 Where V PBS It is the volume of the receiving side (PBS) of the dialysis device, and V 血浆 This refers to the volume of the donor side (plasma) in the dialysis unit. C 回收率 This is the concentration of the analyte measured from the recovery sample. Compounds such as propranolol or fluoxetine can be included in the experiment as controls.

[0023] Unconjugated fraction of the brain (F ub,脑 ) can be based on the measured values ​​(F) in the homogeneous brain tissue. ub,测量 Calculations showed that the dilution factor used in preparing the brain homogenate was taken into account:

[0024]

[0025] Where D = dilution factor.

[0026] Brain / plasma unbound partition coefficient (K) puu This can be determined as the ratio between the concentrations of plasma and free compounds in the brain:

[0027]

[0028] Where C u,脑 = Unbound concentration in the brain (C×F) ub,脑 );

[0029] in:

[0030] C = concentration at steady state; and

[0031] C ub,血浆 = Unbound concentration in plasma (C×F) ub ).

[0032] Alternatively, the ratio of AUC can be used to determine K. puuThe target compound is administered to the relevant target species at a known concentration via oral or intravenous route. The time course of compound concentrations in plasma and cerebrospinal fluid (CSF) is measured. Plasma concentrations are corrected to account for the unbound fraction of the compound. The area under the curve (AUC) for CSF concentrations and the area under the curve (AUC) for the free plasma fraction are calculated using known methods, and the ratio is determined to be given.

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

[0034] For the treatment of CNS diseases, the expectation is that K puu It has the highest possible value above 0. A value of approximately 1 indicates that the free fraction of the compound freely permeates the blood-brain barrier; a value above 1 indicates active inflow and transport mechanisms involved at the blood-brain barrier; a value less than 1 indicates that the free fraction of the compound has poor permeability or is recognized by active efflux mechanisms, thereby reducing exposure in the CNS and returning back to plasma or CSF through the blood-brain barrier. K puu A value of 0 or close to 0 indicates that the compound has poor permeability or a highly active efflux mechanism, which in any case is unlikely to achieve meaningful exposure of the desired active substance in the CNS.

[0035] In addition to effectively targeting and binding to select proteins, compounds that can be used to modulate the activity of select proteins in a target body preferably have optimized pharmacokinetics. This can be equated, for example, to an extended in vivo half-life or improved delivery to the target tissue. Increased persistence of such compounds in the target body is an important clinical parameter. This determines the required dose and frequency of administration of the compound, as well as the formulation requirements necessary to achieve the desired therapeutic effect after administration.

[0036] An increased in vivo half-life ensures that a compound remains therapeutically effective in the subject for as long as possible before being metabolized or excreted by the body. This allows for the administration of therapeutic compounds at lower effective doses and / or lower dosing frequencies. Therefore, compounds with such prolonged half-lives have significant pharmaceutical implications.

[0037] The inventors have designed compounds that can modulate the activity of select proteins, as disclosed in European application No. EP22193792.3, the entire contents of which are incorporated herein by reference.

[0038] In light of the above, there is an unmet need for additional compounds that can be used to treat and prevent medical conditions in which the regulation of selectin is beneficial. In particular, there is an unmet need for additional selectin modulators that can cross the blood-brain barrier and thus be used to treat central nervous system disorders. Furthermore, there is a need for selectin modulators with enhanced in vivo half-lives. Summary of the Invention

[0039] Surprisingly, compounds of formula (I) have been found to regulate the activity of selectin and therefore can be used to treat or prevent conditions in which regulation of selectin is beneficial. Furthermore, these compounds can cross the blood-brain barrier and are therefore particularly useful for treating diseases of the central nervous system.

[0040] Without being bound by theory, it is assumed that due to the quaternary carbon adjacent to the carboxylic acid group, the skeleton of the compound of formula (I) is not recognized as a native amino acid residue by peptidases. Therefore, it is expected that the non-native amino acid residues will resist degradation for a longer period and be metabolized at a slower rate. Therefore, it is expected that the compounds of the present invention will exhibit an improved in vivo half-life, for example, compared to the compounds disclosed in EP22193792.3.

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

[0042]

[0043] Or its pharmaceutically usable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs; wherein:

[0044] R 1 yes

[0045] X is CR 3 Or N, where R 3 Selected from H, halogens, and C1-C4 alkyl groups;

[0046] Each Y is independently a CHR 4 NR 5 CR 6 R 6 C(O) or O, where R 4 Independently selected from H, halogens, and C1-C4 alkyl groups; R 5 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), and -C(O)O-(C1-C4 alkyl); and R 6 Independently selected from halogens and C1-C4 alkyl groups;

[0047] R2 Selected from: H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl;

[0048] R 7 It is H or -CH3;

[0049] n = 0 or 1.

[0050] Unexpectedly, the applicant has discovered that when R 7 When -CH3 and n is 1, the compound of formula (I) exhibits enhanced binding to the selected protein. Therefore, in a preferred aspect of the invention, the compound of formula (I) has the following formula:

[0051]

[0052] In some compounds of this invention, R 2 Preferably selected from H, CH3, CH2F, CHF2 and CF3, more preferably, R 2 It is selected from H, CH3, CHF2 and CF3, with H being more preferred.

[0053] R 3 Preferably, it is H or C1-C4 alkyl, more preferably H or methyl.

[0054] Each R 4 H is preferred.

[0055] Each R 5 Preferably, it is independently H, C1-C4 alkyl or -C(O)O-(C1-C4 alkyl), more preferably H, methyl or -C(O)O-(tert-butyl), more preferably H or methyl, and most preferably H.

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

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

[0058]

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

[0060] R 1 The carbon atom in the partially saturated ring of the group may be replaced by one or two substituents as defined above. However, it is preferred that any carbon atom in the partially saturated ring be replaced by no more than one substituent. Therefore, if the ring atom in the partially saturated ring is carbon, it is preferably C(O) or CHR. 4 .

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

[0062] R 1 Some preferred examples of groups include:

[0063]

[0064] In the above preferred R 1 In the group, each Y is independently NR. 5 Or O. However, when a partially saturated ring contains two Y atoms, it is preferable that one Y is O and the other Y is O or N.

[0065] Each R 8 Independently selected from H, halogens, and C1-C4 alkyl groups, or R 8 Together with the carbon atom it is attached to, it forms an oxo group.

[0066] Furthermore, it is preferred that only one carbon atom in the partially saturated ring is substituted by a substituent. Therefore, an R 8 The radical is preferably selected from H, halogens, and C1-C4 alkyl groups or R. 8 Together with the carbon atom it is attached to, it forms an oxo group, and any other R 8 All groups are H. More preferably, one R 8 The radical is H or R 8 Together with the carbon atom it is attached to, it forms an oxo group, and any other R 8 All the radicals are H.

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

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

[0069]

[0070]

[0071] More preferably, R 1 Selected from one of the following groups:

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

[0073]

[0074] Preferably, R 1 Selected from one of the following groups:

[0075]

[0076] Some specific compounds of the present invention are those listed below, or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs:

[0077] 2,5,5-Trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0078] (S)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0079] (R)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0080] 2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0081] 2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0082] 2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0083] 2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0084] 2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0085] (R)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0086] (S)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0087] (S)-2-{[(4-aza-6-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0088] (S)-2-{[(2,3-dihydro-1,4-benzodiphenyl ether] En-6-yl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0089] (S)-2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0090] (S)-2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0091] (S)-2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0092] (S)-2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid.

[0093] According to a second aspect of the invention, a pharmaceutical composition is provided comprising a compound according to the invention, as well as a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0094] According to a third aspect of the invention, a compound or pharmaceutical composition according to the invention is provided for use in treatment.

[0095] According to a fourth aspect of the invention, compounds or pharmaceutical compositions according to the invention are provided for the treatment or prevention of neurodegenerative diseases, mental disorders, inflammatory diseases, lysosomal storage diseases, cancer, pain, diabetes, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, chronic pain, hearing loss, or diseases characterized by misfolded tau.

[0096] Preferably, the neurodegenerative disease is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke. Preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy.

[0097] Preferably, the neurodegenerative disease is 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. Some examples of such diseases include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal degeneration, and frontotemporal dementia.

[0098] Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder;

[0099] Preferably, the inflammatory condition can be selected from inflammatory diseases and neuroinflammation.

[0100] Preferably, the lysosomal storage disease is selected from the following: NCL / Batten disease caused by mutations in the CLN gene CLN1 (PPT1), CLN2 (TPP1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ATP13A2), CLN13 (CTSF), CLN14 (KCTD7), CLCN6 and / or SGSH; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease. Diseases A, B, and C; GM1 ganglioside storage diseases, GM2 ganglioside storage diseases (including Sandhoff and Tay-Sachs), mucopolysaccharidosis (MPS) types I (Hurler's disease) / II (Hunter's disease) / IIIa (Sanfilippo A) / IIIB (Sanfilippo B) / IIIc (Sanfilippo C) / IIId (Sanfilippo D) / IVA (Morqui' A) / VB / VI / VII (Sly) / IX, mucopolysaccharidosis III (I-cell) and IV, multiple sulfatase deficiencies; sialic acid storage diseases, galactosialic acid storage diseases, α-mannoside storage diseases, β-mannoside storage diseases, aspartic glucosamineuria, fucoside storage diseases, Schindler's disease. Diseases including metachromatic leukodystrophy caused by deficiency of arylsulfatase A or saponified protein B, Krabbe disease, Farber lipogranulomatosis, Wolman disease and cholesterol ester storage disease, dense bone development disorder, cystine storage disease, Salla disease, Danon disease, Griscellidisease type 1 / 2 / 3, Hermansky Pudliak disease, and Chédiak-Higashi syndrome.

[0101] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0102] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0103] 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.

[0104] According to a fifth aspect of the invention, the use of the compounds according to the invention in the preparation of a medicament is provided for the treatment or prevention of neurodegenerative diseases, mental disorders, inflammatory diseases, lysosomal storage diseases, cancer, pain, diabetes, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, chronic pain, hearing loss, or diseases characterized by misfolded tau.

[0105] According to a sixth aspect of the invention, a method for treating or preventing diseases or conditions that respond to selection protein regulation is provided, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.

[0106] The compounds of this invention may include compounds in isotopically labeled and / or isotopically enriched forms. The compounds of this invention may contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. Some examples of isotopes that may 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.

[0107] The compounds of the present invention can be used as is, or, where appropriate, as their pharmaceutically acceptable salts (acid or base addition salts). The pharmaceutically acceptable addition salts mentioned below refer to non-toxic acid and base addition salt forms that can be formed from the compounds and possess therapeutic activity. Compounds with basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Some exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, glycolic 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, para-aminosalicylic acid, papric acid, benzoic acid, ascorbic acid, etc. Compounds with acidic properties can be converted into their pharmaceutically acceptable base addition salts by treating the acid form with a suitable base. Some exemplary base addition salt forms are sodium, potassium, and calcium salts, as well as salts containing pharmaceutically acceptable amines such as ammonia, alkylamines, benzathine, and amino acids such as arginine and lysine. The term addition salt as used herein also includes solvates, such as hydrates, alcoholates, etc., that the compounds and their salts can form.

[0108] Throughout this disclosure, the given chemical formula or nomenclature will also encompass all its pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and / or prodrug forms. It should be understood that the compounds of this invention include any and all hydrates and / or solvates of the compound formula. It should be understood that in the various physical forms of said compounds, certain functional groups, such as hydroxyl, amino, etc., form complexes and / or coordination compounds with water and / or various solvents. Therefore, the above formula should be understood to include and represent those various hydrates and / or solvates.

[0109] The compounds of this invention also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton-mutant tautomers, which are isomeric protonated states having the same empirical formula and total charge. Some exemplary proton-mutant tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be brought into equilibrium by appropriate substitution or sterically locked into one form.

[0110] The compounds described herein may be asymmetric (e.g., having one or more stereoisomeric centers). Unless otherwise specified, all stereoisomers are intended, such as enantiomers and diastereomers. Compounds of the present invention containing asymmetric substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing the optically active form from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are considered in the present invention. Cis- and trans-geometric isomers of the compounds of the present invention are described, and they can be isolated as mixtures of isomers or as separate isomeric forms.

[0111] In the case of compounds containing asymmetric carbon atoms, the present invention relates to D-type, L-type, and D,L mixtures, and in the case of more than one asymmetric carbon atom, the present invention also relates to diastereomeric forms. Those compounds of the present invention containing asymmetric carbon atoms and typically produced as racemates can be isolated into optically active isomers in a known manner, for example, using optically active acids. However, it is also possible to use an optically active starting material from the outset, subsequently obtaining the corresponding optically active or diastereomeric compound as the final product.

[0112] Preferably, the compound of formula (I) is the compound of formula (Ia):

[0113]

[0114] The term "prodrug" refers to a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvent degradation. When administered to a subject in need, the prodrug may be inactive but is converted into the active compound of the present invention in vivo. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the present invention, for example by hydrolysis in the blood. Prodrug compounds generally offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd ed., Elsevier Academic Press (2004), pp. 498-549). Prodrugs of the compounds of the present invention can be prepared by modifying functional groups, such as hydroxyl, amino, or thiol groups, present in the compounds of the present invention in such a manner as to cleave the modification into the parent compound of the present invention in conventional operation or in vivo. Some examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxyl functional groups or phenyl carbamate derivatives of amino functional groups.

[0115] The compounds of this invention can be selectin inhibitors, binders, modulators, or antagonists. The terms “selectin antagonist,” “selectin inhibitor,” “selectin binder,” or “selectin modulator” (used interchangeably) as used herein refer to substances that interfere with, block, or otherwise attenuate the binding of selectin to granule protein precursors, neurotensin or other extracellular ligands, or proneurotrophs (e.g., pro-NGF, proNT3, pro-BDNF), or prevent the formation of a trimer complex between selectin, p75NTR, and proneurotrophs. The term “selectin antagonist” also includes substances or agents that interfere with the formation of high-affinity trimer complexes. In the latter case, it is recognized that trimer complexes can form because selectin can bind to p75NTR (but not pro-NGF), and p75NTR can simultaneously bind to the NGF domain of pro-NGF. However, the resulting trimer complex may have a lower affinity for its receptor and thus a significantly reduced ability to stimulate apoptosis via the mechanisms described above. Skeldale et al. (2012) demonstrated that the apoptotic function of the trimeric complex is eliminated when selectin lacks its intracellular domain. The term "selectin antagonist" also includes substances or agents that interfere with, block, or otherwise weaken the interaction between selectin and p75NTR. This interaction can be completely blocked, in which case the formation of the trimeric complex is prevented; or the interaction can be only partially blocked, in which case the trimeric complex can form but may have reduced biological potency. Skeldale et al. showed that the formation of the complex between selectin and p75NTR depends on the contact point in the receptor's extracellular domain, and that the interaction is critically dependent on the sequence of the 23 amino acids near the extracellular membrane of p75NTR. Therefore, selectin antagonists can interfere with this 23 amino acid sequence or the proximal sequence of the molecule. "Selectin antagonists" can act as inhibitors of ligand cellular uptake, where the ligand can be a granule protein precursor, neurotensin, BDNF, etc.

[0116] The compounds of this invention can cross the blood-brain barrier and are therefore particularly useful for the treatment or prevention of central nervous system diseases, including neurodegenerative diseases selected from: motor neuron disease, frontotemporal degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Kreutzfeldt-Jacob disease (CJD), acute brain injury, spinal cord injury, and stroke; mental disorders selected from: bipolar disorder, major depressive disorder, 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.

[0117] K of the compound of the present invention puu It can be greater than 0.1, for example 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.

[0118] The term "treatment" as used herein may include preventing a specified obstacle or condition, or mitigating or eliminating the obstacle once it has been identified. The term "prevention" refers to preventing a specified obstacle or condition.

[0119] The methods described herein include those in which subjects are identified as requiring a specific treatment. Identifying the need for such treatment can be based on the judgment of the subject or a healthcare professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by testing or diagnostic methods).

[0120] In other aspects, the methods described herein also include those that monitor the subject's response to treatment administration. Such monitoring may include periodic imaging or sampling of the subject's tissues, fluids, samples, cells, proteins, chemical markers, genetic material, etc., as biomarkers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as requiring such treatment by evaluating biomarkers or indicators associated with the suitability of such treatment.

[0121] This invention provides a method for monitoring treatment progress. The method includes the steps of determining the level of a diagnostic biomarker (marker) (e.g., any target or cell type regulated by compounds described herein) or diagnostic measurement (e.g., screening, assay) in a subject who has or is susceptible to the disease or symptoms described herein, wherein the subject has been administered a therapeutic amount of a compound described herein sufficient to treat the disease or symptoms. The biomarker level determined in this method can be compared with known levels of the biomarker in healthy controls or other diseased patients to establish the subject's disease status. In some preferred embodiments, a second level of the biomarker in the subject is determined at a time later than the determination of the first level, and the two levels are compared to monitor disease progression or treatment efficacy. In some preferred embodiments, the pre-treatment level of the biomarker in the subject is determined before the start of treatment according to the invention; this pre-treatment level of the biomarker can then be compared with the biomarker level in the subject after the start of treatment to determine the efficacy of the treatment.

[0122] The level of biomarkers or biomarker activity in the subject can be determined at least once. Comparison of biomarker levels, for example, with another measurement of biomarker levels previously or subsequently obtained from the same patient, another patient, or a normal subject, can be used to determine whether the treatment according to the invention has the desired effect and thus allow for appropriate adjustment of the dosage level. The determination of biomarker levels can be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, tissue or fluid samples are first removed from the subject. Some examples of suitable samples include blood, urine, tissue, oral or buccal cells, and hair samples containing the roots. Other suitable samples will be known to those skilled in the art. The determination of protein and / or mRNA levels (e.g., biomarker levels) in the sample can be performed using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence methods, real-time PCR, etc.

[0123] For clinical applications, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for use in a variety of administration routes. It should be understood that the compounds of the present invention can be administered 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 via any suitable route, preferably via oral, rectal, nasal, surface (including ocular, oral, and sublingual), sublingual, dermal, intrathecal, mucosal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. Other formulations may be readily available in unit dosage forms (e.g., tablets and sustained-release capsules) and as liposomes, and can be prepared by any method known in the pharmaceutical field. Pharmaceutical formulations are typically prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Some examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium glycolate starch, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc. Such formulations may also contain other pharmacologically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc. Typically, the amount of the active compound is 0.1% to 95% by weight of the formulation, preferably 0.2% to 20% by weight for parenteral use, and more preferably 1% to 50% by weight for oral administration. The formulation can also be prepared by known methods, such as granulation, compression, microencapsulation, spraying, etc. The formulation can be prepared by conventional methods in dosage forms such as tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections. Liquid formulations can be prepared by dissolving or suspending the active substance in water or other suitable carriers. Tablets and granules can be coated in a conventional manner. To maintain therapeutically effective plasma concentrations for extended periods, the compounds disclosed herein can be incorporated into slow-release formulations.

[0124] The dosage level and frequency of administration for a specific compound will vary depending on a number of factors, including the potency of the specific compound used, its metabolic stability and duration of action, the patient's age, weight, general health condition, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the condition to be treated, and the patient's ongoing treatments. Daily doses can be, for example, from about 0.001 mg to about 100 mg / kg body weight, administered, for example, in single or multiple doses of about 0.01 mg to about 25 mg per administration. Typically, such doses are administered orally, but parenteral administration is also an option.

[0125] definition

[0126] As used herein, the term "selectin" can refer to a full-length selectin (also known as an immature selectin) containing 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 a mature selectin, or a naturally occurring fragment, homology, or variant thereof, containing the Vps10p domain, the 10CC domain, the transmembrane domain, and a large cytoplasmic tail, having the amino acid sequence according to SEQ ID NO:3. The terms "selectin" and "selectin molecule" are used interchangeably herein. It should be understood that selectins can interact with proneurotrophin molecules to form selectin / proneurotrophin complexes. Such selectin / proneurotrophin complexes may or may not interact with p75NTR molecules to form a trimeric complex comprising selectin, proneurotrophin, and p75NTR. It should be understood that this trimer complex may be responsible for adverse biological responses, such as stimulating apoptosis of retinal and ganglion cells, and controlling the retraction of growth cones of synaptic axons (Jansen et al., 2007; Nykjaer et al., 2004; Santos et al., 2012; Skeldalet et al., 2012).

[0127] As used in this article, the term "preneurotrophin" refers to a larger precursor of a neurotrophin that undergoes proteolytic cleavage to produce its mature form. Neurotrophins are a family of proteins that induce neuronal survival, development, and function, and are often referred to as growth factors. Preneurotrophins are biologically active and have different roles compared to their neurotrophin counterparts, such as inducing apoptosis. Some examples of preneurotrophins include pro-NGF, pro-BDNF, proNT3, and proNT4. Preneurotrophins can also control synaptic plasticity. While mature neurotrophins induce synaptic strength, they can weaken synapses in their precursor forms.

[0128] "Optional" or "optionally" means that the event or situation described below may but does not have to happen, and the description includes both situations in which the event or situation occurs and situations in which the event or situation does not occur.

[0129] The term "heteroatoms" refers to O, N, or S.

[0130] The term "(C1-C)" n "(C1-C2)alkyl" indicates a straight-chain, branched, cyclic, or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3... or n carbon atoms. For alkyl groups containing a cyclic moiety, "(C1-C2)alkyl" is used. n "(C1-C1)alkyl", which should be formed by at least three carbon atoms. n The "(C1-C4)alkyl" part considers all its subgroups. For example, within the (C1-C4)alkyl range, all subgroups include (C1-C4)alkyl, (C1-C3)alkyl, (C1-C2)alkyl, (C1)alkyl, (C2-C4)alkyl, (C2-C3)alkyl, (C2)alkyl, (C3-C4)alkyl, (C3)alkyl, and (C4)alkyl. Some examples of "C1-C4 alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, etc.

[0131] The term "(C1-C)" n "Halogenated alkyl" refers to a C1-C alkyl group as described above that has been substituted with at least one halogen atom. n Alkyl group, wherein the halogen atom is preferably F, Cl, Br and I, more preferably F and Cl, and most preferably F.

[0132] The term "(C1-C)" n "Hydroxyalkyl" indicates a C1-C alkyl group as described above that has been substituted with at least one -OH group. n alkyl.

[0133] The term "(C1-C)" n ")alkoxy" represents -O-((C1-C n )alkyl, wherein (C1-C n The alkyl group is as defined above and is connected to the rest of the compound via an oxygen atom.

[0134] When terms indicate a range, such as “1 to 4 carbon atoms” in the definition of (C1-C4)alkyl, each integer is considered to be public, namely 1, 2, 3, and 4.

[0135] The term "halogenated" refers to a halogen atom, and is preferably F, Cl, Br and I, more preferably F and Cl, and most preferably F.

[0136] "Effective amount" refers to the amount of the compound of the present invention that imparts a therapeutic effect to the treated subject. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives indication of the effect or feels the effect).

[0137] As used herein, the term "administration" or variations thereof refers to the route of administration of the compounds disclosed herein. Some exemplary routes of administration include, but are not limited to, oral, intraocular, intravenous, intraperitoneal, intraarterial, and intramuscular administration. Preferred routes of administration may vary depending on a number of factors, such as the components of the pharmaceutical composition comprising the compounds disclosed herein, the site of potential or actual disease, and the severity of the disease.

[0138] The terms “object” and “patient” are used interchangeably herein. It refers to a human or other mammal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) who may have or be susceptible to a disease or condition, but may also have or may not yet have the disease or condition. Preferably, the object is a human.

[0139] The compounds of this invention may be disclosed by name or chemical structure. If there is a difference between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0140] The invention will now be further illustrated by the following non-limiting embodiments. The specific embodiments described below should be interpreted as illustrative only and in no way limit the remainder of this disclosure. Without further explanation, those skilled in the art will be able to utilize the invention to its fullest extent based on the description herein. All references and publications cited herein are incorporated herein by reference in their entirety.

[0141] Preparation of the compounds of the present invention

[0142] The compounds of this invention can be prepared according to the following general synthetic procedure scheme using methods known and understood in the art. Suitable reaction conditions are known in the art, and appropriate substitutions of solvents and co-agents are within the scope of common knowledge to those skilled in the art. Likewise, those skilled in the art will understand that, as desired or desired, synthetic intermediates can be isolated and / or purified by a variety of known techniques, and that multiple intermediates can often be used directly in subsequent synthetic steps with minimal or no purification. Furthermore, those skilled in the art will understand that in some cases, the order of the introducing moieties is not important. The specific order of steps required to produce compounds of formula (I) depends on the particular compound being synthesized, the relative preference of the starting compound and the substituted moieties, as is well known to those skilled in the art. Unless otherwise stated, all substituents are as defined above, and all reagents are known and understood in the art.

[0143] Suitable starting materials (whether as optically active substances of a single enantiomer or as racemic mixtures) and protected amino acids of general formula AA-1 are commercially available or can be prepared by various methods. For example, as shown in 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 a free acid, PG=H, or protected as a suitable derivative (e.g., as a methyl ester). Functionalization of the primary amine present in Int1 can be accomplished by various methods, and for illustrative purposes, it is accomplished by a condensation step involving a suitably substituted carbonyl compound aldehyde or ketone to produce an imine type Int 2. The imine functional group can be reduced by treatment with a reducing agent (e.g., but not limited to sodium triacetoxyborohydride) in a suitable solvent mixture such as acetic acid and dichloromethane to give an Int 3 type intermediate, which is a precursor of the compound of formula (I) after the release of the carboxylic acid functional group. Alternatively, AA-2 type amino acids can be used as starting materials. As discussed earlier, an Int 4 type intermediate is obtained by using a condensation step, as shown in Scheme 2. Upon treatment with a suitable base, this intermediate loses its most acidic proton, generating a transient carbanion, which can then be quenched by an alkylating agent (e.g., but not limited to methyl iodine) to produce an Int 2 type compound. The imine functional group can be reduced to provide an Int 3 type intermediate by treatment with a reducing agent (e.g., but not limited to sodium triacetoxyborohydride) in a suitable solvent mixture such as acetic acid and dichloromethane, or hydrolyzed by treatment with an acidic or alkaline aqueous solution to provide the universal intermediate Int 5. As in Scheme 1, the compound of formula (I) can then be obtained directly from Int 3 by releasing the acidic moiety, with or without further functionalization of the amino group.

[0144] As illustrated in general synthetic procedure scheme 3, another feasible method for obtaining the AA-3 type starting amino acid from easily handled amino acids involves an alkylation step between a suitably protected AA-3 or Int 6 and a 1-bromo-3,3-dimethylbutane-type reagent for illustrative purposes, to produce the previously discussed Int 2 type universal intermediate. Advantageously, AA-1 to AA-3 type intermediates can be obtained through procedures known to those skilled in the art or purchased from commercial sources.

[0145] General synthesis procedure

[0146]

[0147]

[0148] Compounds of general formula (I) 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, grinding, crystallization, etc.

[0149] Compounds of general formula (I) may contain one or more stereocenters. These can be introduced from available single enantiomers, optically active AA-1, AA-2, or AA-3 type starting materials. The integrity of existing stereocenters can be determined by analytical techniques 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, a single isomer product can be obtained in the form of a single enantiomer or a single diastereomer by known techniques such as preparative chiral support high-pressure chromatography.

[0150] Those skilled in the art will also understand that not all substituents in the compound of formula (I) will be tolerant of certain reaction conditions used to synthesize the compound. These moieties may be introduced at a conventive point during synthesis, or may be protected as needed or desired and subsequently deprotected, as is well known in the art. Those skilled in the art will understand that protecting groups may be removed at any suitable point during the synthesis of the compounds of the present invention. The methods used in this invention for introducing or removing protecting groups are well known in the art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons, New York (2006). Example

[0151] abbreviation

[0152] approx: approx.; aq: aqueous solution; br: broad peak; ca.: approx.; CDI: 1,1'-carbonyldiimidazole; CPME: cyclopentylmethyl ether; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl; h: hour; min: minute; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea Hexafluorophosphate (V); HPLC: High Performance Liquid Chromatography; IPA: Isopropanol; LC: Liquid Chromatography; m: Multiplet; M: Mole, Mole ion; MeCN: Acetonitrile; MeOH: Methanol; MS: Mass Spectrometry; NMR: Nuclear Magnetic Resonance; PDA: Photodiode Array; q: Quartet; rt: Room temperature (approximately 20°C); RT : 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-high performance liquid chromatography; UV: Ultraviolet light.

[0153] Other abbreviations are intended to convey their generally accepted meaning.

[0154] General experimental conditions

[0155] All starting materials and solvents were obtained from commercial sources or prepared according to cited literature. The reaction mixture was magnetically stirred and reacted at room temperature (approximately 20°C) unless otherwise specified.

[0156] On automated rapid chromatography systems such as the CombiFlash Rf system, column chromatography is performed using a pre-packed silica (40 μm) column, unless otherwise specified.

[0157] Analytical methods

[0158] Record at 400MHz on a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. 1 H-NMR spectra. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane unless otherwise specified. The following abbreviations or combinations thereof are used for the multiplicity of NMR signals: br = broad peak, d = doublet, m = multiplet, q = quartet, quintet = quintet, s = singlet, and t = triplet.

[0159] Method 1: Instruments: Waters IClass; Bin. Pump: UPIBSM, SM: UPISM MTN with SO; UPCMA, PDA: UPPTATC, 210 to 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, posttime: 0.3 min, eluent A: 10 mM ammonium bicarbonate in water (pH = 9.5), eluent B: acetonitrile.

[0160] Method 2: Instruments: Agilent 1260 Infinity, 1260G1312B Bin. Pump, 1260G1367E WPS, 1260TCC G1316A Column Comp. 1260G1315C DAD (210 to 320 nm, 210 and 220 nm), PDA (210 to 320 nm), G6130B MSD ESIpos / neg (mass range 100 to 1000), Column: Waters XSelect CSH C18 (30 × 2.1 mm, 3.5 μ), Flow rate: 1 ml / min; Column temperature: 25 °C, Eluent A: 10 mM ammonium bicarbonate in water (pH 9), Eluent B: Acetonitrile, Gradient: t = 0 min 5% B, t = 1.6 min 98% B, t = 3 min 98% B, Post-run: 1.3 min.

[0161] Method 3: Instrument: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100×30mm, 10μm); Flow rate: 55mL / min; Column temperature: room temperature (RT); Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; 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 to 320 nm); Detection: MSD (ESI pos / neg); Mass range: 100 to 1000; Fractional collection based on MS and DAD.

[0162] Method 4: Instrument: ACQ-SQD2; HPLC instrument type: Waters Modular preparative HPLC system; Column: Waters XSelect (C18, 100×30mm, 10μm); Flow rate: 55ml / min preparative pump; Column temperature: room temperature; Eluent A: 10mM ammonium bicarbonate in water, pH=9.5; Eluent B: 100% acetonitrile; Detection: DAD (220 to 320nm); Detection: MSD (ESIpos / neg), mass range: 100 to 800; fractional collection based on MS and DAD.

[0163] Method 5: Instruments: Waters IClass; Bin. Pump: UPIBSM, SM: UPISM™ with SO; UPCMA, PDA: UPPTATC, 210 to 320 nm, SQD: MS: QDA ESI, pos / neg 100 to 800; Column: Waters XSelect CSHC18, 50 × 2.1 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: 2500V; Cone: 20V; Extractor: 3.0V; RF: 2.5V; Source temperature: 150℃; Desolvation temperature: 600℃; Cone gas flow rate: 80L / h; Desolvation gas flow rate: 1000L / h; Full MS scan: MS range 100 to 800 (positive and negative modes); Scan: 0.4 seconds.

[0164] Method 6: Instruments: Waters I-Class UPLC, Binary Solvent Manager (BSM), Sample Manager-FTN (SM-FTN) and Sample Organizer (SO), Column Manager (CM-A), PDA 210 to 320 nm, QDa ESI 100 to 800 (pos) 100 to 800 (neg), Column: XSelect CSH C18 XP (50 × 2.1 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.

[0165] Method 7: Instruments: Waters Acquity UPC2; Waters ACQ-ccBSM Binary Pump; Waters ACQ-CCM Convergence Manager; Waters ACQ-SM Sample Manager-Fixed Loop; Waters ACQ-CM Column Manager-30S; Waters ACQ-PDA Photodiode Array Detector; Waters ACQ-ISM Make Up Pump; Waters Acquity QDa MS Detector; Column: Lux i-Cellulose-5 (100×4.6mm 5μm); Column temperature: 35℃; Flow rate: 2.5ml / min; ABPR: 170 bar; Eluent A: CO2; Eluent B: Methanol + 20mM ammonia; Gradient: t=0 min 5% B, t=5 min 50% B, t=6 min 50% B; Detection: 210 to 320 nm.

[0166] Method 8: Instruments: Waters Prep 100SFC UV / MS orientation system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity Qda MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux i-Cellulos-5 (250 × 21.2 mm, 5 μm); Column temperature: 35℃; Flow rate: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Detection: PDA (210 to 400 nm); Gradient: t = 0 min 25% B; t = 5 min 45% B. Sample concentration: 20 mg / ml. Injection volume: 500 μl. Timed fractional collection.

[0167] Method 9: Instruments: Waters Prep 100SFC UV / MS orientation system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity Qda MS detector; Waters 2767 Sample Manager; Column: Diacel Chiralpak IC (250 × 20 mm, 5 μm) for SFC; Column temperature: 35 °C; Flow rate: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Linear gradient: 20% B at t = 0 min, 50% B at t = 4.5 min; Detection: PDA (210 to 400 nm); Fractional collection: PDA TIC.

[0168] Method 10: Instruments: Waters Acquity UPC2; Waters ACQ-ccBSM Binary Pump; Waters ACQ-CCM Convergence Manager; Waters ACQ-SM Sample Manager-Fixed Loop; Waters ACQ-CM Column Manager-30S; Waters ACQ-PDA Photodiode Array Detector; Waters ACQ-ISM Make Up Pump; Waters Acquity QDa MS Detector; Column: Chiralpak IC (100×4.6mm5μm); Column temperature: 35℃; Flow rate: 2.5ml / min; ABPR: 170 bar; Eluent A: CO2; Eluent B: Methanol + 20mM ammonia; Linear gradient: t=0 min 5% B, t=5 min 50% B, t=6 min 50% B; Detection: 210 to 320 nm.

[0169] Method 11: Instruments: Waters Acquity UPC2; Waters ACQ-ccBSM Binary Pump; Waters ACQ-CCM Convergence Manager; Waters ACQ-SM Sample Manager-Fixed Loop; Waters ACQ-CM Column Manager-30S; Waters ACQ-PDA Photodiode Array Detector; Waters ACQ-ISM Make Up Pump; Waters Acquity QDa MS Detector; Column: phenomenonxiAmylose-3 (100×4.6mm 5μm); Column temperature: (35℃); Flow rate: (2.5ml / min); ABPR: (170 bar); Eluent A: CO2; Eluent B: Methanol + 20mM ammonia; Linear gradient: t=0 min 5% B, t=5 min 50% B, t=6 min 50% B; Detection: 210 to 320 nm.

[0170] Method 12: Instruments: Waters Prep 100SFC UV / MS orientation system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity Qda MS detector; Waters 2767 Sample Manager; Column: phenomenex iAmylose-3 (250×20mm, 5μm); Column temperature: 35℃; Flow rate: 70ml / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: 20mM ammonia in methanol; Linear gradient: t=0 min 20% B, t=4.5 min 50% B; Detection: PDA (210 to 400nm); Fractional collection: PDA TIC.

[0171] Examples 1, 2 and 3

[0172]

[0173] Synthesis of methyl 2-amino-2,5,5-trimethylhexanoate hydrochloride (int-8)

[0174] Under an argon atmosphere, thionyl chloride (0.261 ml, 3.58 mmol, 3.0 equivalence) was added dropwise to an ice-cold solution of 2-amino-2,5,5-trimethylhexanoate hydrochloride (250 mg, 1.192 mmol) in methanol (1 ml). The mixture was stirred at 0 °C for 15 min, followed by stirring at room temperature for 3 h. A white, viscous suspension was formed. The suspension was diluted with a small amount of MeOH and stirred overnight. Thionyl chloride (0.261 ml, 3.58 mmol) was added again, and the mixture was refluxed and heated for 4.5 h after the addition. The mixture was cooled to room temperature and the solvent was evaporated. MeCN was added and the solvent was evaporated to give 2-amino-2,5,5-trimethylhexanoate methyl hydrochloride (233 mg, 1.041 mmol, 87% yield) as a grayish-white, turbid, oily substance. LCMS (Method 2, 1.782 min; M + H - HCl = 188.1; calculated value 188.2).

[0175] 1 H-NMR (400MHz, DMSO) δ8.53 (s, 2H), 3.77 (s, 3H), 1.83-1.70 (m, 2H), 1.47 (s, 3H), 1.33-1.20 (m, 1H), 1.06-0.93 (m, 1H), 0.85 (s, 9H).

[0176] Synthesis of 2,5,5-trimethyl-2-(((5,6,7,8-tetrahydronaphth-2-yl)methyl)amino)hexanoic acid compound containing methanesulfonic acid (Example 1)

[0177] 6-(bromomethyl)-1,2,3,4-tetrahydronaphthalene (131 mg, 0.581 mmol) and DIPEA (304 μl, 1.743 mmol, 3 equivalents) were added to a suspension of 2-amino-2,5,5-trimethylhexanoate methyl hydrochloride (130 mg, 0.581 mmol) in MeCN (1.5 mL). The mixture was heated at 80 °C for 3 hours. The mixture was cooled to room temperature, diluted with water (1.5 mL), and lithium hydroxide monohydrate (122 mg, 2.91 mmol, 7.5 equivalents) was added. The mixture was heated at 80 °C for 2 days. The crude product was filtered and purified by alkaline preparative preparation (Method 4). The purified fraction was processed in Geneva. cThe solution was concentrated and reformulated, weighed, and redissolved in MeCN (0.05 M). A 0.1 M MsOH (1 equivalent) solution in MeCN was then added. A small amount of water was added and the solvent was evaporated to give a white solid of 2,5,5-trimethyl-2-(((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)amino)hexanoic acid compound containing methanesulfonic acid (6.3 mg, 0.015 mmol, 2.62% yield). LCMS Method 1, 1.247 min; M+H-MsOH = 318.5, calculated 318.2.

[0178] 1 H NMR (400MHz, DMSO) δ9.00 (s, 2H), 7.18 (d, J=6.3Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 4.14-3.88 (m, 2H), 2.78-2.69 (m, 4H), 2.29 (s, 3H, MsOH), 1.88 (td , J=13.1, 4.6Hz, 1H), 1.83-1.77(m, 1H), 1.77-1.70(m, 4H), 1.53(s, 3H), 1.25 (dt, J=12.9, 6.4Hz, 1H), 1.17 (td, J=13.3, 4.5Hz, 1H), 0.87 (s, 9H).

[0179] Synthesis of (S)-2,5,5-trimethyl-2-((5,6,7,8-tetrahydronaphth-2-yl)methyl)amino)hexanoic acid containing methanesulfonic acid (Example 2) and (R)-2,5,5-trimethyl-2-((5,6,7,8-tetrahydronaphth-2-yl)methyl)amino)hexanoic acid containing methanesulfonic acid (Example 3)

[0180] Methyl 2,5,5-trimethyl-2-(((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)amino)hexanoate (516 mg, 1.557 mmol) was purified by SFC (Method 8). The purified fractions were combined, evaporated, weighed, and redissolved in MeCN (0.05 M), and a 0.1 M MsOH (1 equivalent) solution in MeCN was added. A small amount of water was added and the mixture was lyophilized to give (S)-2,5,5-trimethyl-2-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)amino)hexanoate compound containing methanesulfonic acid (40.7 mg, 0.098 mmol, 6.32% yield, >95% EE). LCMS (Method 6, 1.291 min; M+H-MsOH = 318.3, calculated 318.2). LCMS (Method 7, 4.080 min; M+H-MsOH = 318.1, calculated value 318.2).

[0181] 1H-NMR (400MHz, DMSO) δ14.69-13.65 (m, 1H), 9.03 (s, 2H), 7.24-7.16 (m, 2H), 7 .13(d, J=8.4Hz, 1H), 4.18-3.88(m, 2H), 2.79-2.68(m, 4H), 2.30(s, 3H, MsOH) , 1.90 (td, J=13.3, 4.6Hz, 1H), 1.85-1.77 (m, 1H), 1.77-1.72 (m, 4H), 1.54 (s, 3H), 1.26 (td, J=13.3, 4.0Hz, 1H), 1.16 (td, J=12.9, 4.6Hz, 1H), 0.87 (s, 9H).

[0182] And a (R)-2,5,5-trimethyl-2-(((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)amino)hexanoic acid compound containing methanesulfonic acid (36.6 mg, 0.088 mmol, 5.69% yield, >95% EE). LCMS (Method 6, 1.293 min; M+H-MsOH = 318.2, calculated 318.2). LCMS (Method 7, 4.846 min; M+H-MsOH = 318.1; calculated 318.2).

[0183] 1 H-NMR (400MHz, DMSO) δ9.69-8.24 (m, 2H), 7.21-7.15 (m, 2H), 7.11 (d, 1H), 4. 05(d, J=12.6Hz, 1H), 3.92(d, J=12.5Hz, 1H), 2.73(s, 4H), 2.29(s, 3H, MsOH), 1.87(td, J=12.5, 3.9Hz, 1H), 1.81-1.76(m, 1H), 1.76-1.69(m, 4H), 1.50(s, 3H), 1.26 (td, J=13.0, 4.6Hz, 1H), 1.17 (dt, J=12.9, 6.5Hz, 1H), 0.87 (s, 9H).

[0184]

[0185]

[0186]

[0187] Starting with the corresponding bromides, Examples 4 through 8 were prepared in a manner similar to that of Example 1. The compounds were prepared as racemic mixtures.

[0188]

[0189]

[0190]

[0191] Examples 9 to 16 can be prepared in a manner similar to the foregoing examples.

[0192]

[0193]

[0194]

[0195]

[0196] Biological data

[0197] Neurotensin scintillation affinity assay

[0198] The exemplary compounds of the present invention were tested in a neurotensin (NTS) scintillation proximity assay (SPA). 50 The data are shown in the table below. NTS, a 13-amino acid neuropeptide, is a select protein ligand. IC 50 It is a measure of the amount of compound required to inhibit the binding of NTS to select proteins by 50%. Technicians will recognize that IC... 50 The lower the value, the fewer compounds are needed to achieve the desired effect, and therefore, the less chance of undesirable off-target effects.

[0199] In the SPA format, by measuring [ 3 The affinity of the compound was determined by substitution of [3H]-neurotensin with h-selectin. A total volume of 40 μl of 50 mM HEPES pH 7.4 assay buffer containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween-20 was used. The compound was pre-incubated with 150 nM h-selectin at room temperature for 30 min, followed by the addition of 5 nM [3H]-neurotensin and Ni-chelated imaging beads (Perkin Elmer). The plate was read on a ViewLux after 6 h with an exposure time of 360 s. The dose-response of the compound was evaluated using eight drug concentrations (covering three decimal degrees). The IC50 was calculated using nonlinear regression of sigmoid concentration-response (variable slope) with CDD Vault software. 50 Values. All reported values ​​are the average of at least two measurements.

[0200] Human protein GCI binding assay

[0201] The exemplary compounds of the present invention were tested in a grating-coupled interferometry (GCI) protein binding assay. GCI data are shown in the table below. Equilibrium dissociation constant (K0) D K is a measure of the tendency of a complex (i.e., ligand and receptor) to dissociate and is used to describe the affinity of the interactions between the components of the complex (i.e., ligand and receptor). Those skilled in the art will recognize that K... D The lower the value, the fewer compounds are needed to achieve the desired effect, and therefore, the less chance of undesirable off-target effects.

[0202] Compound affinity was determined by measuring association and dissociation between the compound and human (6-His) selected protein (RnD system) using a CreoptixWave instrument (Creoptix-Malvern Panalytical). Both human (6-His) selected protein fixation and compound evaluation were performed in HBS-N running buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 1% DMSO-Cytiva. This buffer was filtered and degassed for 15 min before use.

[0203] Prior to immobilization, the 4PCH WAVEchip (Creoptix-Malvern Panalytica) was conditioned using 0.2×HBS-N running buffer (Xantec Bioanalytics) with 0.1M borate (pH 9.0) and 1M NaCl injected through all flow cells. Buffer exchange to 1×HBS-N running buffer was performed, and after activation on the EDC / NHS (Cytiva) surface, human (6-His) select protein was immobilized in pH 5.0 acetate solution (Cytiva) via amine coupling, followed by passivation by injection of 50 mM Tris at pH 7.4.

[0204] Using either the "Weak Bound Compound" (settings: 400 μl / min flow rate, 40 Hz acquisition rate, 5 sec association time, 20 sec dissociation time) or the "Intermediate Bound Compound" (settings: 100 μl / min flow rate, 10 Hz acquisition rate, 25 sec association time, 300 sec dissociation time) settings, test compounds in a time-response manner (short pulses of increasing duration) at a single concentration (typically: 1 μM, 10 μM, or 100 μM) in a "WAVE-RAPID" assay. Determine which setting is most suitable based on the affinity and kinetics of the compound being tested.

[0205] DMSO calibration was performed by injecting run buffer containing 0.5% more DMSO than the run buffer (1.5% in this example) every 20 cycles, as per the manufacturer's instructions. All data were dual-referenced (minus blank and reference channels), and K... D The values ​​were calculated by fitting a 1:1 dynamics combined model using the "WAVEcontrol" software (Creoptix-Malvern Panalytical).

[0206] The data in Table 1 below show that the compounds of the present invention are protein-selective binding agents and inhibitors.

[0207] Table 1

[0208]

[0209] Some embodiments of the present invention

[0210] Implementation Scheme 1. Compound of Formula (I):

[0211]

[0212] Or its pharmaceutically usable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs; wherein:

[0213] R 1 yes

[0214] X is CR 3 Or N, where R 3 Selected from H, halogens, and C1-C4 alkyl groups;

[0215] Each Y is independently a CHR 4 NR 5 CR 6 R 6 Or O, where R 4 Independently selected from H, halogens, oxo groups, and C1-C4 alkyl groups; R 5 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), and -C(O)O-(C1-C4 alkyl); and R 6 Independently selected from halogens and C1-C4 alkyl groups;

[0216] R 2 Selected from: H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl;

[0217] R 7It is H or -CH3; and

[0218] n = 0 or 1.

[0219] Implementation Scheme 2. The compound according to Implementation Scheme 1, wherein R 2 Selected from H, CH3, CH2F, CHF2 and CF3, preferably R 2 It is selected from H, CH3, CHF2 and CF3, with H being more preferred.

[0220] Implementation Scheme 3. The compound according to Implementation Scheme 1 or 2, wherein each Y is independently CHR. 4 NR 5 Or O; and / or

[0221] Where R 3 It is an H or C1-C4 alkyl group, preferably H or methyl; and / or

[0222] Each R 4 It is independently H or oxo; and / or

[0223] Each R 5 Independently, it is H, C1-C4 alkyl, or -C(O)O-(C1-C4 alkyl), preferably H, methyl, or -C(O)O-(tert-butyl), more preferably H or methyl; and / or

[0224] Where R 7 It is -CH3; and / or

[0225] Where n = 1.

[0226] Implementation Scheme 4. The compound according to any one of the foregoing implementation schemes, wherein R 1 Selected from one of the following groups:

[0227]

[0228] Preferably, no more than one or two of the Ys are NR. 5 Or O, and the rest of Y is CHR 4 .

[0229] Implementation Scheme 5. The compound according to Implementation Scheme 4, wherein R 1 Selected from one of the following groups:

[0230]

[0231] Each Y is independently an NR. 5 Or O, preferably one of the R 4 The group is H or oxo, and other R 4 All the radicals are H.

[0232] Implementation Scheme 6. The compound according to Implementation Scheme 5, wherein R 1 Selected from one of the following groups:

[0233]

[0234]

[0235] Implementation Scheme 7. The compound according to Implementation Scheme 6, wherein R 1 Selected from one of the following groups:

[0236]

[0237] Implementation Scheme 8. The compound according to Implementation Scheme 7, wherein R 1 Selected from one of the following groups:

[0238]

[0239]

[0240] Preferably, R 1 Selected from one of the following groups:

[0241]

[0242] Implementation Scheme 9. The compound according to any one of the preceding embodiments, wherein the compound is one of the following, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug:

[0243] 2,5,5-Trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0244] (S)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0245] (R)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid;

[0246] 2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0247] 2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0248] 2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0249] 2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0250] 2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0251] (R)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0252] (S)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0253] (S)-2-{[(4-aza-6-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0254] (S)-2-{[(2,3-dihydro-1,4-benzodiphenyl ether] En-6-yl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0255] (S)-2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0256] (S)-2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0257] (S)-2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid;

[0258] (S)-2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid.

[0259] Implementation Scheme 10. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0260] Implementation Scheme 11. The compound according to any one of Implementation Schemes 1 to 9 or the pharmaceutical composition according to Implementation Scheme 10, for use in treatment.

[0261] Implementation Scheme 12. The compound according to any one of Implementation Schemes 1 to 9 or the pharmaceutical composition according to Implementation Scheme 10, for the treatment or prevention of neurodegenerative diseases, mental disorders, inflammatory diseases, lysosomal storage diseases, cancer, pain, diabetes, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, chronic pain, hearing loss, or diseases characterized by tau folding;

[0262] Preferably, the neurodegenerative disease is selected from motor neuron disease, frontotemporal degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Kreutzfeldt-Jacob 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.

[0263] Preferably, the neurodegenerative disease is characterized by misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal degeneration, or frontotemporal dementia.

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

[0265] Preferably, the inflammatory condition is selected from inflammatory diseases and neuroinflammation;

[0266] Preferably, the lysosomal storage disease is selected from the following: NCL / Barten disease caused by mutations in the CLN gene CLN1 (PPT1), CLN2 (TPP1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ATP13A2), CLN13 (CTSF), CLN14 (KCTD7), CLCN6 and / or SGSH; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease type A, B and C; GM1 ganglioside storage disease, GM2 ganglioside storage disease (including Sandhof disease and Tai-Sachs disease), mucopolysaccharidosis (MPS) type I (Hurler disease) / II (Hunter disease) / IIIa (Sanfilippo A) / IIIB (Sanfilippo B) / IIIc (Sanfilippo A) / IIIa (Sanfilippo B) / IIIc (Sanfilippo A) / IIIa (Sanfilippo B) / IIIa (Sanfilippo C ... C) / IIId(Sanfilippo D) / IVA(Morqui”A) / 'VB / VI / VII(Sly) / IX, Mucolipid storage disease III (I-cell) and IV, Multiple sulfatase deficiencies; Sialic acid storage disease, Galactosialic acid storage disease, α-mannoside storage disease, β-mannoside storage disease, Aspartic glucosamineuria, Fucoside storage disease, Schindler's disease, Metachromatic leukodystrophy caused by arylsulfatase A or saponified protein B deficiency, Globular leukodystrophy (Clapey's disease), Farber lipogranulomatosis, Wolman's disease and cholesterol ester storage disease, Dysplastic osteodystrophy, Cystine storage disease, Sara disease, Danon's disease, Griselly's disease type 1 / 2 / 3, Hermansky-Pudlerk's disease, and Chédiak-Higashi syndrome;

[0267] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer;

[0268] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; and

[0269] 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.

[0270] References

[0271] Andersen, J et al., Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of thereceptor-ligand complex. Acta Crystallogr D Biol Crystallogr(2014), 70(Pt 2), pp.451-460;

[0272] Baker, M.et al., Mutations in progranulin cause tau-negativefrontotemporal dementia linked to chromosome 17. Nature (2006), 442(7105), pp.916-919;

[0273] Brouwers, N.etal., Genetic variability in progranulin contributes torisk for clinically diagnosed Alzheimer disease. Neurology, (2008), 71(9), pp.656-664;

[0274] Buttenshon,H.N.et al.,Increased serum levels of sortilin areassociated with depression and correlated with BDN F and VEGF,NatureTranslational Psychiatry(2015),5(e677),pp.1-7;

[0275] Carecchio,M.,et al.,Cerebrospinal fluid biomarkers in Progranulinmutations carriers.J Alzheimers Dis(2011),27(4),pp.781-790;

[0276] Carrasquillo,M.et al.,.Genome-wide screen identifies rs646776 nearsortilin as a regulator of progranulin levels in human plasma.Am J Hum Genet(2010),87(6),pp.890-897;

[0277] Chen,Z.Y.et al.,Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway.J Neurosci(2005),25(26),pp.6156-6166;

[0278] Cruts,M.et al.,Loss of progranulin function in frontotemporal lobardegeneration.Trends Genet(2008),24(4),pp.186-194;

[0279] De Muynck,L.et al.,The neurotrophic properties of progranulin dependon the granulin E domain but do not require sortilin binding.Neurobiol Aging(2013),34(11),pp.2541-2547;

[0280] Egashira,Y.et al.,The growth factor progranulin attenuates neuronalinjury induced by cerebral ischemia-reperfusion through the suppression ofneutrophil recruitment.J Neuroinflammation(2013),10,pp.105;

[0281] Galimberti,D.et al.,.GRN variability contributes to sporadicfrontotemporal lobar degeneration.J Alzheimers Dis(2010),19(1),pp.171-177;

[0282] Galimberti,D.et al.,.Progranulin as a therapeutic target fordementia.Expert Opin Ther Targets(2018),22(7),pp.579-585.doi:10.1080 / 14728222.2018.1487951

[0283] Gao,A.et al.,lmplications of Sortilin in Lipid Metabolism and LipidDisorder Diseases.DNA and Cell Biology(2017),36(12),pp.1050-1061;

[0284] Gass,J.et al.,Progranulin regulates neuronal outgrowth independent ofsortilin.Mol Neurodegener(2012),7,pp.33;

[0285] Gass,J.et al.,Progranulin:an emerging target for FTLD therapies.BrainRes(2012),1462,pp.118-128;

[0286] Gijselinck,I.,et al.,Granulin mutations associated withfrontotemporal lobar degeneration and related disorders:an update.Hum Mutat(2008),29(12),pp.1373-1386;

[0287] Goettsch,C.,et al.,Sortilin and Its Multiple Roles in Cardiovascularand Metabolic Diseases.Atherosclerosis,Thrombosis and Vascular Biology(2017),38(1),pp.19-25

[0288] Jansen,P.,et al.,Roles for the pro-neurotrophin receptor sortilin inneuronal development,aging and brain injury.Nature Neuroscience(2007),10(11),pp.1449-1457;

[0289] Hu,F.etal.,Sortilin-mediated endocytosis determines levels of thefrontotemporal dementia protein,progranulin.Neuron(2010),68(4),pp.654-667;

[0290] Huang,G.et al.,Insulin responsiveness of glucose transporter 4in 3T3-L1 cells depends on the presence of sortilin.Mol Biol Cell(2013),24(19),pp.3115-3122;

[0291] Kaddai,V.et al.Involvement of TNF-α in abnormal adipocyte and musclesortilin expression in obese mice and humans.Diabetologia(2009)52,pp.932-940;

[0292] Kjolby,M.et al.,Sort1,encoded by the cardiovascular risk locus1p13.3,is a regulator of hepatic lipoprotein export.Cell Metab(2010),12(3),pp.213-223;

[0293] Laird,A.S.et al.,Progranulin is neurotrophic in vivo and protectsagainst a mutant TDP-43 induced axonopathy.PLoS One(2010),5(10),e13368;

[0294] Lee,W.et al.,Targeted manipulation of the sortilin-progranulin axisrescues progranulin haploinsufficiency.Hum Mol Genet(2014),23(6),pp.1467-1478;

[0295] Martens,L.et al.,Progranulin deficiency promotes neuroinflammationand neuron loss following toxin-induced injury.J Clin Invest(2012),122(11),pp.3955-3959;

[0296] Mazella,J.et al.,The 100-kDa neurotensin receptor is gp95 / sortilin,anon-G-protein-coupled receptor.J Biol Chem(1998),273(41),pp.26273-26276;

[0297] Miyakawa,S.et al,Anti-sortilin1 Antibody Up-Regulates Progranulin viaSort.lin1 Down-Regulation.Front Neurosci(2020),14,pp.586107;

[0298] et al.Sortilin as a Biomarker for Cardiovascular DiseaseRevisited.Frontiers in Cardiovascular Medicine(2021),8,652584;

[0299] Mortensen,M.B.et al.,Targeting sortilin in immune cells reducesproinflammatory cytokines and atherosclerosis.J Clin Invest(2014),124(12),pp.5317-5322;

[0300] Nykjaer,A et al.,Sortilin is essential for proNGF-induced neuronalcall daath.Nature(2014),427(6977),pp.843-848;

[0301] Nykjaar,A.,&Willnow,T.E,Sortilin:a raceptor to regulate neuronalviability and function.Trends Neurosci(2012),35(4),pp.261-270.

[0302] Oh,T.J.et al.,Circulating sortilin leval as a potantial biomarker forcoronary atherosclerosis and diabetes mellitus.Cardiovascular Diabetology(2017),16(92);

[0303] Pan,X.et al.,Sortilin and retromar mediate retrograde transport ofGlut4 in 3T3-L1 adipocytes.Mol Biol Cell(2017),28(12),pp.1667-1675;

[0304] Petersen,C.et al.,Molecular identification of a novel candidatesorting receptor purified from human brain by receptor-associated proteinaffinity chromatography.J Biol Chem(1997),272(6),pp.3599-3605;

[0305] Pickford,F.et al.,Progranulin is a chemoattractant for microglia andstimulates their andocytic activity.Am J Pathol(2011),178(1),pp.284-295;

[0306] Pottier,C.,et al.,Potential genetic modifiers of disease risk and ageat onset in patiants with frontotemporal lobar degeneration and GRNmutations:a genome-wide association study.Lancet Neurol(2018),17(6),pp.548-558;

[0307] Quistgaard,E.et al.,Ligands bind to Sortilin in the tunnelof a ten-bladed beta-propeller domain.Nat Struct Mol Biol(2009),16(1),pp.96-98;

[0308] Santos,A.M.et al.,Sortilin Participates in Light-dependentPhotoreceptor Degeneration in Vivo.PLoS ONE(2012),7(4),pp.e36243-e36243.16.Kuruvilla,R.et al.,A neurotrophin signaling cascade coordinatessympathetic neuron development through differential control of TrkAtrafficking and retrograde signalling.Cell(2004),118(2),pp.243-255;

[0309] Shi,J.&Kandror,K.V.,Sortilin Is Essential and Sufficient for theFormation of Glut4 Storage Vesicles in 3T3-L1 Adipocytes.Developmental Cell(2005),9,pp.99-108;

[0310] Schroder,T.et al.,The identification of AF38469:an orallybioavailable inhibitor of the VPS10P family sorting receptor Sortilin.BioorgMed Chem Lett(2014),24(1),pp.177-180;

[0311] Sheng,J.et al.,Progranulin polymorphism rs5848 is associated withincreased risk of Alzheimer′s disease.Gene(2014),542(2),pp.141-145;SkeIdaI,S.et al.,Mapping of the Interaction Site between Sortilin and the p75Neurotrophin Receptor Reveals a Regulatory Role for the SortilinIntracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis.JBiol Chem(2012),21(287),pp.43798-43809;

[0312] Tauris,J.,etal.,Proneurotrophin-3May Induce Sortilin-Dependent DeathIn Inner Ear Neurons.Eur J Neuroscience(2020),33(4),pp.622-31;

[0313] Tang,W.et al.,The growth factor progranulin binds to TNF receptorsand is therapeutic against inflammatory arthritis in mice.Science(2011),332(6028),pp.478-484;

[0314] Tao,J.et al.,Neuroprotective effects of progranulin in ischemicmice.Brain Res(2012),1436,pp.130-136;

[0315] Tenk,H.K.,et al.,ProBDNF induces neuronal apoptosis via activation ofa receptor complex of p75NTR and sortilin.J Neuroscience(2005),10(11),pp.1449-1457

[0316] Van Kampen,J.M.,et al.,Progranulin gene delivery protectsdopaminergic neurons in a mouse model of Par kinson's disease.PLoS One(2014),9(5),e97032;

[0317] Willnow,T.E.et al.,VPS10P-domain receptors-regulators of neuronalviability and function.Nat Rev Neurosci(2008),9(12),pp.899-909;

[0318] Willnow,T.E.,et al.,Sortilins:new players in lipoproteinmetabolism.Current Opinion in Lipidology(2011),22(2),pp.79-85.

[0319] Wuts,P.G.M.and Greene,T.W,Greene’s Protective Groups in OrganicSynthesis,4th Edition,John Wiley and Sons,New York(2006);

[0320] Xu,S.H.et al.,Regional and Cellular Mapping of SortilinImmunoreactivity in Adult Human Brain,Frotiers in Neuroanatomy(2019),13(31),pp.1-27;

[0321] Yano,H.,et al.,Proneurotrophin-3 is a neuronal apoptotic ligand:evidence for retrograde-directed cell killing.J Neurosci(2009),29(47),pp.14790-14802;

[0322] Yin,F.,et al.,Exaggerated inflammation,impaired host defense,andneuropathology in progranulin-deficient mice.J Exp Med(2010),207(1),pp.117-128;

[0323] 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;

[0324] Zhou,X.et al.,Prosaposin facilitates sortilin-independent lysosomaltrafficking of progranulin.J Cell Biol(2015),210(6),pp.991-1002;

[0325] Meneses et al.,TDP-43 Pathology in Alzheimer’s Disease,MolNeurodegeneration(2021),16,84;

[0326] 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;

[0327] Beel et al., Progranulin reduces insoluble TDP-43 levels, slows downaxonal degeneration and prolongs survival in mutant TDP-43 mice, MolNeurodegener. (2018), 13: 55.

[0328] The sequences referenced throughout this specification and forming part of this specification are...

[0329] SEQ ID NO: 1 (Full-length selected protein-isotype 1)

[0330]

[0331] SEQ ID NO:2 (Full-length selected protein-isotype 2)

[0332]

[0333]

[0334] SEQ ID NO: 3 (Mature Selected Protein)

[0335]

[0336] SEQ ID NO: 4 (Mouse Select Protein)

[0337]

[0338]

Claims

1. Compound of formula (I): Or its pharmaceutically usable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs; wherein: R 1 yes X is CR 3 Or N, where R 3 Selected from H, halogens, and C1-C4 alkyl groups; Each Y is independently a CHR 4 NR 5 CR 6 R 6 C(O) or O, where R 4 Independently selected from H, halogens, and C1-C4 alkyl groups; R 5 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), and -C(O)O-(C1-C4 alkyl); and R 6 Independently selected from halogens and C1-C4 alkyl groups; R 2 Selected from: H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl; R 7 It is H or -CH3; and n = 0 or 1.

2. The compound according to claim 1, wherein R 2 Selected from H, CH3, CH2F, CHF2 and CF3, preferably R 2 It is selected from H, CH3, CHF2 and CF3, with H being more preferred.

3. The compound according to claim 1 or 2, wherein each Y is independently CHR. 4 NR 5 C(O) or O; and / or Where R 3 It is an H or C1-C4 alkyl group, preferably H or methyl; and / or Each R 4 It is H; and / or Each R 5 Independently, it is H, C1-C4 alkyl, or -C(O)O-(C1-C4 alkyl), preferably H, methyl, or -C(O)O-(tert-butyl), more preferably H or methyl; and / or Where R 7 It is -CH3; and / or Where n = 1.

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 of the Ys are NR. 5 Or O, and the remaining Y is independently C(O) or CHR. 4 .

5. The compound according to claim 4, wherein R 1 Selected from one of the following groups: Each Y is independently an NR. 5 Or O, and each R 8 Independently selected from H, halogens, and C1-C4 alkyl groups or R 8 Together with the carbon atom to which it is attached, it forms an oxo group, preferably wherein each R 8 Is it H or R? 8 Together with the carbon atom to which it is attached, it forms an oxo group, more preferably one of the R atoms. 8 The radical is H or R 8 The group, together with the carbon atom it is attached to, forms an oxo group, and other R... 8 All the radicals are 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: Preferably, R 1 Selected from one of the following groups:

9. The compound according to any one of the preceding claims, wherein the compound is one of the following, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug: 2,5,5-Trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid; (S)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid; (R)-2,5,5-trimethyl-2-{[(5,6,7,8-tetrahydro-2-naphthyl)methyl]amino}hexanoic acid; 2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (R)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(5-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(4-aza-6-indanyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(2,3-dihydro-1,4-benzodiphenyl ether] En-6-yl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(6-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(6-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(7-isobenzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(7-benzodihydropyranyl)methyl]amino}-2,5,5-trimethylhexanoic acid.

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

11. The compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10, for use in treatment.

12. The compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10, for the treatment or prevention of neurodegenerative diseases, mental disorders, inflammatory diseases, lysosomal storage diseases, cancer, pain, diabetes, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, chronic pain, hearing loss, or diseases characterized by tau folding; Preferably, the neurodegenerative disease is selected from motor neuron disease, frontotemporal degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Kreutzfeldt-Jacob 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 disease is characterized by misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal degeneration, or frontotemporal dementia. Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder; Preferably, the inflammatory condition is selected from inflammatory diseases and neuroinflammation; Preferably, the lysosomal storage disease is selected from the following: NCL / Barten disease caused by mutations in the CLN gene CLN1 (PPT1), CLN2 (TPP1), CLN3, CLN4 (DNAJC5), CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10 (CTSD), CLN11, CLN12 (ATP13A2), CLN13 (CTSF), CLN14 (KCTD7), CLCN6 and / or SGSH; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease type A, B and C; GM1 ganglioside storage disease, GM2 ganglioside storage disease (including Sandhof disease and Tai-Sachs disease), mucopolysaccharidosis (MPS) type I (Hurler disease) / II (Hunter disease) / IIIa (Sanfilippo A) / IIIB (Sanfilippo B) / IIIc (Sanfilippo A) / IIIa (Sanfilippo B) / IIIc (Sanfilippo A) / IIIa (Sanfilippo B) / IIIa (Sanfilippo C ... C) / IIId(Sanfilippo D) / IVA(Morqui”A) / 'VB / VI / VII(Sly) / IX, Mucolipid storage disease III (I-cell) and IV, Multiple sulfatase deficiencies; Sialic acid storage disease, Galactosialic acid storage disease, α-mannoside storage disease, β-mannoside storage disease, Aspartic glucosamineuria, Fucoside storage disease, Schindler's disease, Metachromatic leukodystrophy caused by arylsulfatase A or saponified protein B deficiency, Globular leukodystrophy (Clapey's disease), Farber lipogranulomatosis, Wolman's disease and cholesterol ester storage disease, Dysplastic osteodystrophy, Cystine storage disease, Sara disease, Danon's disease, Griselly's disease type 1 / 2 / 3, Hermansky-Pudlerk's disease, and Chédiak-Higashi syndrome; Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease; and 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.

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