Modifiers for soltirin activity

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 present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, and the use thereof in the treatment or prevention of medical conditions in which modification of soltirin is beneficial. JPEG2026509826000033.jpg33170

Description

[Technical Field]

[0001] This invention relates to compounds of formula (I) that have been found to remarkably modify the activity of soltirin. The invention also relates to pharmaceutical compositions comprising these compounds, and their use in the treatment or prevention of medical conditions in which modification of soltirin activity is beneficial. In particular, the compounds of this invention may be able to cross the blood-brain barrier and therefore may be particularly useful in the treatment of central nervous system disorders. The compounds of this invention may also have improved half-lives in vivo. [Background technology]

[0002] Sortirin is a type I transmembrane protein that acts as a receptor for several ligands (Petersen et al., 1997). Sortirin is involved in the nervous system, inner ear, and metabolic regulation. It is abundantly expressed in neurons and microglia in some peripheral tissues (Tauris et al., 2020; Goettsch et al., 2017; Willnow et al., 2011; Kjolby et al., 2010). In addition to acting as a receptor involved in signal transduction, soltirin mediates the sorting of selected cargo between the trans-Golgi network on the cell surface and the endosomal pathway (Nykjaer & Willnow, 2012; Willnow, Petersen, & Nykjaer, 2008). Soltirin is, It possesses a large extracellular domain called VPS10, which defines a receptor family called soltilin or VS10p domain receptors. The VPS10P domain in soltilin is homologous to yeast VPS10P and consists of a β-propeller structure with 10 blades and a cysteine-rich 10CC module (Nykjaer & Willnow, 2012; Zheng, Brady, Meng, Mao, & Hu, 2011).

[0003] Sortirin binds to multiple 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, Sortirin binds to progranulin (PGRN), a secreted protein involved in many cellular functions, including securing lysosomal processes, anti-inflammatory responses, and neurotrophic stimulation (Galimberti, Fenoglio, & Scarpini, 2018). Sortirin targets PGRN for rapid endocytosis and degradation, and it is now well established that sortirin is the most important clearance receptor for PGRN (Hu et al., 2010). However So, soltirin negatively regulates extracellular levels of PGRN not only in the brain but also in the periphery. In fact, the absence or blockade of this receptor increases plasma PGRN levels in both mice and humans (Carrasquillo et al., 2010; Gass, Prudencio, Stetler, & Petrucelli, 2012; Hu et al., 2010; Lee et al., 2014; Miyakawa et al., 2020; Pottier et al., 2018).

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

[0005] However, sorbitol is not required for PGRN to function. Therefore, neurons lacking sorbitol expression respond equally to PGRN-induced neuronal extension (De Muynck et al., 2013; Gass, Lee, et al., 2012). Furthermore, sorbitol-deficient cells... In this study, PGRN is successfully transported to neuronal lysosomes, suggesting the existence of an alternative transport pathway. In fact, PGRN can bind to the lysosomal protein prosaposin (PSAP). When PSAP binds to its congener receptors, the cation-independent mannose-6-phosphate receptor and LRP1, it transports PGRN to lysosomes (Zhou et al., 2015). Finally, using a monoclonal anti-soltirin antibody... In the Phase II clinical trial, markers indicating lysosome integrity were normal (NCT03987295).

[0006] Functional PGRN receptors have not yet been identified. However, studies suggest that PGRNs promote neuronal survival, reduce inflammation, and increase A□ endocytosis by microglia (Martens et al., 2012; Pickford et al., 2011; Yin et al., 2010).

[0007] The binding of PGRN to soltirin requires the three C-terminal amino acids of PGRN (QLL in humans, PLL in mice), and the peptide derived from the last 24 amino acids of PGRN binds with affinity similar to that of the full-length protein (Zheng et al., 2011). This binding mode is structurally similar to neurotensin binding, and has been proposed to be binding at the NTIS1 binding site of soltirin (Zheng et al., 2011). Aarhus In collaborative research with the University, we successfully screened small molecules to identify inhibitors of neurotensin-soltirin binding (Andersen et al., 2014; Schroder et al., 2014).

[0008] While sorbitol exists as a receptor with full-length sorting ability, it can also form multimeric signaling receptor-ligands. A portion of sorbitol can be released from the cell membrane to capture a ligand (NT in the case of pain) and regulate its activity. For example, sorbitol is involved in synaptic plasticity by regulating the rate of conversion from pro-BDNF to BDNF. This may also be true for other proneurotrophins.

[0009] Finally, the propeptide of the receptor ligand, soltirin (also known as spadin), has been shown to regulate the activity of the membrane transporter TREK-1, a target of many diseases, particularly major depressive disorder. Structurally, soltirin has the amino acid sequence shown in SEQ ID NO: 1 and includes a signal peptide, propeptide, Vps10p domain, 10cc domain (10CCa+10CCb), transmembrane domain, and cytoplasmic end. The luminal domain of soltirin has six potential N-linked glycosylation sites, while the cytoplasmic end allows for the recruitment of various adapter proteins.

[0010] Sortirin binds to a vast number of ligands and membrane receptors, and as a result, is involved in functions known to be important for cell signaling and sorting. For example, sortirin is involved in signaling by proneurotrophins, which are precursors of nerve growth factor (pro-NGF), brain-derived neurotrophic factor (pro-BDNF), and neurotrophin-3 (proNT3), respectively. In complex with the protein p75NTR (p75 neurotrophin receptor), sortirin has been reported to form a receptor for proneurotrophin-mediated apoptotic effects that lead to degeneration and cell death in cell and animal models (Jansen et al., 2007; Tenk et al., 2005; Nykjaer et al., 2004).

[0011] Previous studies have suggested the role of soltirin in cell sorting and signaling associated with diseases such as diabetes and obesity (Huang et al 2013). Soltirin promotes the translocation of GLUT4 to the cell membrane and rescues it from denaturation in lysosomes (Pan et al., 2017). Soltirin levels have been shown to be modified by the level of inflammation associated with these diseases. The pro-inflammatory cytokine TNFα reduces both soltirin mRNA and protein levels in cultured mouse and human adipocytes, and in vivo when injected into mice (Kaddai et al., 2009). Soltirin Furthermore, it may also affect cytokine secretion, and it has been proposed to target soltirin in immune cells to reduce inflammation and slow the progression of atherosclerotic disease (Mortensen et al., 2014). In addition, U.S. Patent Application Publication No. 2016 / 0331746 describes various small molecule skeletons that can bind to the active site of soltirin. Soltirin is involved in the regulation of glucose uptake (Shi & Kandror. 2005), and It is involved in the development of dyslipidemia (Gao et al., 2017).

[0012] Furthermore, plasma soltirin levels have been reported to have potential as a biomarker for identifying patients with either coronary heart disease or diabetes mellitus (Oh et al., 2017; Moller et al., 2021). Patients who showed elevated plasma soltirin levels and were therefore identifiable as having the above conditions also exhibited elevated glucose levels, suggesting soltirin as a therapeutic target for treating these conditions. Soluble soltirin has also been proposed as a treatment for type II diabetes (International Publication No. 2021116290(A1), 2021).

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

[0014] TDP-43 regulates the splicing of several gene products, including sorbitol. In humans, this splicing involves the insertion of a hidden exon 17b (between exons 17 and 18), which can introduce a stop codon into the stalk, potentially generating a non-membrane-bound fragment (Prudencio et al., 2012). Furthermore, PGRNs have been shown to reduce insoluble TDP-43 levels and delay axonal degeneration (Beel et al., (2018). Sortirin inhibition increases PGRN levels, therefore TDP-43 is involved. It is beneficial in the treatment of neurodegenerative diseases.

[0015] Sortirin has been associated with various pathological conditions affecting the central nervous system (CNS). Several studies have suggested a role for circulating sortirin in patients with mental disorders such as depression, which may be related to altered activity of neurotrophic factors (Buttenshon et al., 2015), and sortirin may also be linked to brain aging, Alzheimer's disease, and frontotemporal syndrome. It has also been reported to play a role in type 1 dementia (Xu et al., 2019). However Therefore, delivering therapeutic agents that can cross the blood-brain barrier to the central nervous system (CNS) is a major challenge.

[0016] The blood-brain barrier is a highly selective, semipermeable boundary mediated by endothelial cells, preventing solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system (CNS) where neurons reside. Therefore, treatment options for neurological diseases are limited due to the restricted penetration of therapeutic agents across the blood-brain barrier.

[0017] Therefore, therapeutic agents for treating CNS diseases must be able to cross the blood-brain barrier. In addition, the free-form hypothesis posits that only unbound compounds can interact and induce pharmacological effects, therefore, a sufficient concentration of unbound drugs in the brain is also necessary.

[0018] To identify the unbound fraction (Fub) of the test compound, the sample supernatant can be analyzed by methods such as liquid chromatography with tandem mass spectrometry (LC-MS / MS). Then, from the peak area ratios obtained for each matrix, the following formula is derived: Fub=CPBS / Cplasma The unbound fraction can be calculated according to the following formula, where CPBS and Cplasma are the concentrations of the analyte in PBS (receiving side) and plasma (donor side), respectively.

[0019] The recovered samples may be prepared under each condition, but without dialysis, using the following formula: % Recovery Rate = 100 × (VPBS × CPBS + Vplasma × Cplasma) / Vplasma × Crecovery This formula can be used to evaluate the recovery rate from dialysis experiments, where VPBS is the volume of the receiving side (PBS) of the dialysis machine, and Vplasma is the volume of the donor side (plasma). Recovery is the analyte concentration measured from the recovered sample. Compounds such as propranolol or fluoxetine may be included in the experiment as controls.

[0020] The unbound fraction in the brain (Fub,brain) can be calculated from the measurements in the brain homogenate (Fub,meas), taking into account the dilution ratio used in the preparation of the brain homogenate:

number

[0021] The brain / plasma unbound partition coefficient (Kpuu) can be identified as the ratio of free compound concentrations in plasma and brain:

number

[0022] Alternatively, Kpuu may be determined using the AUC ratio. The compound of interest is administered orally or intravenously to the target species at a known concentration. The changes in the concentration of the compound in plasma and cerebrospinal fluid (CSF) over time are measured. The plasma concentration is corrected to account for the unbound fraction of the compound. The area under the CSF concentration curve and the area under the plasma free fraction concentration curve are calculated by known methods, and the ratios are determined to obtain the following: Kpuu=AUC0-infcsf / (AUC0-infplasma×(%Fuplasma / 100))

[0023] For the treatment of CNS diseases, a Kpuu value greater than 0 is desirable as high as possible. A value around 1 indicates that compounds in the free fraction can freely pass through the blood-brain barrier; a value greater than 1 suggests the involvement of an active influx transport mechanism at the blood-brain barrier; and a value less than 1 indicates that compounds in the free fraction are recognized by a low permeability or active efflux mechanism, resulting in reduced exposure in the CNS and their return to plasma or CSF across the blood-brain barrier. A Kpuu value of 0 or near 0 indicates low permeability of the compound or a very active efflux mechanism, and in either case, achieving meaningful exposure of the desired active species in the CNS becomes highly unlikely.

[0024] Compounds that effectively target and bind to soltirin, as well as modify soltirin activity in the target, preferably have optimized pharmacokinetics. For example, this could correspond to an extended half-life in vivo or improved delivery to the target tissue. Improved persistence of such compounds within the target body is a crucial clinical parameter. This determines the required dosage and frequency of administration of the compound, as well as the formulation requirements necessary to achieve the desired therapeutic effect after administration.

[0025] An increased in vivo half-life ensures that the compound remains therapeutically effective in the target body for as long as possible before being metabolized or excreted, thereby enabling administration of lower effective doses and / or less frequently of the therapeutic compound. Therefore, compounds with increased half-lives are of great pharmacy importance.

[0026] The inventors have devised compounds that can modify soltirin activity, as disclosed in full in European Patent Application Publication No. 21194937.5 and International Patent Application No. PCT / EP2022 / 074536, which are incorporated herein by reference. [Overview of the Initiative]

[0027] In light of the above, there is an unmet need for further compounds that can be used to treat and prevent medical conditions in which modification of soltirin is beneficial. In particular, there is an unmet need for further soltirin modifiers that can cross the blood-brain barrier and are therefore useful in treating central nervous system diseases. Furthermore, there is a need for soltirin modifiers with improved half-lives in vivo. [Brief explanation of the drawing]

[0028] [Figure 1] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 2] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 3] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 4] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 5] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 6] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 7] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 8] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 9] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 10] Figures 1 to 10 show X-ray images of Example 5 bound to h-soltilin. [Figure 11A] Figures 11A to 11C show electron density maps obtained from the X-ray diffraction data of Example 5. [Figure 11B] Figures 11A to 11C show electron density maps obtained from the X-ray diffraction data of Example 5. [Figure 11C] Figures 11A to 11C show electron density maps obtained from the X-ray diffraction data of Example 5. [Modes for carrying out the invention]

[0029] Surprisingly, the compound of formula (I) was found to modify the activity of sorbitolin and therefore be useful in treating or preventing conditions in which modification of sorbitolin is beneficial. Furthermore, this compound may be able to cross the blood-brain barrier and therefore may be particularly useful in treating diseases of the central nervous system.

[0030] Although not bound by theory, it is considered that the skeleton of the compound of formula (I) is not recognized as a natural amino acid residue by peptidase due to the quaternary carbon adjacent to the carboxylic acid group. Therefore, this unnatural amino acid residue is expected to be more resistant to degradation and undergo metabolism at a slower rate. Thus, the compounds of the present invention are expected to exhibit an improved half-life in vivo compared to, for example, the compounds disclosed in European Patent Application Publication No. 21194937.5 and International Application No. PCT / EP2022 / 074536.

[0031] In a first aspect of the present invention, formula (I):

Chemical formula

[0032] Surprisingly, the applicant is R 3 We found that when is -CH3 and n is 1, the compound of formula (I) exhibits improved bonding with soltirin. In a preferred embodiment of the present invention, the compound of formula (I) therefore has the following formula: [ka]

[0033] In the compound of the present invention, R 2 Preferably, is selected from the group consisting of H, -CH3, -CH2F, -CHF2, -CF3, -(C2H4)-OH, and phenyl, more preferably R 2 The group is selected from the group consisting of H, -CH3, -CHF2, -CF3, -(C2H4)-OH, and phenyl, and is more preferably H.

[0034] R 4 and R 5 Preferably, each is independently a C1-C2 alkyl group, and more preferably a -CH3 group.

[0035] In a preferred embodiment of the present invention, R 1 The group is selected from the following: (i) Phenyl-substituted C1-C2 alkyl groups; and (ii)-OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, acetyl, cyano, C6-C 10 Aryl, 5-membered ring to 10-membered ring heteroaryl, 5-membered ring to 10-membered ring heterocycloalkyl, -O-(C6~C 10 aryl), -O-CH2-(C6~C10 aryl), and -NR 4 R 5 Phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of the above.

[0036] As used herein, the term “five-membered ring or six-membered ring monocyclic heteroaryl” means an aromatic ring having five or six ring atoms, where at least one ring atom is a heteroatom and the remaining ring atoms are carbon.

[0037] As used herein, the term “9-membered ring or 10-membered ring fused bicyclic heteroaryl” means an aromatic ring system containing two rings fused together so as to share two adjacent ring atoms. Preferably, the 9-membered ring or 10-membered ring fused bicyclic heteroaryl group contains a 6-membered ring fused to a 5-membered ring or a 6-membered ring.

[0038] A 9-membered or 10-membered ring fused bicyclic heteroaryl group has 9 or 10 ring atoms, at least one of which is a heteroatom, and the remaining ring atoms are carbon.

[0039] Preferably, R 1 Each ring atom in the 5-membered or 6-membered monocyclic heteroaryl group and the 9-membered or 10-membered fused bicyclic heteroaryl group is independently selected from the group consisting of C, N, S, and O. More preferably, 1 to 3 ring atoms are independently selected from the group consisting of N, S, and O, and the remaining ring atom is C.

[0040] Comfortable, R 1 Each ring atom in the five-membered or six-membered monocyclic heteroaryl group is independently either carbon (C) or nitrogen (N). Most preferably, one or two ring atoms are nitrogen and the remaining ring atoms are carbon (C).

[0041] R 1Examples of five-membered or six-membered monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl. Preferably, the five-membered or six-membered heteroaryl group is selected from pyrazolyl, pyridyl, and pyrimidinyl. More preferably, the five-membered or six-membered heteroaryl group is one of the following groups: [ka] It is one of them.

[0042] R 1 Examples of 9-membered or 10-membered ring fused bicyclic heteroaryl groups include quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthilidinyl, pyridopyrimidinyl, pyridopyramidinyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, azaindazolyl, pyrazolopyrimidinyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl. Preferably, the 9-membered or 10-membered ring fused bicyclic heteroaryl group is selected from quinolinyl, isoquinolinyl, quinoxalinyl, naphthilidinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, and benzofuranyl. More preferably, the 9-membered ring or 10-membered ring fused bicyclic heteroaryl group is one of the following groups: [ka] It is one of them.

[0043] In a preferred embodiment of the present invention, R 1 The group is selected from the following: (i) Phenyl-substituted C1-C2 alkyl groups; and (ii)-OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, acetyl, cyano, 5-membered ring or 6-membered ring heteroaryl, 5-membered ring heterocycloalkyl, -O-phenyl, and -NR 4 R 5 Independently selected from the group consisting of, preferably -OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 ha Roalkyl, C1-C2 haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5 Phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of the above.

[0044] In a more preferred embodiment of the present invention, R 1 The group is selected from the following: (i) Phenyl-substituted C1-C2 alkyl groups; and (ii)-OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5 Phenyl and 5-membered or 6-membered monocyclic heteroaryls, which are optionally substituted with one or more substituents independently selected from the group consisting of the following; and (iii) Naphthyl and 9-membered ring or 10-membered ring condensed bicyclic heteroaryls, which are optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, and C1-C2 alkoxy.

[0045] In a more preferred embodiment of the present invention, R 1 The group is selected from the following: (i) Phenyl-substituted C1-C2 alkyl groups; (ii)-OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5 Phenyl compounds that are optionally substituted with one or more substituents independently selected from the group consisting of the following; (iii) Five-membered or six-membered ring heteroaryls that are optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, and -O-phenyl; (iv) Naphthyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halos and C1-C2 alkoxys; and (v) A 9-membered ring or 10-membered ring fused bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo and C1-C2 alkyl.

[0046] In a more preferred embodiment of the present invention, R 1 teeth, [ka] [ka] Selected from the group consisting of, more preferably, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0047] In the compound of the present invention, R 2 If R is phenyl, 1 It is preferably phenyl.

[0048] The specific compounds of the present invention are those listed below. (R)-2-benzylamino-2,5,5-trimethylhexanoic acid; (S)-2-benzylamino-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (S)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; 2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (R)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; (S)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5-dimethylhexanoic acid; 2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-benzylamino-2,5,5-trimethylhexanoic acid; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0049] According to a second aspect of the present invention, there exists a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0050] According to a third aspect of the present invention, a compound or pharmaceutical composition according to the present invention is provided for use in treatment.

[0051] A fourth aspect of the present invention provides compounds or pharmaceutical compositions according to the present invention for use in the treatment or prevention of diseases characterized by neurodegenerative disorders, mental disorders, inflammatory disorders, lysosomal storage disorders, cancer, pain, diabetes mellitus, diabetic retinopathy and other retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye conditions, chronic pain, hearing loss, or misfolded tau.

[0052] Preferably, the neurodegenerative disorder is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke. The motor neuron disease is selected, preferably, from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy.

[0053] The neurodegenerative disorder is preferably characterized by misfolded TAR DNA-binding protein 43 (tdp-43). In other words, this neurodegenerative disease is characterized by truncated tdp-43 and inclusion bodies. Examples of such diseases include amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal dementia, and frontotemporal dementia.

[0054] Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorders.

[0055] Preferably, the inflammatory disorder may be selected from inflammatory diseases and neuroinflammation.

[0056] Preferably, lysosomal storage disorders are caused by mutations in the CLN genes 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, resulting in NCL / Batten disease; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease type A, type B, and Type C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysaccharidosis (MPS) type I (Hurler's disease) / type II (Hunter's disease) / type IIIa (Sanfilippo A) / type IIIB (Sanfilippo B) / type IIIc (Sanfilippo C) / type IIId (Sanfilippo D) / type IVA (Morquio A) / type VB / VI / VII (Slye) / type IX, mucolipisosis type III (I-cell) and type IV, various sulfatain -ase deficiency; selected from the group consisting of sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosamiuria, fucosidosis, Schindler's disease, metachromatic leukodystrophy resulting from a deficiency of either arylsulfatase A or saposin B, globoid cell leukodystrophy (Krabbe disease), Faber lipogranuloma, Wolmann disease and cholesterol ester storage disease, pycnodystostosis, cystinosis, Salah disease, Danon disease, Glycerin disease types 1 / 2 / 3, Hermanski-Padlak disease, and Chediak-Higashi syndrome.

[0057] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0058] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0059] Preferably, the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0060] According to a sixth aspect of the present invention, the use of compounds according to the present invention is provided for the manufacture of pharmaceuticals for use in the treatment or prevention of diseases characterized by neurodegenerative disorders, mental disorders, inflammatory disorders, lysosomal storage disorders, cancer, pain, diabetes mellitus, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye conditions, chronic pain, hearing loss, or misfolded tau.

[0061] According to a sixth aspect of the present invention, the treatment or prevention of a disease or condition responsive to soltirin modification comprises administering a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention. A method is provided.

[0062] The compounds of the present invention may include isotopically labeled and / or isotopically enriched forms of the compounds. The compounds of the present invention as described herein may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15O, 17O, 32P, 35S, 18F, and 36Cl.

[0063] The compounds of the present invention may be used as is, or, where appropriate, as pharmaceutically acceptable salts (acid addition salts or base addition salts). The pharmaceutically acceptable addition salts described below are intended to include therapeutically active and non-toxic acid addition salt and base addition salt forms in which the compounds can be formed. Compounds having basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. 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, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, and ascorbic acid. Acidic compounds can be converted to their pharmaceutically acceptable base addition salts by treating their acidic form with a suitable base. Exemplary forms of base addition salts include sodium salts, potassium salts, calcium salts, and salts with pharmaceutically acceptable amines such as ammonia, alkylamines, benzathine, and amino acids such as arginine and lysine. As used herein, the term addition salt also includes solvates that the compound and its salts can form, such as hydrates and alkoxides.

[0064] Throughout this disclosure, any chemical formula or chemical name shall also encompass all pharmaceutically acceptable forms of its salts, solvates, hydrates, N-oxides, and / or prodrugs. It should be understood that the compounds of the present invention include all hydrates and / or solvates of the compound's formula. It should be understood that certain functional groups, such as hydroxyl groups and amino groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Therefore, it should be understood that the above formulas include and represent various hydrates and / or solvates.

[0065] The compounds of the present invention also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, accompanied by the simultaneous transfer of protons. Tautomers include prototropic tautomers, which are protonated isomers having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or may be sterically fixed into one form by appropriate substitution.

[0066] The compounds described herein may be asymmetric (e.g., having one or more chiral centers). Unless otherwise specified, all stereoisomers, including enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers, such as olefins and C=N double bonds, are also present in the compounds described herein. Such stable isomers may exist, and all such stable isomers are intended herein. The cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as mixtures of isomers or as separated isomers.

[0067] In the case of compounds containing one chiral carbon atom, the present invention relates to the D form, the L form, and mixtures of D and L, and in the case of compounds containing two or more chiral carbon atoms, it also relates to the diastereomer form. Compounds of the present invention containing a chiral carbon atom and obtained in principle as racemates can be separated into optically active isomers by known methods, such as using optically active acids. However, it is also possible to obtain the corresponding optically active or diastereomer compounds as final products by using optically active starting materials from the outset.

[0068] Preferably, the compound of formula (I) is the compound of formula (Ia). [ka]

[0069] The term "prodrug" refers to a compound that can be converted to the bioactive compound of the present invention under physiological conditions or by solvolysis. A prodrug may be inactive at the time of administration to a target requiring it, but is converted to the active compound of the present invention in vivo. Typically, a prodrug is rapidly converted in vivo, for example, by hydrolysis in the blood, to obtain the parent compound of the present invention. Prodrug compounds typically offer advantages such as solubility, histocompatibility, or delayed release in mammalian organisms (Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004)). (See pages 498-549). Prodrugs of the compounds of the present invention can be prepared by modifying functional groups such as hydroxyl groups, amino groups, or mercapto groups present in the compounds of the present invention so that the modified product is cleaved by conventional procedures or in vivo to become the parent compound of the present invention. Examples of prodrugs, but not limited to, include acetate, formate, and succinate derivatives of hydroxyl functional groups or phenylcarbamate derivatives of amino functional groups.

[0070] The compounds of the present invention may be sorotirin inhibitors, binders, modifiers, or antagonists. As used herein, the terms “sorotirin antagonist,” “sorotirin inhibitor,” “sorotirin binder,” or “sorotirin modifier” (used interchangeably) mean substances that interfere, block, or otherwise attenuate the effect of the sorotirin protein on binding to progranulin, neurotensin, another extracellular ligand, or proneurotrophin (e.g., pro-NGF, proNT3, pro-BDNF), and prevent the formation of a trimer complex between sorotirin, p75NTR, and proneurotrophin. The term “sorotirin antagonist” also includes substances or agents that interfere with the formation of a high-affinity trimer complex. In the latter scenario, it is recognized that a trimer complex may be formed in such a way that sorotirin can bind to p75NTR (but not to pro-NGF), and at the same time, p75NTR can bind to the NGF domain of pro-NGF. However, the resulting trimer complex may have a lower affinity for its receptor, and as a result, its ability to stimulate apoptosis through the mechanism described above is reduced. The effect is reduced. Skeldal et al. (2012) demonstrated that when sorbilin lacks an intracellular domain, the apoptotic function of the trimer complex is lost. The term “sorbilin antagonist” also includes substances or drugs that interfere with, block, or otherwise attenuate the effect of the sorbilin protein interacting with p75NTR. This interaction may be completely prevented, in which case the formation of the trimer complex is prevented, or this interaction may be partially prevented, in which case the trimer complex may be formed, but its biological potency may be reduced. Skeldal et al. showed that complex formation between sorbilin and p75NTR is due to the extracellularity of the receptor. We demonstrated that the interaction depends on contact points within the domain and that this interaction is critically dependent on the 23-amino acid sequence near the extracellular membrane of p75NTR. Therefore, sorotirin antagonists can interfere with this 23-amino acid sequence or its proximal sequence in the molecule. "Sortirin antagonists" can act as inhibitors of ligand uptake, and ligands may include progranulin, neurotensin, and BDNF.

[0071] Because the compounds of the present invention can cross the blood-brain barrier, they may be particularly useful in the treatment or prevention of central nervous system diseases, including motor neuron disease, prion diseases such as frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Creutzfeldt-Jakob 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, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors, retinopathy, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau.

[0072] The compounds of the present invention may have Kpuu greater than 0.1, such as 0.1-10, 0.1-5, 0.1-3, 0.1-2, 0.1-1, 0.1-0.8, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2.

[0073] As used herein, the term “treatment” may include the prevention of the disorder or condition described, or the remission or disappearance of a disorder once it has developed. The term “prevention” means the prevention of the disorder or condition described.

[0074] The methods described herein include methods used when a subject is identified as requiring a specific described treatment. Identifying a subject requiring such treatment may be based on the judgment of the subject or a healthcare professional, and may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0075] In other embodiments, the methods of this specification further include monitoring the subject's response to therapeutic administration. Such monitoring may include periodic imaging or sampling of the subject's tissues, fluids, specimens, cells, proteins, chemical markers, genetic material, etc., as markers or indicators for the treatment plan. In other methods, the subject is pre-screened or identified as requiring such treatment by evaluation of relevant markers or indicators of suitability for such treatment.

[0076] The present invention provides a method for monitoring the progress of treatment. The method comprises the step of identifying the level of a diagnostic marker (e.g., any of the targets or cell types shown herein modified with the compounds herein) or a diagnostic measurement (e.g., screening, assay) in a subject who is suffering from or susceptible to the disorder or symptoms thereof as described herein, the subject having been administered a therapeutic dose of the compounds herein sufficient to treat the disease or symptoms thereof. To establish the disease status of the subject, the marker level identified by this method may be compared to a known marker level in either a healthy normal control or another affected patient. In a preferred embodiment, a second level of the marker in the subject is The first level is identified at a later point in time, and these two levels are compared to monitor the course of the disease or the effectiveness of the treatment. In a particular preferred embodiment, the pre-treatment level of Marker in a subject is identified before initiating treatment according to the present invention, and subsequently, this pre-treatment level of Marker may be compared to the level of Marker in the subject after initiation of treatment in order to determine the effectiveness of the treatment.

[0077] The level or activity of a marker in a subject can be identified at least once. Comparing the marker level to other previously or later measurements of marker levels obtained, for example, from the same patient, another patient, or a normal subject, may be useful in determining whether the treatment according to the present invention has the desired effect, thereby allowing for appropriate adjustment of the dosage level. The identification of marker levels may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or body fluid sample is first taken from the subject. Examples of suitable samples include blood, urine, tissue, oral or cheek cells, and hair samples containing hair follicles. Other suitable samples will be known to those skilled in the art. The identification of protein levels and / or mRNA levels (e.g., marker levels) in the sample may be performed using any suitable technique known in the art, but is not limited to, enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence, and real-time PCR.

[0078] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It is understood that the compounds of the present invention may be administered together with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all of these). The pharmaceutical compositions disclosed herein may be administered by any suitable route, preferably orally, rectally, nasally, topically (including intraocular, buccal, and sublingual), sublingual, percutaneously, intrathecally, transmucosally, or parenterally (including subcutaneous, intramuscular, intravenous, and intradermal). Other formulations may be conveniently provided in unit dosage forms, such as tablets and sustained-release capsules, and in liposomes, and may be prepared by any method known in the art of pharmaceuticals. Pharmaceutical formulations are typically prepared by mixing an active substance or a pharmaceutically acceptable salt thereof with a conventionally pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients include water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, and colloidal silicon dioxide. Such formulations may also contain other pharmacological agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, and buffering agents. Typically, the amount of the active compound is 0.1 to 95% by weight of the preparation, preferably 0.2 to 20% by weight in parenteral preparations, and more preferably 1 to 50% by weight in oral preparations. The formulations may further be prepared by known methods such as granulation, compression, microencapsulation, and spray coating. The formulations may be prepared by conventional methods in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable medium. Tablets and granules may be coated by conventional methods. To maintain therapeutically effective plasma concentrations over extended periods, the compounds disclosed herein may be incorporated into sustained-release formulations.

[0079] The dosage level and frequency of administration of a particular compound vary depending on various factors, including the potency of the compound used, its metabolic stability and duration of action, the patient's age, weight, general health, sex, diet, mode and timing of administration, elimination rate, drug combinations, severity of the medical condition to be treated, and the treatment the patient is receiving. The daily dose may range, for example, from approximately 0.001 mg to approximately 100 mg per kg of body weight, and may be administered as a single or multiple doses, for example, in doses of approximately 0.01 mg to approximately 25 mg each. Such doses are usually administered orally, but parenteral administration may be chosen.

[0080] definition As used herein, the term "soltirin" may mean full-length soltirin (also referred to as immature soltirin) having the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, including a signal peptide, propeptide, Vps10p domain, 10CC domain, transmembrane domain, and large cytoplasmic end; or it may mean mature soltirin having the amino acid sequence of SEQ ID NO: 3, including a Vps10p domain, 10CC domain, transmembrane domain, and large cytoplasmic end; or it may mean native fragments, homologs, or variants thereof. The terms "soltirin" and "soltirin molecule" are interchangeable herein. It is understood that soltirin can interact with proneurotrophin molecules to form a soltirin / proneurotrophin complex. This soltirin / proneurotrophin complex may or may not interact with p75NTR molecules to form a trimer complex containing soltirin, proneurotrophin, and p75NTR. It is understood that this trimer complex may be responsible for adverse biological responses such as the stimulation of apoptosis in retinal and ganglion cells and the suppression of growth cone retraction in projecting axons (Jansen et al., 2007; Nykjaer et al., 2004; Santos et al., 2012; Skeldal et al., 2012).

[0081] As used herein, the term “proneurotrophin” refers to a larger precursor of neurotrophin that undergoes protein cleavage to produce the mature neurotrophin. Neurotrophins are a family of proteins that induce neuronal survival, development, and function, and are commonly referred to as growth factors. Proneurotrophins are biologically active and have different roles compared to their neurotrophin counterparts, such as inducing apoptosis. Examples of proneurotrophins include pro-NGF, pro-BDNF, proNT3, and proNT4. Proneurotrophins can also regulate synaptic plasticity. While mature neurotrophins induce synaptic strength, their precursors can weaken synapses.

[0082] "Optional" or "optionally" means that the event or situation described thereafter is not essential but may occur, and that the description includes examples of cases in which the event or situation occurs and examples in which it does not occur.

[0083] The term "heteroatom" refers to O, N, or S.

[0084] (C1~C n The term "(C1-C)alkyl" refers to a linear, branched, cyclic, or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3... or n carbon atoms. n For an alkyl group to contain a cyclic portion, it must be formed from at least three carbon atoms. nFor the "(C1-C4)alkyl" range, all subgroups are intended. For example, in the (C1-C4)alkyl range, all subgroups such as (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 are included. Examples of "(C1-C4)alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and cyclobutyl.

[0085] (C1~C n The term "haloalkyl" refers to the above C1-C alkyl group substituted with at least one halogen atom. n The alkyl group is preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0086] (C1~C n The term "hydroxyalkyl" refers to the above C1-C alkyl group substituted with at least one -OH group. n It indicates an alkyl group.

[0087] (C1~C n The term "alkoxy" is -O-((C1~C n )alkyl) indicates, in this case (C1~C n The alkyl group is as defined above and is bonded to the rest of the compound via an oxygen atom.

[0088] (C1~C n The term "haloalkoxy" refers to the above C1-C substituted with at least one halogen atom. n The compound exhibits alkoxy properties, and the halogen atoms are preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0089] (C1~C n The term "hydroxyalkoxy" refers to the above C1-C substituted with at least one -OH group.n It shows an alkoxy.

[0090] When a term indicates a range, for example, "1 to 4 carbon atoms" in the definition of an alkyl group (C1-C4), each integer, i.e., 1, 2, 3, and 4, is considered disclosed.

[0091] The term "halo" refers to a halogen atom, preferably F, Cl, Br, and I, more preferably F, Cl, and Br.

[0092] "C6~C 10 The term "aryl" refers to an aromatic monocyclic or fused bicyclic hydrocarbon ring system containing 6 to 10 ring atoms.

[0093] The term "5-10 membered ring heterocycloalkyl" refers to a non-aromatic ring system having 5-10 ring atoms, where at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Preferably, each heteroatom is independently selected from N, S, or O, and more preferably N. Preferably, two or fewer ring atoms are heteroatoms. More preferably, only one ring atom is a heteroatom.

[0094] "Effective dose" means the amount of the compound of the present invention that imparts a therapeutic effect to the subject being treated. The therapeutic effect may be objective (i.e., measurable by a test or marker) or subjective (i.e., the subject exhibits signs of or feels an effect).

[0095] As used herein, the terms “administer” or “to administer” mean the route of administration of the compounds disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intraocular, intravenous, intraperitoneal, intra-arterial, and intramuscular. Preferred routes of administration may vary depending on various factors, such as the components of the pharmaceutical composition containing the compounds disclosed herein, the potential or actual site of disease, and the severity of the disease.

[0096] The terms “subject” and “patient” are interchangeable herein. They mean a human or other mammal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that may or may not have the disease or disorder, but is susceptible to the disease or disorder. The subject is preferably a human.

[0097] The compounds of the present invention may be disclosed by name or chemical structure. In the event of any discrepancy between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0098] Next, the present invention will be further described by the following examples, which are not limited to this invention. The following specific examples are simple These are illustrative examples and should not be construed as limiting the remainder of this disclosure in any way. Without further detail, it should be assumed that those skilled in the art can utilize the invention to the fullest extent based on the description herein. All references and publications cited herein are incorporated herein by reference in their entirety.

[0099] Preparation of the compound of the present invention The compounds of the present invention can be prepared according to the following general synthesis procedure scheme by methods known and recognized in the art. Suitable reaction conditions are known in the art, and the substitution of solvents and co-reagents as appropriate is within the scope of common knowledge for those skilled in the art. Similarly, those skilled in the art will recognize that synthetic intermediates can be isolated and / or purified by various known techniques as needed or desired, and that in many cases, various intermediates can be used directly in the next synthesis step with little or no purification. Furthermore, those skilled in the art will understand that in some situations the order in which the parts are introduced is not definitive. As will be fully understood for those skilled in the art, the specific order of steps required to produce a compound of formula (I) varies depending on the relative tendencies of the specific compound to be synthesized, the starting compound, and the parts to be substituted. Unless otherwise specified, all substituents are as defined herein, and all reagents are known and recognized in the art.

[0100] Suitable optically active single enantiomers or racemic mixtures of suitable starting materials and protected amino acids of general formula AA-1 may be commercially available or prepared by various methods. For example, as shown in Scheme 1 of the general synthesis procedure, the carboxylic acid functional group of a suitably substituted amino acid of general formula AA-1 may be used, protected as a free acid, PG=H, or a suitable derivative such as a methyl ester. Functionalization of the primary amine present in Int 1 may be carried out by various methods, and for illustrative purposes, an imine type Int 2 may be obtained by a condensation step involving a suitably substituted carbonyl compound aldehyde or ketone. By treatment with a reducing agent such as sodium triacetoxyborohydride, for example but not limited to, in a suitable solvent mixture such as acetic acid and dichloromethane, the imine functional group can be reduced to an Int 3 type intermediate, which is a precursor to the compound of formula (I) after the liberation of the carboxylic acid functional group. Alternatively, an AA-2 type amino acid may be used as a starting material. As shown in Scheme 2, as already discussed, an Int 4 type intermediate can be obtained by using a condensation step, which, when treated with a suitable base, loses its most acidic proton to form a transient carbanion, which can then be stopped by an alkylating agent such as methyl iodide (but not limited to) to obtain an Int 2 type compound. When treated with a reducing agent such as sodium triacetoxyborohydride (but not limited to) in a suitable solvent mixture such as acetic acid and dichloromethane, the imine functional group can be reduced to obtain an Int 3 type intermediate, or hydrolyzed by treatment with an acidic or basic aqueous solution to obtain a general intermediate Int 5. Next, as in Scheme 1, the compound of formula (I) can be obtained directly from Int 3 by liberation of the acidic moiety, with or without further functionalization of the amine group.

[0101] Another possible approach from an amenable starting amino acid of type AA-3 involves an alkylation step between a suitable protected AA-3 or Int 6 and a 1-bromo-3,3-dimethylbutane reagent, as shown in general synthesis procedure scheme 3, to obtain the general intermediate of type Int 2 discussed earlier. Advantageously, intermediates of types AA-1 to AA-3 can be obtained by procedures known to those skilled in the art or purchased from commercial sources.

[0102] General synthesis procedure [ka]

[0103] Compounds of general formula (I) may be prepared by various 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, polishing, and crystallization.

[0104] Compounds of general formula (I) may contain one or more chiral centers. These can be introduced from available single enantiomers of type AA-1, AA-2, or AA-3, optically active starting materials. The integrity of existing chiral centers can be confirmed by analytical techniques known to those skilled in the art, such as chiral support high-pressure chromatography. Alternatively, if racemic starting materials are used, it is understood that single isomer products, either as single enantiomers or as single diastereoisomers, can be obtained, if desired, by known techniques such as preparative chiral support high-pressure chromatography.

[0105] Those skilled in the art will know that all substituents of the compound of formula (I) are used in the synthesis of the compound. It is understood that these groups may not withstand specific reaction conditions. As is known to those skilled in the art, these groups may be introduced or protected at a convenient point in the synthesis and subsequently deprotected as needed or desired. Those skilled in the art will understand that protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention. Methods for introducing or removing protecting groups used in the present invention are known to those skilled in the art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons, New York (2006). [Examples]

[0106] Abbreviation approx: approximately; aq: aqueous; br: broad; ca.: approximately; CDI: 1,1'-carbonyldiimidazole; CPME: cyclopentyl methyl ether; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; Â: ethyl acetate; EtOH: ethanol; Fmoc: fluorenyl methoxycarbonyl; Boc: tert-butoxycarbonyl; h: hours; min: minutes; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-teto Lamethylisouronium hexafluorophosphate (V); HPLC: High-performance liquid chromatography; IPA, isopropanol; LC: Liquid chromatography; m: Multiplet; M: Molar concentration, molecular ion; MeCN: Acetonitrile; MeOH: Methanol; MS: Mass spectrometry; NMR: Nuclear magnetic resonance; PDA: Photodiode array; q: Quartet; rt: Room temperature (approx. 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; ULC: Ultra-high-performance liquid chromatography; UV: Ultraviolet

[0107] Other abbreviations are intended to indicate their generally accepted meanings.

[0108] General experimental conditions All starting materials and solvents were obtained from commercially available sources or prepared according to the referenced literature. Unless otherwise specified, the reaction mixtures were stirred with a magnetic stirrer, and the reactions were carried out at room temperature (approximately 20°C).

[0109] Unless otherwise specified, column chromatography was performed using a pre-packed silica (40 μm) cartridge on an automated flash chromatography system such as the CombiFlash Rf system.

[0110] Analysis method ¹H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 instrument. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane unless otherwise specified. The following abbreviations or combinations thereof are used for the multiplexing of NMR signals: br=broad, d=doublet, m=multiplet, q=quartet, quint=quintet, s=singlet, and t=triplet.

[0111] Method 1: Apparatus: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN, with SO; UPCMA, PDA: UPPDATC, 210~320nm, SQD: ACQ-SQD2 ESI; ELSD: Gas pressure 40psi, Drift tube temperature: 50℃; Column: Waters XSelect CSH C18, 50×2 0.1 mm, 2.5 μm, Temperature: 25℃, 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 aqueous solution (pH=9.5), Eluent B: Acetonitrile

[0112] Method 2: Apparatus: Agilent 1260 Infinity, 1260 G1312B binary pump, 1260 G1367E WPS, 1260 TCC G1316A column compartment, 1260 G1315C DAD (210-320nm, 210 and 220nm), PDA (210-320nm), G6130B MSD ESI Positive / Negative (mass range 100-1000), Column: Waters XSelect CSH C18 (30×2.1mm, 3.5μ), Flow rate: 1ml / min; Column temperature: 25℃, Eluent A: 10mM ammonium bicarbonate aqueous solution (pH=9), Eluent B: Acetonitrile, Gradient: t=0 min 5%B, t=1.6 min 98%B, t=3 min 98%B, Postrun: 1.3 min

[0113] Method 3: Apparatus: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 mincate LC; Column: Waters XSelect CSH (C18, 100 × 30 mm, 10 μm); Flow rate: 55 mL / min; Column temperature: Room temperature; Eluent A: 0.1% formic acid aqueous solution; Eluent B: 100% acetonitrile; Linear gradient: t=0 min 20% B, t=2 min 20%B, t=8.5 min; 60%B, t=10 min; 100%B, t=13 min; 100%B; Detection: DAD (220~320nm); Detection: MSD (ESI positive / negative) mass range: 100~1000; Fractions collected based on MS and DAD.

[0114] Method 4: Apparatus: ACQ-SQD2; HPLC instrument type: Waters Modular preparative HPLC system; Column: Waters XSelect (C18, 100 × 30 mm, 10 μm); Flow rate: 55 ml / min; Preparative pump; Column temperature: Room temperature; Eluent A: 10 mM ammonium bicarbonate aqueous solution pH=9.5; Eluent B: 100% acetonitrile; Detection: DAD (220~320 nm); Detection: MSD (ESI positive / negative) mass range: 100~800; Fractions were collected based on MS and DAD.

[0115] Method 5: Apparatus: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN, with SO; UPCMA, PDA: UPPDATC, 210~320nm, SQD: MS: QDA ESI, positive / negative 100~800; Column: Waters XSelect CSH C18, 50×2.1mm, 2.5μm, Temperature: 25℃, Flow rate: 0.6mL / min, Gradient: t0=5%B, t1.3min=98%B, t1.7min=98%B, Post time: 0.3min, Eluent A: 10mM Ammonium bicarbonate aqueous solution (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 / hour; Desolvation gas flow rate: 1000L / hour; Full MS scan: MS range 100~800 (positive and negative modes); Scan: 0.4 seconds

[0116] Method 6: Apparatus: Waters I-Class UPLC, Binary Solvent Manager (BSM), Sample Manager-FTN (SM-FTN) and Sample Organizer (SO), Column Manager (CM-A), PDA 210~320nm, QDa ESI 100~800 (positive) 100~800 (negative), Column: XSelect CSH C18 XP (50×2.1mm 2.5μm), Flow rate: 0.6ml / min; Column temperature: 25℃, Eluent A: 10mM ammonium bicarbonate aqueous solution (pH9.5), Eluent B: Acetonitrile, Gradient: t=0min 5%B, t=2min 98%B, t= 2.7 minutes, 98% B, Post-run: 0.3 minutes

[0117] Method 7: Apparatus: 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 makeup pump, Waters Acquity QDa MS detector; Column: Lux i-Cellulose-5 (100 × 4.6 mm 5 μm); Column temperature: 35°C, Flow rate: 2.5 ml / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: Methanol + 20 mM Ammonia; Gradient: t=0 min 5%B, t=5 min 50%B, t=6 min 50%B; Detection: 210~320 nm

[0118] Method 8: Apparatus: Waters Prep 100 SFC UV / MS 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°C, Flow rate: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Detection: PDA (210~400 nm); Gradient: t=0 min 25% B; t=5 min 45% B. Sample concentration 20 mg / ml. Injection volume: 500 μl. Fraction recovery by time.

[0119] Method 9: Apparatus: Waters Prep 100 SFC UV / MS system; Waters 2998 photodiode array (PDA) detector; Waters Acquity QDa MS detector; Waters 2767 sample manager; Column: Diacel Chiralpak IC for SFC (250 × 20 mm, 5 μm); Column temperature: 35°C, Flow rate: 70 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Linear gradient: t=0 min 20%B, t=4.5 min 50%B; Detection: PDA (210~400 nm); Fraction recovery: PDA TIC

[0120] Method 10: Apparatus: 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 makeup pump, Waters Acquity QDa MS detector; Column: Chiralpak IC (100 × 4.6 mm, 5 μm); Column temperature: 35°C, Flow rate: 2.5 ml / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: Methanol + 20 mM ammonia; Linear gradient: t=0 min 5%B, t=5 min 50%B, t=6 min 50%B; Detection: 210~320 nm

[0121] Method 11: Apparatus: 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 makeup pump, Waters Acquity QDa MS detector; Column: phenomenex iAmylose-3 (100 × 4.6 mm 5 μm); Column temperature: (35°C); Flow rate: (2.5 ml / min); ABPR: (170 bar); Eluent A: CO2, Eluent B: Methanol + 20 mM ammonia; Linear gradient: t=0 min 5%B, t=5 min 50%B, t=6 min 50% B; Detection: 210~320nm

[0122] Method 12: Apparatus: Waters Prep 100 SFC UV / MS system; Waters 2998 photodiode array (PDA) detector; Waters Acquity QDa MS detector; Waters 2767 sample manager; Column: phenomenex iAmylose-3 (250 × 20 mm, 5 μm); Column temperature: 35°C, Flow rate: 70 ml / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Linear gradient: t=0 min 20%B, t=4.5 min 50%B; Detection: PDA (210~400 nm); Fraction recovery: PDA TIC

[0123] Examples 1, 2, and 3 [ka]

[0124] Synthesis of methyl(E)-2-(benzylideneamino)propanoate (Int 1-a) Methyl L-alaninate hydrochloride (20 g, 143 mmol) was stirred in toluene (100 ml) for 20 minutes. Benzaldehyde (14.71 ml, 145 mmol, 1.01 equivalents), triethylamine (30.0 ml, 215 mmol, 1.5 equivalents), and sodium sulfate (12.21 g, 86 mmol, 0.6 equivalents) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered. The residue was washed with toluene (20 mL), and the organic layer was concentrated under vacuum. Crude methyl(E)-2-(benzylideneamino)propanoate (23.5 g, 123 mmol, 86%, purity 85%) was obtained as a white solid. LC-MS (Method 2, 1.815 min; M+H=192.1; calculated value 192.2) was performed, and this was used without further purification.

[0125] Synthesis of methylmethyl(E)-2-(benzylideneamino)-2,5,5-trimethylhexanoate (Int 1-b) Methyl(E)-2-(benzylideneamino)propanoate (10 g, 52.3 mmol) in dry toluene (50 mL) was heated to 40°C. 1-bromo-3,3-dimethylbutane (11.22 g, 68.0 mmol, 1.3 equivalents) was added, followed by KOtBu (5.87 g, 52.3 mmol, 1.0 equivalent) in dry tetrahydrofuran (50 mL). The mixture was stirred overnight. The mixture was cooled to room temperature and the reaction was stopped with water (20 mL). The mixture was extracted with ethylethanol, washed with brine, and dried on sodium sulfate. Methyl(E)-2-(benzylideneamino)-2,5,5-trimethylhexanoate (9.86 g, 35.8 mmol, yield 68%) was obtained by vacuum concentration. LCMS (Method 2, 2.345 min; M+H=276.2; calcd 276.2). 1 H-NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.85 - 7.70 (m, 2H), 7.48 - 7.36 (m, 3H), 3.74 (s, 3H), 1.90 (tt, J = 8.6, 6.6 Hz, 2H), 1.49 (s, 3H), 1.25 - 1.14 (m, 2H), 0.89 (s, 9H)

[0126] Synthesis of rac-2-benzylamino-2,5,5-trimethylhexanoic acid (Example 1), (S)-2-benzylamino-2,5,5-trimethylhexanoic acid (Example 2), and (R)-2-benzylamino-2,5,5-trimethylhexanoic acid (Example 3) Sodium borohydride (0.824 g, 21.79 mmol, 2.0 equivalents) is mixed with methyl(E)-2-(benzylideneamino)-2,5,5-tri The mixture was added at 0°C to a solution of methylhexanoate (3.0 g, 10.89 mmol) and stirred overnight at room temperature. The mixture was partially concentrated and partitioned between DCM and water. The aqueous layer was extracted once with DCM, and the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain 1.95 g of yellow oil. The mixture was purified by flash column chromatography (reveleris 40 g silica cartridge, gradient heptane with 0% to 100% siRNA) to obtain methyl 2-(benzylamino)-2,5,5-trimethylhexanoate (781 mg, 2.82 mmol, yield 25%) as yellow oil. LCMS (Method 2, 2.304 min; M+H=278.2; calculated value 278.2). This oil was dissolved in MeCN / water / THF (1 / 1 / 1, volume / volume / volume, 9 mL), lithium hydroxide monohydrate (591 mg, 14.08 mmol, 5.0 equivalents) was added, and the mixture was heated overnight at 80°C. Only 20% saponification product was observed, but a light brown, sticky solid precipitated from the solution. This was recovered by filtration and dried overnight on a vacuum stove to obtain the target product containing impurities, which was subjected to basic preparative purification (Method 2). After purification, 20 mg was retained as a racemic mixture, and the remaining substance (60 mg) was subjected to SFC purification (Method 8). The purified fractions were combined, evaporated, weighed, redissolved in MeCN (0.05 M), and 0.1 M MsOH solution in MeCN (1 equivalent) was added. A small amount of water was added, and the mixture was freeze-dried to obtain rac-2-benzylamino-2,5,5-trimethylhexanoic acid methanesulfonic acid (Example 1, 29 mg, 0.081 mmol, yield 2%, purity 100%). LC-MS (Method 6, 1.020 min; M+H-MsOH=264.2; calculated value 264.2). 1 H-NMR (400 MHz, DMSO) δ 14.94 - 13.59 (m, 1H), 9.14 (s, 2H), 7.55 - 7.38 (m, 5H), 4.25 - 4.00 (m, 2H), 2.30 (s, 3H, MsOH), 1.92 (td, J = 13.3, 4.6 Hz, 1H), 1.81 (td, J = 13.3, 4.6 Hz, 1H), 1.56 (s, 3H), 1.28 (td, J = 13.0, 4.6 Hz, 1H), 1.17 (td, J = 12.9, 4.6 Hz, 1H), 0.88 (s, 9H)

[0127] (S)-2-benzylamino-2,5,5-trimethylhexanoic acid compound with methanesulfonic acid (Example 2, 21.2 mg, 0.059 mmol, yield 2%, purity 87.35%). LC-MS (Method 6, 1.007 min; M+H-MsOH=264.2; calculated value 264.2). LC-MS (Method 7, 3.280 min; M+H-MsOH=264.1; calculated value 264.2). 1 H-NMR (400 MHz, DMSO) δ 9.59 - 8.45 (m, 2H), 7.52 - 7.39 (m, 5H), 4.13 (d, J = 12.7 Hz, 1H), 4.00 (d, J = 12.8 Hz, 1H), 2.29 (s, 3H, MsOH), 1.88 (td, J = 12.8, 4.4 Hz, 1H), 1.77 (td, J = 13.2, 4.4 Hz, 1H), 1.51 (s, 3H), 1.27 (td, J = 12.0, 3.6 Hz, 1H), 1.17 (td, J = 12.9, 4.8 Hz, 1H), 0.87 (s, 9H)

[0128] (R)-2-benzylamino-2,5,5-trimethylhexanoic acid compound with methanesulfonic acid (Example 3, 26.4 mg, 0.073 mmol, yield 2%, purity 95.65%). LCMS (Method 6, 1.001 min; M+H-MsOH=264.2; calculated value 264.2). LCMS (Method 7, 3.773 min; M+H-MsOH=264.1; calculated value 264.2). 1H-NMR (400 MHz, DMSO) δ 9.14 (s, 2H), 7.54 - 7.41 (m, 5H), 4.25 - 4.10 (m, 1H), 4.10 - 3.99 (m, 1H), 2.30 (s, 3H), 1.92 (td, J = 13.4, 4.7 Hz, 1H), 1.81 (td, J = 13.3, 4.7 Hz, 1H), 1.56 (s, 3H), 1.28 (td, J = 13.0, 4.8 Hz, 1H), 1.17 (td, J = 12.9, 4.7 Hz, 1H), 0.88 (s, 9H)

[0129] Examples 4, 5, and 6 [ka]

[0130] Synthesis of methyl 2-amino-2,5,5-trimethylhexanoate hydrochloride (Int 2-b) To an ice-cold solution of commercially available 2-amino-2,5,5-trimethylhexanoate (Int 2-a, 250 mg, 1.192 mmol) in methanol (1 ml), thionyl chloride (0.261 ml, 3.58 mmol, 3.0 equivalents) was added dropwise under an argon atmosphere. The mixture was stirred at 0°C for 15 minutes, followed by 3 hours at room temperature. A thick white suspension was formed. The suspension was diluted with a small amount of MeOH and stirred overnight. Further addition of thionyl chloride (0.261 ml, 3.58 mmol) was made, and the mixture was heated under reflux for 4.5 hours. The mixture was allowed to cool to room temperature, the solvent was evaporated, MeCN was added, and the solvent was evaporated to obtain methyl 2-amino-2,5,5-trimethylhexanoate hydrochloride (233 mg, 1.041 mmol, yield 87%) as an off-white, cloudy oil. LCMS (Method 2, 1.782 min; M+H-HCl=188.1; calcd. 188.2). 1H-NMR (400 MHz, DMSO) δ 8.53 (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)

[0131] The following intermediate Int 3-b was prepared starting from the corresponding commercially available amino acid Int 3-a using a method similar to that for intermediate Int 2-b. [Table 1]

[0132] Synthesis of 2-((3-methoxybenzyl)amino)-2,5,5-trimethylhexanoate. Example 4 A suspension of methyl 2-amino-2,5,5-trimethylhexanoate hydrochloride (58.25 mg, 0.260 mmol) in acetonitrile (1 ml) was mixed with DIPEA (0.136 ml, 0.781 mmol) and 1-(bromomethyl)-3-methoxybenzene (0.036 ml, 0.260 mmol). The mixture was heated at 80°C for 2 hours. The mixture was cooled to room temperature, diluted with water (1 mL), and lithium hydroxide monohydrate (54.6 mg, 1.302 mmol, 5 equivalents) was added. The mixture was heated at 80°C overnight. The crude product was filtered and purified by basic preparative fractionation (Method 4). The purified fraction was concentrated in Genevac and reformatted with 1 M HCl to obtain 2-((3-methoxybenzene (L)amino-2,5,5-trimethylhexanoate (Example 4, 25.8 mg, 0.078 mmol, yield 30%, purity 100%) was obtained as a white solid. LC-MS (Method 1, 1.163 min; M+H-HCl=294.3; calculated value 294.2). 1 H-NMR (400 MHz, DMSO) δ 9.94 - 8.64 (br, 1H)7.34 (t, J = 7.9 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.97 (dd, J = 8.2, 2.6 Hz, 1H), 4.12 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 12.7 Hz, 1H), 1.98 - 1.75 (m, 2H), 1.52 (s, 3H), 1.31 - 1.12 (m, 2H), 0.86 (s, 9H)

[0133] Examples 7-9 below were prepared starting from the corresponding esters and in a manner similar to that of Example 4. [Table 2]

[0134] (S)-2-((3-methoxybenzyl)amino)-2,5,5-trimethylhexanoate (Example 5) and (R)-2-((3-methoxybenzyl)amino)-2,5, Synthesis of 5-trimethylhexanoate (Example 6). Stereochemistry assigned by X-ray crystal structure analysis. 2-((3-methoxybenzyl)amino)-2,5,5-trimethylhexanoic acid (Example 4, 158 mg, 0.539 mmol) was purified by SFC (Method 9). The purified fractions were combined and concentrated. The fractions were reconstituted with 1 M aqueous HCl to obtain (S)-2-((3-methoxybenzyl)amino)-2,5,5-trimethylhexanoic acid (64 mg, 0.194 mmol, yield 27%, purity 99.69%, >99%ee). LCMS (Method 6, 0.993 min; M+H-HCl=294.3; calculated value 294.2). LCMS (Method 10, 3.138 min; M+H-HCl=294.1; calculated value 294.2). 1 H-NMR (400 MHz, DMSO) δ 14.67 - 13.61 (br, 1H), 9.98 - 8.91 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.99 (dd, J = 8.2, 2.6 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.97 (d, J = 12.7 Hz, 1H), 3.79 (s, 3H), 1.96 (td, J = 13.2, 4.9 Hz, 1H), 1.86 (td, J = 13.1, 5.0 Hz, 1H), 1.56 (s, 3H), 1.32 - 1.12 (m, 2H), 0.87 (s, 9H)

[0135] (R)-2-((3-methoxybenzyl)amino)-2,5,5-trimethylhexanoate (57.8 mg, 0.175 mmol, yield 24%, purity 99.76%, >99%ee) was also obtained. LCMS (Method 6, 0.992 min; M+H-HCl=294.3; calculated value 294.2). LCMS (Method 10, 3.658 min; M+H-HCl=294.1; calculated value 294.2). 1 H-NMR (400 MHz, DMSO) δ 14.86 - 13.43 (br, 1H), 9.38 (s, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.1, 2.6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.79 (s, 3H), 1.95 (td, J = 13.9, 5.6 Hz, 1H), 1.85 (td, J = 13.2, 4.9Hz, 1H), 1.56 (s, 3H), 1.32 - 1.13 (m, 2H), 0.87 (s, 9H)

[0136] Examples 10 and 11 below were prepared starting from the corresponding racemic mixtures in a manner similar to that of Examples 5 and 6. [Table 3]

[0137] Examples 12 and 13 below can be prepared starting from the corresponding racemic mixtures in a manner similar to that of the other examples. [Table 4]

[0138] In the examples above, if the stereochemistry is not specified, the compound was prepared as a racemic mixture.

[0139] Biological data Neurotensin Scintillation Proximity Assay The exemplary compounds of the present invention were tested by neurotensin (NTS) scintillation proximity assay (SPA). 50 The data is shown in the table below. NTS, a 13-amino acid neuropeptide, is a ligand for soltirin. 50 IC is a measure of the amount of compound required to inhibit the binding of NTS to soltirin by 50%. Those skilled in the art will know IC 50 It is recognized that a lower value means fewer compounds are needed to achieve the desired effect, and as a result, the probability of undesirable off-target effects is reduced.

[0140] The affinity of a compound is expressed in the SPA format as follows: 3 This was identified by measuring the substitution of [3H]-neurotensin binding to h-soltilin. A total volume of 40 μl was used in 50 mM HEPES pH 7.4 assay buffer containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween-20. The compound was pre-incubated with 150 nM 6-his-soltilin at room temperature for 30 minutes, then 5 nM [3H]-neurotensin and Ni chelate imaging beads (Perkin Elmer) were added. After 6 hours, the plate was read on ViewLux with a 360-second exposure time. Dose-response evaluation of the compound was performed at eight drug concentrations (including three orders of magnitude). IC5 The zero value was calculated using CDD Vault software via nonlinear regression with a sigmoid concentration response (variable gradient). All reported values ​​are the average of at least two specific values.

[0141] Human sorbitin GCI binding assay The exemplary compounds of the present invention were tested by grating-binding interference (GCI) soltirin binding assay. The GCI data are shown in Table 1 below. Equilibrium dissociation constant (K D K is a measure of the tendency of a complex (i.e., ligand and receptor) to dissociate and is used to represent the affinity of the interaction between the components of the complex (i.e., ligand and receptor). As those skilled in the art will know, D It is recognized that a lower value means fewer compounds are needed to achieve the desired effect, and as a result, the probability of undesirable off-target effects is reduced.

[0142] The affinity of the compound was determined using a Creoptix Wave instrument (Creoptix-Malvern Panalytical) to determine human (6-His) soltirin (RnD The compounds were identified by measuring their association and dissociation with (Systems). Immobilization of human (6-His) sorbitol and evaluation of the compounds were both performed in HBS-N running buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 1% DMSO (Cytiva), filtered and degassed for 15 minutes before use.

[0143] Before immobilization, the 4PCH WAVEchip (Creoptix - Malvern Panalytical) was conditioned by injecting 0.2×HBS-N running buffer containing 0.1M borate pH 9.0 and 1M NaCl (Xantec Bioanalytics) into all flow cells. The buffer was then replaced with 1×HBS-N running buffer, and human (6-His) sorbitin was immobilized in a pH 5.0 acetate solution (Cytiva) by amine coupling after surface activation with EDC / NHS (Cytiva), followed by passivation with 50mM Tris pH 7.4.

[0144] Compounds were tested using the "WAVE-RAPID" assay at a single concentration (typically 1 μM, 10 μM, or 100 μM) in a time-reaction format (increasing the duration of short pulses), using either "Weak-Binders" (settings: flow rate 400 μl / min, acquisition rate 40 Hz, association time 5 sec, and dissociation time 20 sec) or "Intermediate Binders" (settings: flow rate 100 μl / min, acquisition rate 10 Hz, association time 25 sec, and dissociation time 300 sec). The most appropriate setting was determined based on the affinity and kinetics of the compound tested.

[0145] Calibration with DMSO was performed by injecting a running buffer containing 0.5% more DMSO than the running buffer (1.5% in this example) every 20 cycles, as required by the manufacturer. All data were double-referenced (blank and reference channel subtracted) and fitted to a "1:1 dynamic" coupled model using "WAVEcontrol" software (Creoptix - Malvern Panalytical). D The value was calculated.

[0146] Programurin cell surface binding assay The exemplary compounds of the present invention were tested using a progranulin (PGRN) cell surface binding assay. 50The data is shown in Table 1 below. PGRN is a ligand for sorbitol. IC 50 IC is a measure of the amount of compound required to inhibit the binding of PGRN to soltirin by 50%. Those skilled in the art will know that IC 50 It is recognized that a lower value means fewer compounds are needed to achieve the desired effect, and as a result, the probability of undesirable off-target effects is reduced.

[0147] The affinity of the compound was determined by measuring the compound's ability to replace the binding of progranulin-Alexa Fluor647 (PGRN-AF647) to the sorotirin receptor on the cell surface. HEK293 cells engineered to express sorotirin were pre-incubated with the compound on ice for 30 minutes in 20 μl of assay buffer containing 1% BSA in PBS. The dose-response evaluation of the compound was performed at 10 drug concentrations (10-point semi-logarithmic curve). PGRN-AF647 was added at a concentration of 100 nM in 20 μl of assay buffer on ice for 2 hours. Data were acquired using an iQue flow cytometer (IntelliCyt). IC 50 The values ​​were calculated using CDD Vault software via nonlinear regression with sigmoid concentration-response (variable gradient). All reported values ​​are the average of at least two specific values.

[0148] The data in the table below shows that the compounds of the present invention are binders and inhibitors for h-soltirin. [Table 5]

[0149] X-ray crystallography s-Sortiline and the luminal domain of Sortiline were obtained as previously reported (Andersen et al., Acta Cryst. D, 2017). For crystallization, 2 μl of 5 mg / ml s-Sortiline in 50 mM Tris-HCl pH 7.3 and 150 mM NaCl was mixed with 0.2 μl of Example 5 dissolved in DMSO at a concentration of 8.49 mM. This droplet was mixed with 2 μl of a reservoir solution consisting of 100 mM Hepes pH 7.3, 400 mM Malonate pH 7.3, 7 vol / vol% glycerol, and 24 wt / vol% PEG3350. The sitting drop was left with 500 μl of the reservoir solution and equilibrated by vapor diffusion. The crystals were subjected to litho-loops without further freeze protection. The sample was placed on a 3D scanner and instantaneously cooled with liquid nitrogen. Diffraction data was collected at beamline ID23-2, ESRF, Grenoble, and packaged in XDS format (Kabsch, W., Acta Cryst. D, 2010). The data was processed using (see Table 2 below).

[0150] The phase for the structure factor was obtained using the known structure of soltirin as a search model (PDB entry: 3F6K) and molecular substitution using the Phaser program implemented in the Phenix software package (Afonine et al., Acta Cryst. D, 2012). The refined model was obtained by multi-cycle model construction using Coot (Emsley P. et al., Acta Cryst. D, 2010) and maximum likelihood refinement using Phenix.

[0151] The details of the diffraction data are shown in Table 2 below (statistics for the highest resolution shell are shown in parentheses). [Table 6]

[0152] X-ray images of Example 5, bound to h-soltilin, are shown in Figures 1 to 10. Figures 9 and 10 also show the atomic contribution to the estimated binding affinity.

[0153] Figures 11A to 11C show electron density maps illustrating the crystal structure obtained by applying the electron density observed by X-ray crystallography to the molecular structure.

[0154] Details of the electron density map are as follows: Figure 11A - 2fo-fc map. Density contour level = 1.5σ Figure 11B - Omit map. Density contour = 4.0σ Figure 11C - Polder map. Density contour = 6.0σ

[0155] Embodiments of the present invention Embodiment 1. Formula (I) [ka] A compound of, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein, R 1 teeth, (i) C6~C 10 C1-C4 alkyl groups optionally substituted with aryl groups; and (ii)-OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, acetyl, cyano, C6-C 10 Aryl, 5-membered ring to 10-membered ring heteroaryl, 5-membered ring to 10-membered ring heterocycloalkyl, -O-(C6~C 10 aryl), -O-CH2-(C6~C 10 aryl), and -NR 4 R 5Optionally substituted with one or more substituents independently selected from the group consisting of, C6-C 10 aryl and 5- to 10-membered heteroaryl, selected from the group consisting of; R 2 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and phenyl; ; R 3 is H or -CH3; R 4 and R 5 are each independently H or C1-C4 alkyl; and ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​(Aryl), -O-CH2-(C6-C 10 (Aryl), and -NR 4 R 5 Phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of: A compound according to embodiment 1 or 2, selected from the group consisting of:

[0158] 4.R 1 In the 5-membered or 6-membered monocyclic heteroaryl group and 9-membered or 10-membered fused bicyclic heteroaryl group of, each ring atom is independently selected from the group consisting of C, N, S, and O, preferably 1 to 3 ring atoms are independently selected from the group consisting of N, S, and O, and the remaining ring atoms are C. A compound according to embodiment 3.

[0159] 5.R 1 In the 5-membered or 6-membered monocyclic heteroaryl group of, each ring atom is independently C or N, preferably 1 or 2 ring atoms are N, and the remaining ring atoms are C. A compound according to embodiment 4. <00​​​​​​​​​​​​​​​​​​The 9-membered or 10-membered ring fused bicyclic heteroaryl group is independently selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthilidinyl, pyridopyrimidinyl, pyridopyradinyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, azaindazolyl, pyrazolopyrimidinyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl, preferably independently selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, naphthilidinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, and benzofuranyl, more preferably the following group: [ka] A compound according to any one of embodiments 3 to 6, wherein each group is optionally substituted.

[0162] 8.R 1 but, (i) C1-C2 alkyl groups optionally substituted with phenyl; and (ii)-OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, acetyl, cyano, 5-membered ring or 6-membered ring heteroaryl, 5-membered ring heterocycloalkyl, -O-phenyl, and -NR 4 R 5 A group independently selected from the following, preferably -OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5Phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of A compound according to any one of Embodiments 1 to 7, selected from the group consisting of

[0163] 9.R 1 is (i) C1-C2 alkyl optionally substituted with phenyl; and (ii) -OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5 Phenyl and 5-membered or 6-membered monocyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of; and (iii) Naphthyl and 9-membered or 10-membered fused bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, and C1-C2 alkoxy, A compound according to any one of Embodiments 1 to 8, selected from the group consisting of

[0164] 10.R 1 is (i) C1-C2 alkyl optionally substituted with phenyl; (ii) -OH, halo, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, acetyl, cy ano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR 4 R 5 Phenyl, optionally substituted with one or more substituents independently selected from the group consisting of; (iii) A 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, and -O-phenyl; (iv) naphthyl optionally substituted with one or more substituents independently selected from the group consisting of halo and C1-C2 alkoxy; and (v) a 9- or 10-membered fused bicyclic heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of halo and C1-C2 alkyl, The compound according to embodiment 9, selected from the group consisting of.

[0165] 11. R 1 is

Chemical formula

Chemical formula

化

Chemical formula

[0166] 12. The compound is (R)-2-benzylamino-2,5,5-trimethylhexanoic acid; (S)-2-benzylamino-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (S)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; 2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (R)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; (S)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5-dimethylhexanoic acid; 2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-benzylamino-2,5,5-trimethylhexanoic acid; The compounds according to any one of Embodiments 1 to 11, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0167] 13. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 12, and a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0168] 14. A compound according to any one of Embodiments 1 to 12 or a pharmaceutical composition according to Embodiment 13, for use in therapeutic purposes.

[0169] 15. For use in the treatment or prevention of neurodegenerative disorders, mental disorders, inflammatory disorders, lysosomal storage disorders, cancer, pain, diabetes mellitus, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye conditions, chronic pain, hearing loss, or diseases characterized by misfolded tau; Preferably, the neurodegenerative disorder is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy; Preferably, neurodegenerative disorders include amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia, which involve misfolded TAR DNA-binding proteins. Characterized by quality 43; Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder. Preferably, the inflammatory disorder is selected from inflammatory diseases and neuroinflammation; Preferably, lysosomal storage disorders are caused by mutations in the CLN genes 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. NCL / Batten disease; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysaccharidosis (MPS) type I (Harler disease) / type II (Hunter disease) / type IIIa (Sanfilippo A) / type IIIB (Sanfilippo B) / type IIIc (Sanfilippo A) Selected from the group consisting of 'Nfilippo C) / IIId (Sanfilippo D) / IVA (Morquio A) / VB / VI / VII (Slye) / IX, mucolipisosis type III (I-cell) and IV, multiple sulfatase deficiencies; sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosamineuria, fucosidosis, Schindler's disease, metachromatic leukodystrophy resulting from a deficiency of either arylsulfatase A or saposin B, globoid cell leukodystrophy (Krabbe disease), Faber lipogranuloma, Wolmann disease and cholesterol ester storage disease, concentrated dysostosis, cystinosis, Salla disease, Danon disease, Glycerin disease types 1 / 2 / 3, Hermanskie-Padlak disease, and Chediak-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 preferably 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, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss. A compound according to any one of Embodiments 1 to 12, or a pharmaceutical composition according to Embodiment 13.

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[0171] Sequences that are referenced throughout this specification and form part of the description. Sequence ID: 1 (Full-length sorbitol-isoform 1) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCKAD LGALELWRTS DLGKSFKTIG 301 VKIYSFGLGG RFLFASVMAD KDTTRRIHVS TDQGDTWSMA QLPSVGQEQF 351 YSILAANDDM VFMHVDEPGD TGFGTIFTSD DRGIVYSKSL DRHLYTTTGG 401 ETDFTNVTSL RGVYITSVLS EDNSIQTMIT FDQGGRWTHL RKPENSECDA 451 TAKNKNECSL HIHASYSISQ KLNVPMAPLS EPNAVGIVIA HGSVGDAISV 501 MVPDVYISDD GGYSWTKMLE GPHYYTILDS GGIIVAIEHS SRPINVIKFS 551 TDEGQCWQTY TFTRDPIYFT GLASEPGARS MNISIWGFTE SFLTSQWVSY 601 TIDFKDILER NCEEKDYTIW LAHSTDPEDY EDGCILGYKE QFLRLRKSSM 651 CQNGRDYVVT KQPSICLCSL EDFLCDFGYY RPENDSKCVE QPELKGHDLE 701 FCLYGREEHL TTNGYRKIPG DKCQGGVNPV REVKDLKKKC TSNFLSPEKQ 751 NSKSNSVPII LAIVGLMLVT VVAGVLIVKK YVCGGRFLVH RYSVLQQHAE 801 ANGVDGVDAL DTASHTNKSG YHDDSDEDLL E

[0172] Sequence ID: 2 (Full-length sorbitol-isoform 2) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCTDL GALELWRTSD LGKSFKTIGV 301 KIYSFGLGGR FLFASVMADK DTTRRIHVST DQGDTWSMAQ LPSVGQEQFY 351 SILAANDDMV FMHVDEPGDT GFGTIFTSDD RGIVYSKSLD RHLYTTTGGE 401 TDFTNVTSLR GVYITSVLSE DNSIQTMITF DQGGRWTHLR KPENSECDAT 451 AKNKNECSLH IHASYSISQK LNVPMAPLSE PNAVGIVIAH GSVGDAISVM 501 VPDVYISDDG GYSWTKMLEG PHYYTILDSG GIIVAIEHSS RPINVIKFST 551 DEGQCWQTYT FTRDPIYFTG LASEPGARSM NISIWGFTES FLTSQWVSYT 601 IDFKDILERN CEEKDYTIWL AHSTDPEDYE DGCILGYKEQ FLRLRKSSVC 651 QNGRDYVVTK QPSICLCSLE DFLCDFGYYR PENDSKCVEQ PELKGHDLEF 701 CLYGREEHLT TNGYRKIPGD KCQGGVNPVR EVKDLKKKCT SNFLSPEKQN 751 SKSNSVPIIL AIVGLMLVTV VAGVLIVKKY VCGGRFLVHR YSVLQQHAEA 801 NGVDGVDALD TASHTNKSGY HDDSDEDLLE

[0173] Sequence ID: 3 (Mature Sortirin) 1 MTFGQSKLYR SEDYGKNFKD ITDLINNTFI RTEFGMAIGP ENSGKVVLTA 51 EVSGGSRGGR IFRSSDFAKN FVQTDLPFHP LTQMMYSPQN SDYLLALSTE 101 NGLWVSKNFG GKWEEIHKAV CLAKWGSDNT IFFTTYANGS CTDLGALELW 151 RTSDLGKSFK TIGVKIYSFG LGGRFLFASV MADKDTTRRI HVSTDQGDTW 201 SMAQLPSVGQ EQFYSILAAN DDMVFMHVDE PGDTGFGTIF TSDDRGIVYS 251 KSLDRHLYTT TGGETDFTNV TSLRGVYITS VLSEDNSIQT MITFDQGGRW 301 THLRKPENSE CDATAKNKNE CSLHIHASYS ISQKLNVPMA PLSEPNAVGI 361 VIAHGSVGDA ISVMVPDVYI SDDGGYSWTK MLEGPHYYTI LDSGGIIVAI 401 EHSSRPINVI KFSTDEGQCW QTYTFTRDPI YFTGLASEPG ARSMNISIWG 451 FTESFLTSQW VSYTIDFKDI LERNCEEKDY TIWLAHSTDP EDYEDGCILG 501 YKEQFLRLRK SSVCQNGRDY VVTKQPSICL CSLEDFLCDF GYYRPENDSK 551 CVEQPELKGH DLEFCLYGRE EHLTTNGYRK IPGDKCQGGV NPVREVKDLK 601 KKCTSNFLSP EKQNSKSNSV PIILAIVGLM LVTVVAGVLI VKKYVCGGRF 651 LVHRYSVLQQ HAEANGVDGV DALDTASHTN KSGYHDDSDE DLLE

[0174] Accession number: 4 (mouse sortilin) >sp|Q6PHU5|SORT_MOUSE Sortilin OS=Mus musculus OX=10090 GN=Sort1 PE=1 SV=1 MERPRGAADGLLRWPLGLLLLLQLLPPAAVGQDRLDAPPPPAPPLLRWAGPVGVSWGLRA AAPGGPVPRAGRWRRGAPAEDQDCGRLPDFIAKLTNNTHQHVFDDLSGSVSLSWVGDSTG VILVLTTFQVPLVIVSFGQSKLYRSEDYGKNFKDITNLINNTFIRTEFGMAIGPENSGKV ILTAEVSGGSRGGRVFRSSDFAKNFVQTDLPFHPLTQMMYSPQNSDYLLALSTENGLWVS KNFGEKWEEIHKAVCLAKWGPNNIIFFTTHVNGSCKADLGALELWRTSDLGKTFKTIGVK IYSFGLGGRFLFASVMADKDTTRRIHVSTDQGDTWSMAQLPSVGQEQFYSILAANEDMVF MHVDEPGDTGFGTIFTSDDRGIVYSKSLDRHLYTTTGGETDFTNVTSLRGVYITSTLSED NSIQSMITFDQGGRWEHLRKPENSKCDATAKNKNECSLHIHASYSISQKLNVPMAPLSEP NAVGIVIAHGSVGDAISVMVPDVYISDDGGYSWAKMLEGPHYYTILDSGGIIVAIEHSNR PINVIKFSTDEGQCWQSYVFTQEPIYFTGLASEPGARSMNISIWGFTESFITRQWVSYTV DFKDILERNCEEDDYTTWLAHSTDPGDYKDGCILGYKEQFLRLRKSSVCQNGRDYVVAKQ PSVCPCSLEDFLCDFGYFRPENASECVEQPELKGHELEFCLYGKEEHLTTNGYRKIPGDK CQGGMNPAREVKDLKKKCTSNFLNPTKQNSKSNSVPIILAIVGLMLVTVVAGVLIVKKYV CGGRFLVHRYSVLQQHAEADGVEALDSTSHAKSGYHDDSDEDLLE

Claims

1. Equation (I) 【Chemistry 1】 Compounds of, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof, wherein, R １ teeth, (i) C ６ ~C １０ C replaced by aryl １ ~C ４ alkyl; and (ii) -OH, halo, C １ ~C ４ alkyl, C １ ~C ４ alkoxy, C １ ~C ４ hydroxyalkyl, C １ ~C ４ haloalkyl, C １ ~C ４ haloalkoxy, C １ ~C ４ hydroxyalkoxy, acetyl, cyano, C ６ ~C １０ aryl, 5 - to 10 - membered heteroaryl, 5 - to 10 - membered heterocycloalkyl, -O-(C ６ ~C １０ aryl), -O - CH ２ -(C ６ ~C １０ aryl), and -NR ４ R ５ which is optionally substituted with one or more substituents independently selected from the group consisting of, C ６ ~C １０ aryl and 5 - to 10 - membered heteroaryl, Selected from the group consisting of; R ２ H, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Selected from the group consisting of hydroxyalkyl and phenyl; R ３ is H or -CH ３ And; R ４ and R ５ Each of these is independently H or C １ ~C ４ Alkyl; and n = 0 or 1, Compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

2. R ２ However, H, -CH ３ ien-CH ２ F, -CHF ２ , -CF ３ , - (C ２ H ４ Selected from the group consisting of )-OH and phenyl, preferably R ２ However, H, -CH ３ ,-CHF ２ , -CF ３ , - (C ２ H ４ ) -OH and phenyl are selected from the group consisting of H and / or R ３ However, -CH ３ and / or R ４ and R ５ However, each is independent of C １ ~C ２ It is alkyl, preferably -CH ３ and / or n = 1, The compound according to claim 1.

3. R １ but, (i) C substituted with phenyl １ ~C ２ alkyl; and (ii) - OH, Halo, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Haloalkoxy, C １ ~C ４ Hydroxyalkoxy, Acetyl, Cyano, C ６ ~C １０ Aryl, 5-membered to 10-membered heteroaryl, 5-membered to 10-membered heterocycloalkyl, -O-(C ６ ~C １０ Ariel), -O-CH ２ - (C ６ ~C １０ Aryl), and -NR ４ R ５ Phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl, which are optionally substituted with one or more substituents independently selected from the group consisting of the above. A compound according to claim 1 or 2, selected from the group consisting of the following.

4. R １ The compound according to claim 3, wherein each ring atom in the five-membered or six-membered monocyclic heteroaryl group and the nine-membered or ten-membered fused bicyclic heteroaryl group is independently selected from the group consisting of C, N, S, and O, preferably 1 to 3 ring atoms are independently selected from the group consisting of N, S, and O, and the remaining ring atom is C.

5. R １ The compound according to claim 4, wherein each ring atom in the five-membered ring or six-membered ring monocyclic heteroaryl group is independently C or N, preferably one or two ring atoms are N and the remaining ring atoms are C.

6. R １ The aforementioned five-membered or six-membered monocyclic heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl, preferably selected from the group consisting of pyrazolyl, pyridyl, and pyrimidinyl, and more preferably the following group: 【Chemistry 2】 The compound according to any one of claims 3 to 5, wherein each group is optionally substituted.

7. R １ The aforementioned nine-membered or ten-membered ring fused bicyclic heteroaryl group is independently selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthilidinyl, pyridopyrimidinyl, pyridopyramidinyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, azaindazolyl, pyrazolopyrimidinyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl, preferably independently selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, naphthilidinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, and benzofuranyl, more preferably the following group: 【Transformation 3】 The compound according to any one of claims 3 to 6, wherein each group is optionally substituted.

8. R １ is (i) C substituted with phenyl １ ~C ２ alkyl; and (ii) -OH, halo, C １ ~C ４ alkyl, C １ ~C ４ alkoxy, C １ ~C ４ hydroxyalkyl, C １ ~C ４ haloalkyl, C １ ~C ４ haloalkoxy, acetyl, cyano, 5-membered or 6-membered heteroaryl, 5-membered heterocycloalkyl, -O-phenyl, and -NR ４ R ５ independently selected from the group consisting of, preferably, -OH, halo, C １ ~C ２ alkyl, C １ ~C ２ alkoxy, C １ ~C ２ hydroxyalkyl, C １ ~C ２ haloalkyl, C １ ~C ２ haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR ４ R ５ phenyl, naphthyl, 5-membered or 6-membered monocyclic heteroaryl, and 9-membered or 10-membered fused bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of A compound according to any one of claims 1 to 7, selected from the group consisting of the following.

9. R １ but, (i) C substituted with phenyl １ ~C ２ alkyl; and (ii) - OH, Halo, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Hydroxyalkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Haloalkoxy, acetyl, cyano, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR ４ R ５ Phenyl and five-membered or six-membered monocyclic heteroaryls, which are optionally substituted with one or more substituents independently selected from the group consisting of the following; and (iii) Hello, C １ ~C ２ Alkyl and C １ ~C ２ Naphthyl and nine-membered or ten-membered ring condensed bicyclic heteroaryls, optionally substituted with one or more substituents independently selected from the group consisting of alkoxys. A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. R １ but, (i) C substituted with phenyl １ ~C ２ Alkyl; (ii) - OH, Halo, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Hydroxyalkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Haloalkoxy, acetyl, shea No, imidazolyl, triazolyl, pyridyl, pyrrolidinyl, -O-phenyl, and -NR ４ R ５ Phenyl, which is optionally substituted with one or more substituents independently selected from the group consisting of; (iii) Hello, C １ ~C ２ Alkyl, C １ ~C ２ A five-membered or six-membered ring heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of alkoxys and -O-phenyls; (iv) Halo and C １ ~C ２ Naphthyl molecules optionally substituted with one or more substituents independently selected from the group consisting of alkoxys; and (v) Halo and C １ ~C ２ A nine-membered ring or ten-membered ring condensed bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups. A compound according to claim 9, selected from the group consisting of the following.

11. R １ but, 【Chemistry 4-1】 【Chemistry 4-2】 Selected from the group consisting of, preferably, R １ but, 【Transformation 5】 A compound according to any one of claims 1 to 10, selected from the group consisting of the following.

12. The aforementioned compound, (R)-2-benzylamino-2,5,5-trimethylhexanoic acid; (S)-2-benzylamino-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (S)-2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; 2,5,5-trimethyl-2-(3-phenylpropylamino)hexanoic acid; (R)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (S)-2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; (R)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; (S)-2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5-dimethylhexanoic acid; 2,5,5-trimethyl-2-{[(5-pyrimidinyl)methyl]amino}hexanoic acid; 2-{[(m-methoxyphenyl)methyl]amino}-2,5,5-trimethylhexanoic acid; 2-benzylamino-2,5,5-trimethylhexanoic acid; The compounds according to any one of claims 1 to 11, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier, excipient, and / or diluent.

14. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13, for use in treatment.

15. It is intended for use in the treatment or prevention of neurodegenerative disorders, mental disorders, inflammatory disorders, lysosomal storage disorders, cancer, pain, diabetes mellitus, retinopathy such as diabetic retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye conditions, chronic pain, hearing loss, or diseases characterized by misfolded tau. Preferably, the neurodegenerative disorder is selected from motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Creutzfeldt-Jakob disease (CJD), acute brain injury, spinal cord injury, and stroke; preferably, the motor neuron disease is selected from amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and progressive muscular atrophy; Preferably, the neurodegenerative disorder is a misfolded TAR DNA-bound tangent, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia. Characterized by protein 43; Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder. Preferably, the inflammatory disorder is selected from inflammatory diseases and neuroinflammation; Preferably, the lysosome accumulation disorder is 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. NCL / Batten disease caused by; Pompe disease, Fabry disease, Gaucher disease, Niemann-Pick disease types A, B, and C; GM1 gangliosidosis, GM2 gangliosidosis (including Sandhoff and Tay-Sachs), mucopolysaccharidosis (MPS) type I (Hurler disease) / type II (Hunter disease) / type IIIa (Sanfilippo A) / type IIIB (Sanfilippo B) / type IIIc ( Selected from the group consisting of Sanfilippo C) / IIId (Sanfilippo D) / IVA (Morquio A) / VB / VI / VII (Sly) / IX, Mucolipisosis III (I-cell) and IV, multiple sulfatase deficiencies; sialidosis, galactosialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosamineuria, fucosidosis, Schindler's disease, metachromatic leukodystrophy resulting from a deficiency of either arylsulfatase A or saposin B, globoid cell leukodystrophy (Krabbe disease), Faber lipogranuloma, Wolmann disease and cholesterol ester storage disease, concentrated dysostosis, cystinosis, Salla disease, Danon disease, Glycerin disease types 1 / 2 / 3, Hermansky-Padlak disease, and Chediak-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 preferably 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, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss. A compound according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13.

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