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. TIFF2026509274000091.tif41170

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. [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, mutated PGRN alleles have been identified in patients with Alzheimer's disease (AD) (Brouwers et al., 2008; Sheng, Su, Xu, & Chen, 2014), and high levels of extracellular PGRN are protective in models of ALS, Parkinson's disease, stroke, arthritis, and atherosclerosis (Egashira et al., 2013; Laird et al., 2010; Martens et al., 2012; Tang et al., 2011; Tao, Ji, Wang, Liu, & Zhu, 2012; Van Kampen, Baranowski, & Kay, 2014).

[0005] However, 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 Aβ 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, a therapeutic agent for treating CNS diseases must be able to cross the blood-brain barrier. In addition to this, according to the free drug hypothesis, only the unbound compound can interact and elicit a pharmacological effect and thus it is also necessary to have a sufficient unbound drug concentration in the brain.

[0018] To identify the unbound fraction (F ub,brain , , ub,meas , ) of a test compound, the sample supernatant can be analyzed by methods such as liquid chromatography tandem mass spectrometry (LC-MS / MS). Next, from the peak area ratios obtained for each matrix, the following equation: F ub = C PBS / C plasma is used to calculate the unbound fraction, where C PBS and C plasma are the analyte concentrations in PBS (receiving side) and plasma (donating side), respectively.

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

[0020] The unbound fraction (F ub,brain ) in the brain can be calculated from the measured value (F ub,meas ) in the brain homogenate, taking into account the dilution rate used in the preparation of the brain homogenate:

number

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

number

[0022] Another option is to use the AUC ratio to determine K puu The target species may be identified. The compound of interest is administered orally or intravenously to a suitable species of interest 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 ratio is determined to obtain the following: K puu =AUC0-infcsf / (AUC0-infplasma×(%Fuplasma / 100))

[0023] For the treatment of CNS diseases, K puu However, it is the highest possible value greater than 0. This is desirable. A value around 1 indicates that the compounds in the free fraction can freely pass through the blood-brain barrier, a value greater than 1 suggests that an active influx transport mechanism is involved in the blood-brain barrier, and a value less than 1 indicates that the compounds in the free fraction have low permeability or are recognized by an active efflux mechanism, resulting in reduced exposure in the CNS and simultaneous return to plasma or CSF across the blood-brain barrier. K puuWhen the value is 0 or close to 0, it indicates a 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. [Overview of the project]

[0024] In light of the above, there is an unmet need for compounds that can be used to treat and prevent medical conditions in which modification of sorbitol is beneficial. In particular, there is an unmet need for sorbitol modifiers that can cross the blood-brain barrier and are therefore useful in treating central nervous system disorders. [Brief explanation of the drawing]

[0025] [Figure 1] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 2] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 3] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 4] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 5] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 6] Figures 1 to 6 show X-ray images of Example 8 bound to h-soltilin. [Figure 7A] Figures 7A to 7C show electron density maps obtained from the X-ray diffraction data of Example 8. [Figure 7B] Figures 7A to 7C show electron density maps obtained from the X-ray diffraction data of Example 8. [Figure 7C] Figures 7A to 7C show electron density maps obtained from the X-ray diffraction data of Example 8. [Modes for carrying out the invention]

[0026] 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.

[0027] In a first aspect of the present invention, formula (I): [ka] Compounds of the same, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof are provided, in which, R 1 teeth, [ka] and; R 2 is H or -CH3; R 3 C6~C 10 Selected from the group consisting of aryl and 5-membered to 10-membered heteroaryl rings, optionally including -OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, acetyl, cyano, and 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), and -O-CH2-(C6~C 10 Substituted with one or more substituents independently selected from the aryl group; R 4 is H or -CH3; and n is either 0 or 1.

[0028] Surprisingly, the applicant is R 1 is -CO2H, and R 4We 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]

[0029] In the compound of the present invention, R 2 It is preferable that it is H.

[0030] In a preferred embodiment of the present invention, R 3 The group is selected from the group consisting of phenyl, naphthyl, a 5-membered or 6-membered monocyclic heteroaryl, and a 9-membered or 10-membered fused bicyclic heteroaryl, preferably selected from the group consisting of phenyl, naphthyl, a 6-membered monocyclic heteroaryl, and a 9-membered or 10-membered fused bicyclic heteroaryl, and more preferably selected from the group consisting of a 10-membered fused bicyclic heteroaryl, with each group being optionally substituted as defined above.

[0031] 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.

[0032] 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.

[0033] A 9-membered ring or 10-membered ring fused bicyclic heteroaryl group has 9 or 10 ring atoms, At least one ring atom is a heteroatom, and the remaining ring atoms are carbon.

[0034] Preferably, R 3Each 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 C or N. More preferably, 1 to 3 ring atoms are N and the remaining ring atoms are C.

[0035] Comfortable, R 3 In the 5-membered or 6-membered monocyclic heteroaryl group, one or two ring atoms are nitrogen (N), and the remaining ring atoms are carbon (C).

[0036] R 3 Examples of six-membered monocyclic heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl, with pyridyl, pyrimidinyl, and pyrazinyl being preferred. More preferably, the six-membered monocyclic heteroaryl group is one of the following groups: [ka] It is one of these, and each group is optionally substituted.

[0037] R 3 Examples of 9-membered or 10-membered ring fused bicyclic heteroaryl groups include indolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, azindazolyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthylidinyl, pyridopyrimidinyl, and pyridopyramidinyl, preferably azaindolyl, pyridopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, and quinazolinyl. More preferably, the 9-membered or 10-membered ring fused bicyclic heteroaryl group is one of the following groups: [ka] It is one of these, and each group is optionally substituted.

[0038] Comfortable, R 3 The 9-membered ring or 10-membered ring fused bicyclic heteroaryl group is [ka] Each group is optionally substituted. Surprisingly, the applicant found that these groups improve the binding of the compound to soltirin.

[0039] R in the compound of formula (I) 3 Any of the groups may be optionally substituted with one or more substituents defined above. Preferably, R 3 The optional substituents for are independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, phenyl, 6-membered heterocycloalkyl, -O-phenyl, and -O-CH2-phenyl.

[0040] Comfortable, R 3 The optional substituents on are independently selected from the group consisting of halo, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, phenyl, morpholinyl, -O-phenyl, and -O-CH2-phenyl.

[0041] Comfortable, R 3 The optional substituents for are independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, phenyl, morpholinyl, -O-phenyl, and -O-CH2-phenyl.

[0042] In a preferred embodiment of the present invention, R 3 The group is selected from the following: (i) Phenyl and six-membered monocyclic heteroaryls that are optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, phenyl, -O-phenyl, -O-CH2-phenyl, and morpholinyl; and (ii) Naphthyl and a 9-membered ring or 10-membered ring fused bicyclic heteroaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and phenyl, preferably independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and phenyl.

[0043] In a more preferred embodiment of the present invention, R 3 The group is selected from the following: (i) Phenyls that are optionally substituted with one or more substituents independently selected from the group consisting of halo and -O-phenyl; (ii) A six-membered monocyclic heteroaryl ring that is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, phenyl, -O-phenyl, -O-CH2-phenyl, and morpholinyl; (iii) Naphthyl being optionally substituted with one or more halo atoms; and (iv) A nine-membered ring or ten-membered ring fused bicyclic heteroaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and phenyl, preferably independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and phenyl.

[0044] In a more preferred embodiment of the present invention, R 3 The group is selected from the following: [ka]

[0045] In a more preferred embodiment of the present invention, R 3 The group is selected from the following: [ka]

[0046] A specific compound in the first aspect of the present invention is one of the compounds listed below: (S)-2-anilino-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(2-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(1,3,5-triaza-4-naphthylamino)hexanoic acid; (S)-2-[5-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid (S)-2-(5-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(4-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(4-morpholino-2-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(2-quinoxalinylamino)hexanoic acid (S)-5,5-dimethyl-2-(5-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(3-methyl-2-pyradinylamino)hexanoic acid (S)-2-(2-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(6-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(2-methyl-4-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-4-pyrimidinylamino)hexanoic acid (S)-2-(2,6-dimethyl-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(8-methyl-4-quinazolinylamino)hexanoic acid

[0047] (S)-5,5-dimethyl-2-(6-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-phenoxy-2-pyradinylamino)hexanoic acid (S)-2-(4-isoquinolylamino)-5,5-dimethylhexanoic acid (S)-2-(m-chlorophenylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(3-pyridylamino)hexanoic acid [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-2-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrazinylamine hmm; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-phenyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; N-2-pyrimidinyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-5-pyrimidinylamine; N-5-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-2-pyrazinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine;

[0048] [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; N-3-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-2-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-3-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-pyridylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrimidinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]aniline; N-2-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-3-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine;

[0049] [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][6-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][7-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1,3,7-triaza-4-naphthylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-bromo-4-quinazolinyl)amine; [4-Methyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-phenyl-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; N-3-pyridyl[(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; N-3-pyridyl[(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyridylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyrimidinylamine; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-7-quinazoline carbonitrile; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-6-quinazoline carbonitrile; (S)-5,5-dimethyl-2-(o-phenoxyphenylamino)hexanoic acid; (S)-2-anilino-4,4-dimethylvaleric acid; (S)-2-anilino-2,5,5-trimethylhexanoic acid; (S)-5,5-dimethyl-2-(4-phenyl-2-pyrimidinylamino)hexanoic acid; (S)-2-[6-(benzyloxy)-2-pyradinylamino]-5,5-dimethylhexanoic acid; (S)-2-(6-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-(5-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-[4-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(6-phenoxy-4-pyrimidinylamino)hexanoic acid; (S)-2-(2,6-dimethoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-((2-methylquinazoline-4-yl)amino)hexanoic acid; (S)-2-((2-cyclopropylquinazoline-4-yl)amino)-5,5-dimethylhexanoic acid; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof,

[0050] Preferably, the compound is: (S)-2-anilino-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(2-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(1,3,5-triaza-4-naphthylamino)hexanoic acid; (S)-2-[5-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid (S)-2-(5-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(4-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(4-morpholino-2-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(2-quinoxalinylamino)hexanoic acid (S)-5,5-dimethyl-2-(5-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(3-methyl-2-pyradinylamino)hexanoic acid (S)-2-(2-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(6-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(2-methyl-4-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-4-pyrimidinylamino)hexanoic acid (S)-2-(2,6-dimethyl-4-pyrimidinylamino)-5,5-dimethylhexanoic acid

[0051] (S)-5,5-dimethyl-2-(8-methyl-4-quinazolinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-phenoxy-2-pyradinylamino)hexanoic acid (S)-2-(4-isoquinolylamino)-5,5-dimethylhexanoic acid (S)-2-(m-chlorophenylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(3-pyridylamino)hexanoic acid [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-2-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrazinylamine hmm; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-phenyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; N-2-pyrimidinyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-5-pyrimidinylamine; N-5-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-2-pyrazinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine;

[0052] N-2-pyrimidinyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; N-3-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-2-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-3-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-pyridylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrimidinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]aniline; N-2-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-3-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine;

[0053] [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][6-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][7-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1,3,7-triaza-4-naphthylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-bromo-4-quinazolinyl)amine; [4-Methyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-phenyl-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; N-3-pyridyl[(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; N-3-pyridyl[(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyridylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyrimidinylamine; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-7-quinazoline carbonitrile; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-6-quinazoline carbonitrile; (S)-5,5-dimethyl-2-(o-phenoxyphenylamino)hexanoic acid; (S)-2-anilino-4,4-dimethylvaleric acid; (S)-2-anilino-2,5,5-trimethylhexanoic acid; (S)-5,5-dimethyl-2-(4-phenyl-2-pyrimidinylamino)hexanoic acid; (S)-2-[6-(benzyloxy)-2-pyradinylamino]-5,5-dimethylhexanoic acid; (S)-2-(6-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-(5-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-[4-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(6-phenoxy-4-pyrimidinylamino)hexanoic acid; (S)-2-(2,6-dimethoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0054] 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.

[0055] 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.

[0056] According to a fourth aspect of the present invention, compounds or pharmaceutical compositions according to the present invention are provided 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.

[0057] 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.

[0058] 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.

[0059] Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorders.

[0060] Preferably, the inflammatory disorder may be selected from inflammatory diseases and neuroinflammation.

[0061] 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.

[0062] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0063] Preferably, the cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, heart failure, and ischemic heart disease.

[0064] 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.

[0065] 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, diabetic retinopathy and other retinopathy, brain tumors, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye conditions, chronic pain, hearing loss, or misfolded tau.

[0066] According to a sixth aspect of the present invention, a method is provided for the treatment or prevention of a disease or condition responsive to soltirin modification, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0067] The compounds of the present invention may include isotope-labeled and / or isotope-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. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Examples include Cl.

[0068] 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.

[0069] 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.

[0070] The compounds of the present invention also include tautomers. Tautomerism occurs when a single bond is exchanged 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, and 1H- and 2H-isoin. Examples include dole, as well as 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or may be sterically fixed into one form by appropriate substitution.

[0071] 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, may also exist in the compounds described herein, and all such stable isomers are intended herein. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers.

[0072] 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.

[0073] Preferably, the compound of formula (I) is the compound of formula (Ia). [ka]

[0074] 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.

[0075] The compounds of the present invention may be sorbitin inhibitors, binders, modifiers, or antagonists. As used herein, the terms “sorbitin antagonist,” “sorbitin inhibitor,” “sorbitin binder,” or “sorbitin modifier” are (used interchangeably) used to describe the binding of sorbitin protein to progranulin, or neurotensin, or another extracellular ligand, or proneurotrophin (e.g., pro-NGF, proNT3, pro-BDNF). This refers to substances that interfere with, block, or otherwise attenuate the effect of binding to sortirin, p75NTR, and proneurotrophin, or prevent the formation of a trimer complex between sortirin and p75NTR and proneurotrophin. The term "sortirin antagonist" also includes substances or drugs 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 sortirin 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 via the mechanism described above is greatly reduced. Skeldal et al. (2012) demonstrated that the apoptotic function of the trimer complex is lost when sortirin lacks an intracellular domain. The term "sortirin antagonist" also includes substances or drugs that interfere with, block, or otherwise attenuate the effect of the interaction between the sortirin protein and 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. described the complex form between sorbitol and p75NTR. The interaction was shown to depend on a contact point in the extracellular domain of the receptor, and that this interaction is critically dependent on a 23-amino acid sequence near the extracellular membrane of p75NTR. Therefore, sorotirin antagonists may interfere with this 23-amino acid sequence or its proximal sequence in the molecule. "Sortirin antagonists" may act as inhibitors of ligand uptake, and ligands may include progranulin, neurotensin, and BDNF.

[0076] 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.

[0077] The compounds of the present invention have a K value greater than 0.1, such as between 0.1 and 10, between 0.1 and 5, between 0.1 and 3, between 0.1 and 2, between 0.1 and 1, between 0.1 and 0.8, between 0.1 and 0.6, between 0.1 and 0.5, between 0.1 and 0.4, between 0.1 and 0.3, or between 0.1 and 0.2. puu It may have.

[0078] 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.

[0079] 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).

[0080] 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.

[0081] The present invention provides a method for monitoring the progress of treatment. The method comprises the steps of identifying or performing a diagnostic measurement (e.g., screening, assay) of a diagnostic marker (Marker) (e.g., any of the targets or cell types shown herein modified with the compounds herein) in a subject who is suffering from or susceptible to the disorder or symptoms thereof as described herein, wherein the subject has been administered a therapeutic dose of the compounds herein sufficient to treat the disease or symptoms thereof. To establish the disease state of the subject, the Marker levels identified in this method may be compared to known Marker levels in either a healthy, normal control or another affected patient. In a preferred embodiment, a second level of Marker in the subject is identified at a later point in time than the identification of the first level, and these two levels are compared to monitor the course of the disease or the effectiveness of the treatment. In a particular preferred embodiment, a pre-treatment level of Marker in the subject is identified before initiating treatment according to the present invention, and subsequently, this pre-treatment level of Marker may be compared to a Marker level in the subject after initiation of treatment to determine the effectiveness of the treatment.

[0082] 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.

[0083] 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. Therapeutic effectiveness over a long period of time: plasma concentration To maintain the desired level, the compounds disclosed herein may be incorporated into sustained-release formulations.

[0084] 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.

[0085] 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).

[0086] 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.

[0087] "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.

[0088] The term "heteroatom" refers to O, N, or S.

[0089] (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. n For the range "(C1~C4)alkyl", all subgroups are intended. For example, in the range (C1~C4)alkyl, (C1~C3)alkyl, (C1~C2)alkyl, (C1)alkyl, (C2~C4)alkyl, (C2~C3)alkyl, (C2)alkyl This includes all subgroups such as methyl, (C3-C4) alkyl, (C3) alkyl, and (C4) alkyl. Examples of "(C1-C4) alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and cyclobutyl.

[0090] (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.

[0091] (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.

[0092] (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.

[0093] (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.

[0094] (C1~C n The term "hydroxyalkoxy" refers to the above C1-C substituted with at least one -OH group. n It shows an alkoxy.

[0095] When a term indicates a range, for example, "1 to 4 carbon atoms" in the definition of an (C1-C4) alkyl, each integer, i.e., 1, 2, 3, and 4, is considered disclosed.

[0096] The term "halo" refers to a halogen atom, preferably F, Cl, Br, and I, more preferably F, Cl, and Br.

[0097] "C6~C 10 The term "aryl" refers to an aromatic monocyclic or fused bicyclic hydrocarbon ring system containing 6 to 10 ring atoms.

[0098] 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, more preferably from N or O. Preferably, two or fewer ring atoms are heteroatoms.

[0099] "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).

[0100] 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.

[0101] The terms “subject” and “patient” are interchangeable herein. They are individuals who may have or are susceptible to the disease or disorder, but who do not have this disease or disorder. This refers to humans or other mammals (e.g., mice, rats, rabbits, dogs, cats, cows, pigs, sheep, horses, or primates) that may or may not possess the trait. The subject is preferably a human.

[0102] 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.

[0103] Next, the present invention will be further illustrated by the following non-limiting examples. These examples are illustrative and should not be construed in any way as limiting the remainder of this disclosure. Without further detail, those skilled in the art will be able to utilize the present invention to the fullest extent based on the description herein. All references and publications referenced herein are incorporated herein by reference in their entirety.

[0104] Preparation of the compound of the present invention The compounds of the present invention can be prepared by methods known and recognized in the art, according to the following general synthesis procedure scheme. 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 liabilities of the specific compound being synthesized, the starting compound, and the substituted part. Unless otherwise noted, all substituents are as previously defined, and all reagents are known and recognized in the art.

[0105] General synthesis procedure [ka]

[0106] 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.

[0107] Compounds of general formula (I) may contain one or more chiral centers. These can be introduced from available single enantiomers, 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, they can be confirmed, if desired, by known techniques such as preparative chiral support high-pressure chromatography. It is understood that single isomer products can be obtained as a single enantiomer or as a single diastereoisomer.

[0108] Those skilled in the art will understand that not all substituents of the compound of formula (I) can withstand certain reaction conditions used in the synthesis of the compound. As is known to those skilled in the art, these parts 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 the protecting group may be removed at any convenient point in the synthesis of the compound 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]

[0109] 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; Et2O: diethyl ether; Fmoc: fluorenyl methoxycarbonyl; Boc: t ert-butoxycarbonyl; h: hours; min: minutes; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V); HPLC: high-performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiple; 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); R T : Retention time; s: Singlet, solid; SPPS: Solid-phase peptide synthesis; t: Triplet; TBAF: Tetrabutylammonium fluoride; TBME: Tert-butyl methyl ether; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; ULC: Ultra-high performance liquid chromatography; UV: Ultraviolet light.

[0110] Other abbreviations are intended to indicate their generally accepted meanings.

[0111] 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 by magnetic force, and the reactions were carried out at room temperature (approximately 20°C).

[0112] 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.

[0113] Analysis method 1 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.

[0114] 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, 50×2.1mm, 2.5μm, Temperature: 25℃, Flow rate: 0.6mL / min, Gradient: t0=5%B, t2.0min=98%B, t2.7min=98%B, Post-time: 0.3min. Eluent A: 10 mM ammonium bicarbonate aqueous solution (pH=9.5), Eluent B: Acetonitrile.

[0115] Method 2: 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 were collected based on MS and DAD.

[0116] Method 3: 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.

[0117] Method 4: 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=2.7min 98%B, Postrun: 0.3min.

[0118] Method 5: UPLC acid method Column: Waters ACQUITY UPLC (registered trademark) CSH C18, 1.7 μm, 2.1 × 30 mm, 40°C Detection: UV is used at 210-400 nm unless otherwise specified, and MS is performed by electrospray ionization. Solvents: A: 0.1% formic acid aqueous solution, B: MeCN gradient: [Table 1]

[0119] Method 6: LCMS Acidic Method Column: Waters Cortecs C18, 30×2.1 mm, 2.7 μm, 40 °C Detection: UV is 260 nm ± 90 nm unless otherwise specified, MS is by electrospray ionization. Solvent: A: Aqueous solution of 0.1% formic acid, B: MeCN Gradient: [Table 2]

[0120] Method Chiral 7: SFC using Waters UPC2. The column was eluted with Chiralpak IG 4.6×250, 5um, flow rate 4 mL / min-1, 20% MeOH (0.1% ammonia), 80% CO2, wavelength 210 - 400 nm and BPR 120 bar.

[0121] Example 1 [Chemical Structure]

[0122] Synthesis of (R)-2-hydroxy-5,5-dimethylhexanoic acid (Int 1-a) To (R)-2-amino-5,5-dimethylhexanoic acid (12 g, 75 mmol, 1.0 eq) in water (220 ml) was added 1 M aqueous sulfuric acid solution (226 mL, 226 mmol, 3.0 eq). The mixture was cooled to -5 °C and a solution of sodium nitrite (31.2 g, 452 mmol, 6.0 eq) in water (220 ml) was added dropwise while maintaining the temperature below 0 °C. After the addition, the mixture was warmed to room temperature and stirred for 16 hours.

[0123] The mixture was extracted with Et2O (4×200 mL), and the combined organic layers were washed with brine (30 It was washed with 0 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 74% yield) as a yellow solid. 1 1H-NMR (400 MHz, CDCl3) δ 4.28 (dd, J = 7.2, 4.2 Hz, 1H), 1.92 - 1.80 (m, 1H), 1.75 - 1.62 (m, 1H), 1.41 - 1.27 (m, 2H), 0.90 (s, 9H)

[0124] Synthesis of methyl (R)-2-hydroxy-5,5-dimethylhexanoate (Int 1-b) Thionyl chloride (12 ml, 164 mmol, 2.93 eq) was added to (R)-2-hydroxy-5,5-dimethylhexanoic acid (8.98 g, 56.1 mmol, 1 eq) in MeOH (120 ml) at 0 °C. After addition, the mixture was warmed to room temperature and stirred for 16 h. The mixture was basified to pH 9 by adding saturated aqueous NaHCO3 and extracted with Et2O (2 × 400 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to obtain methyl (R)-2-hydroxy-5,5-dimethylhexanoate (10.01 g, 55.0 mmol, 98% yield) as a yellow oil. It contains 4.2% (weight / weight) of MeOH. 1 1H-NMR (400 MHz, CDCl3) δ 4.18 (dd, J = 7.2, 4.2 Hz, 1H), 3.80 (s, 3H), 1.84 - 1.72 (m, 1H), 1.67 - 1.52 (m, 1H), 1.37 - 1.21 (m, 2H), 0.89 (s, 9H)

[0125] Synthesis of methyl (R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (Int 1-c) Anhydrous trifluoromethanesulfonic acid (15.56 ml, 92 mmol) was added dropwise to a cooled solution (ice salt bath) of methyl(R)-2-hydroxy-5,5-dimethylhexanoate (14.59 g, 84 mmol) and triethylamine (14.01 ml, 100 mmol) in dichloromethane (400 ml). The color changed from pale yellow to dark orange. The mixture was stirred for 2 hours, diluted with water (50 ml), the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried on sodium sulfate and concentrated. The dark black oil was taken in a 4 cm silica plug and eluted in two 300 mL batches with heptane:DCM 1:2 (600 mL). The solvent was evaporated to obtain methyl(R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (19.23 g, 60.3 mmol, yield 72%) as a pale yellow oil. 1 H-NMR (400 MHz, CDCl3) δ 5.12 (dd, J = 6.9, 5.0 Hz, 1H), 3.85 (s, 3H), 2.05-1.90 (m, 2H), 1.36-1.24 (m, 2H), 0.90 (s, 9H)

[0126] Synthesis of (S)-2-anilino-5,5-dimethylhexanoate mesylate (Example 1) Methyl(R)-5,5-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)hexanoate (100 mg, 0.326 mmol) in DCM (1 mL) was added dropwise to a solution of aniline (30.4 mg, 0.326 mmol) and triethylamine (50.1 μl, 0.359 mmol; 1.1 equivalents) in dichloromethane (1 mL). The DCM was removed by airflow, and the mixture was incorporated into MeCN (1 mL) and water (1 mL). Lithium hydroxide (39.1 mg, 1.632 mmol; 5 equivalents) was added, and the mixture was stirred overnight. The mixture was subjected to acidic preparative fractionation (Method 2) to obtain (S)-5,5-dimethyl-2-(phenylamino)hexanoic acid (18.9 mg, 0.080 mmol, yield 24%, purity 99%). This substance was incorporated into MeCN (1.6 mL), and an aqueous solution of methanesulfonic acid (800 μl, 0.08 mmol) was added. The product was freeze-dried to obtain (S)-5,5-dimethyl-2-(phenylamino)hexanoic acid compound with methanesulfonic acid (23.0 mg; 0.069 mmol; yield 21%, purity 99%). LC-MS (Method 1, 0.942 min; M+H-MsOH=236.4; calculated value 236.2). 1 H-NMR (400 MHz, DMSO) δ 7.07 (t, J = 7.8 Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 6.56 (t, J = 7.3 Hz, 1H), 3.80 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H; MsOH), 1.68 (dqd, J = 18.0, 12.9, 6.3 Hz, 2H), 1.36 (td, J = 12.5, 5.0 Hz, 1H), 1.23 (td, J = 12.5, 5.2 Hz, 1H), 0.87 ( s, 9H)

[0127] Examples 2 and 3 below were prepared starting from the corresponding precursors and in a manner similar to that of Example 1. [Table 3]

[0128] Example 4 [ka]

[0129] Synthesis of (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid (Example 4) 2-Fluoropyrazine (60.1 mg, 0.612 mmol; 1.5 equivalents) was added to a solution of (S)-2-amino-5,5-dimethylhexanoic acid (65.0 mg, 0.408 mmol) in dimethyl sulfoxide (dried) (1 ml) and DIPEA (0.214 ml, 1.225 mmol; 3.00 equivalents). The reaction mixture was stirred overnight at 110°C. The mixture was subjected to basic preparative treatment (Method 3). The purified fractions were combined, reformatted, weighed, and redissolved in MeCN (0.05 M), and 0.1 M MsO in MeCN was added. A 1.0 equivalent of H solution was added. A small amount of water was added, and the solvent was evaporated to form a (S)-5,5-dimethyl-2-(pyrazine-2-ylamino)hexane oxidative with methanesulfonic acid. A sample (53.8 mg, 0.161 mmol, yield 39%, purity 100%) was obtained. LC-MS (Method 1, 0.773 min; M+H-MsOH=238.3; calculated value 238.2). 1 H-NMR (400 MHz, DMSO) δ 8.05 (d, J = 1.5 Hz, 1H), 7.91 (dd, J = 2.8, 1.5 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.41-7.27 (br, 2H), 4.25 (dd, J = 8.2, 5.0Hz, 1H), 2.33 (s, 3H, MsOH), 1.85-1.63 (m, 2H), 1.39-1.21 (m, 2H), 0.87 (s, 9H)

[0130] The following Example 5 was prepared starting from the corresponding precursor in a manner similar to that of Example 4. [Table 4]

[0131] Example 6 [ka]

[0132] Synthesis of (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid (Example 6) 5-bromopyrimidine (150 mg, 0.942 mmol), potassium carbonate (132 mg, 0.956 mmol), and copper(I) iodide (9.87 mg, 0.052 mmol) were added to a solution of (S)-2-amino-5,5-dimethylhexanoic acid (75 mg, 0.471 mmol) in dimethyl sulfoxide (2 ml). The reaction mixture was stirred overnight at 100°C. The mixture was purified by basic preparative separation (Method 3). The purified fractions were combined and concentrated under vacuum. The filtrate showed residual copper (blue-green solid). The solid was suspended in water containing a small amount of MeOH and filtered on an SCX cation resin. The column was washed with water, then MeOH, then 7 M ammonia in MeOH, to wash away the target product and obtain 12.2 mg of an off-white solid. The compound was redissolved in MeCN, and a 0.1 M MsOH solution (1.0 equivalent) in MeCN was added. A small amount of water was added, and the solvent was evaporated to obtain (S)-5,5-dimethyl-2-(pyrimidine-5-ylamino)hexanoic acid compound (16.6 mg, 0.050 mmol, yield 10%, purity 93%) with methanesulfonic acid. LCMS (Method 1, 0.773 mins; M+H-MsOH=238.2; calculated value 238.2). 1 H-NMR (400 MHz, DMSO) δ 12.96-12.63 (br, 1H), 8.41 (s, 1H), 8.14 (s, 2H), 6.38-6.29 (m, 2H), 4.06-3.96 (m, 1H), 2.30 (s, 3H, MsOH), 1.85-1.61 (m, 2H), 1.39-1.17 (m, 2H), 0.87 (s, 9H)

[0133] Example 7 [Chemical formula]

[0134] Synthesis of (S)-5,5-Dimethyl-2-(4-pyrimidinylamino)hexanoic acid (Example 7) 5-Bromo-4-chloropyrimidine (134 mg, 0.691 mmol) and sodium bicarbonate (264 mg, 3.14 mmol) were added to a solution of (S)-2-amino-5,5-dimethylhexanoic acid (100 mg, 0.628 mmol) in THF (8 mL) / water (2 mL). The reaction mixture was stirred at 70 °C for 3 hours. The mixture was concentrated, purged with nitrogen, 5% palladium on activated carbon (401 mg, 0.188 mmol) was added, and the mixture was placed under hydrogen through three vacuum / hydrogen cycles. It was stirred overnight at room temperature. The mixture was purged with nitrogen, filtered through celite, and the filtrate was concentrated to obtain 185 mg of a white solid. The product was purified by acidic fractionation (Method 2). The purified fractions were combined, reconstituted, weighed, redissolved in MeCN (0.05 M), and a 0.1 M MsOH solution in MeCN (1 equivalent) was added. A small amount of water was added, and the solvent was evaporated to obtain the (S)-5,5-dimethyl-2-(pyrimidin-4-ylamino)hexanoic acid compound with methanesulfonic acid (56.7 mg, 0.170 mmol, yield 27%, purity 100%). LCMS (Method 1, 0.743 min; M+H-MsOH = 238.4; calculated value 238.2). 1 H-NMR (400 MHz, DMSO) δ 13.42 - 12.83 (br, 1H), 9.60 (d, J = 7.6 Hz, 1H), 8.84 (s, 1H), 8.22 (dd, J = 7.1, 1.5 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 4.60 (td, J = 8.0, 4.9 Hz, 1H), 2.32 (s, 3H, MsOH), 1.92 - 1.69 (m, 2H), 1.31 - 1.20 (m, 2H), 0.87 (s, 9H)

[0135] Example 8 [Chemical formula]

[0136] (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid (Example 8) synthesis 4-chloroquinazoline (56.9 mg, 0.345 mmol) and sodium bicarbonate (132 mg, 1.57 mmol) were added to a solution of (S)-2-amino-5,5-dimethylhexanoic acid (50 mg, 0.314 mmol) in tetrahydrofuran (4 mL) water (1 mL). The reaction mixture was stirred overnight at 70°C. The mixture was concentrated and purified by acidic preparative fractionation (Method 2). The purified fractions were combined, reconstituted, 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 solvent was evaporated to obtain (S)-5,5-dimethyl-2-(quinazoline-4-ylamino)hexanoic acid compound with methanesulfonic acid (74.2 mg, 0.193 mmol, yield 61%, purity 97%). LCMS (Method 1, 0.903 mins; M+H-MsOH=288.4; calculated value 288.2). 1 H-NMR (400 MHz, DMSO) δ 13.20-12.85 (m, 1H), 9.64 (d, J = 7.3 Hz, 1H), 8.83 (s, 1H), 8.63 (d, J = 8.9 Hz, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.84-7.74 (m, 2H), 4.86 (q, J = 7.4 Hz, 1H), 2.30 (s, 3H), 2.04-1.89 (m, 2H), 1.45-1.22 (m, 2H), 0.90 (s, 9H)

[0137] Examples 9-28 below were prepared starting from the corresponding precursors and in a manner similar to that of Example 8. [Table 5-1]

[0138] [Table 5-2]

[0139] [Table 5-3]

[0140] [Table 5-4]

[0141] Example 29 [ka]

[0142] Synthesis of (S)-2-(isoquinoline-4-ylamino)-5,5-dimethylhexanoic acid (Example 29) 4-Bromoisoquinoline (212 mg, 98% by weight, 1 equivalent, 1.00 mmol), (S)-2-amino-5,5-dimethylhexanoic acid (209 mg, 99% by weight, 1.30 equivalents, 1.30 mmol), Pd2(dba)3 (18.5 mg, 99% by weight, 0.020 0 equivalents, 20.0 μmol), JohnPhos (15.1 mg, 99 wt%, 0.05 equivalents, 50.0 μmol), and sodium tert-butoxide (233 mg, 99 wt%, 2.40 equivalents, 2.40 mmol) were combined together, flushed with nitrogen for 5 minutes, and then 1,4-dioxane (5.00 mL) was added. The reaction mixture was stirred at room temperature for 1 minute and then heated to 70 °C for 2 hours. The mixture was cooled to room temperature and quenched with hydrogen chloride (87.5 mg, 2.40 mL, 1.00 molar concentration, 2.40 equivalents, 2.40 mmol). The mixture was diluted with DCM (15 mL) and the layers were separated. The aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (solid loading on celite, 12 g cartridge, 0-20% DCM / MeOH) to give (S)-2-(isoquinolin-4-ylamino)-5,5-dimethylhexanoic acid (78.0 mg, 269 μmol, yield 26%, purity 98%) as a yellow solid. UPLC (method 5), 1.23 min; M+H = 287.3. 1 H-NMR (400 MHz, DMSO) δ 12.72 (bs, 1H), 8.59 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.96 (dd, J = 8.2, 1.4 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.66-7.58 (m, 2H), 6.26 (s, 1H), 4.02 (s, 1H), 1.90 (dt, J = 8.6, 6.6 Hz, 2H), 1.55-1.45 (m, 1H), 1.33-1.26 (m, 1H), 0.90 (s, 9H)

[0143] Example 30

Chemical Structure

[0144] Synthesis of tert-butyl(S)-2-((3-chlorophenyl)amino)-5,5-dimethylhexanoate (Int 30-a) A mixture of tert-butyl(S)-2-amino-5,5-dimethylhexanoate (70 mg, 1 equivalent, 0.33 mmol), 1-chloro-3-iodobenzene (78 mg, 40 μL, 1 equivalent, 0.33 mmol), and tBuBrettPhos Pd G3,96% (15 mg, 96% by weight, 0.052 equivalents, 17 μmol) was injected with nitrogen, and then Cs2CO3 (0.16 g, 1.5 equivalents, 0.49 mmol) and 1,4-dioxane (3.0 mL) were added. Nitrogen was injected into the mixture again, and the reaction was heated at 50°C for 18 hours. After the reaction mixture was cooled to room temperature, it was acidified with formic acid (approximately 150 μL), followed by filtration and concentration on silica (approximately 1 g). The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% ethyl acetate / isohexane) to obtain tert-butyl(S)-2-((3-chlorophenyl)amino)-5,5-dimethylhexanoate (14 mg, 42 μmol, yield 13%, purity 98%) as a yellow gum. LC-MS (Method 6), 2.70 min; M- t Bu + H = 270.2. 1 1H-NMR (500 MHz, MeOD) δ 7.07 (app. t, J = 8.0 Hz, 1H), 6.67-6.60 (m, 2H), 6.56 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 3.81 (t, J = 6.6 Hz, 1H), 1.87-1.70 (m, 2H), 1.45 (s, 9H), 1.46-1.38 (m, 1H), 1.32 (app. td, J = 12.8, 5.0 Hz, 1H), 0.95 (s, 9H)

[0145] Synthesis of (S)-2-((3-chlorophenyl)amino)-5,5-dimethylhexanoic acid (Example 30) A solution of tert-butyl(S)-2-((3-chlorophenyl)amino)-5,5-dimethylhexanoate (14 mg, 1 equivalent, 43 μmol) in 4 M HCl in dioxane (3 mL) was stirred at room temperature for 2 hours, and then concentrated to obtain (S)-2-((3-chlorophenyl)amino)-5,5-dimethylhexanoic acid (10 mg, 36 μmol, yield 85%, purity 98%) as a colorless solid. LC-MS (Method 6), 2.14 min, M+H=270.2. 1 H-NMR (500 MHz, DMSO) δ 12.67-12.51 (m, 1H), 7.06 (app. t, J = 8.0 Hz, 1H), 6.58 (app. t, J = 2.2 Hz, 1H), 6.56-6.49 (m, 2H), 6.17-6.13 (m, 1H), 3.81-3.77 (m, 1H), 1.76-1.61 (m, 2H), 1.38-1.17 (m, 2H), 0.87 (s, 9H)

[0146] The following Example 31 was prepared starting from the corresponding aryl bromide and in a manner similar to that of Example 30. [Table 6]

[0147] Example 32 [ka]

[0148] Synthesis of 4-methylpentan-1-ol (Int 32-a) THF (51.0 mL) and BH3.Me2S (1.99 g, 13.1 mL, 2.00 molar concentration, 0.44 equivalents, 26.1 mmol) were combined and cooled to 0°C (internal temperature) in an ice bath. 4-Methylpenta-1-ene (5.00 g, 7.52 mL, 1 equivalent, 59.4 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 1.5 hours. The solution was warmed to room temperature and stirred for 16 hours. Water (8.70 mL), sodium hydroxide (1.05 g, 8.71 mL, 3.00 molar concentration, 0.44 equivalents, 26.1 mmol), and hydrogen peroxide (9.63 g, 8.76 mL, 30% by weight, 1.43 equivalents, 85.0 mmol) were added to 0°C. The reaction mixture was added dropwise to each reaction flask while cooling, and stirred for a further 10 minutes at the same temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with MTBE (300 mL) and washed with brine (3 × 150 mL). The organic layer was dried over MgSO4, and the solvent was removed by vacuum. 4-methylpentan-1-ol (5.5 g, 48 mmol, yield 81%, purity 99%) was obtained as a colorless oil. UPLC (Method 5), (not applicable) minutes; M+H=not applicable. 1 H-NMR (400 MHz, DMSO) δ 4.32 (t, J = 5.2 Hz, 1H), 3.36 (td, J = 6.7, 5.2 Hz, 2H), 1.50 (dp, J = 13.3, 6.7 Hz, 1H), 1.44-1.35 (m, 2H), 1.19-1.12 (m, 2H), 0.86 (s, 3H), 0.84 (s, 3H)

[0149] Synthesis of 4-methylpentanal (Int 32-b) DMSO (8.78 g, 7.98 mL, 2.9 equivalents, 112 mmol) and oxalyl chloride (7.38 g, 5.09 mL, 1.5 equivalents, 58.1 mmol) were combined in DCM (200 mL) at -65°C. After stirring for 10 minutes, 4-methylpentan-1-ol (4.00 g, 4.92 mL, 99% by weight, 1 equivalent, 38.8 mmol) was added, and the mixture was stirred for a further 1 hour. Et3N (11.8 g, 16.2 mL, 3 equivalents, 116 mmol) was added dropwise, and the mixture was stirred for 10 minutes. The mixture was then heated to room temperature and stirred for 2.5 hours. The reaction was stopped with water, followed by the addition of 1 M aqueous HCl (200 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 × 100 mL), and the combined organic layer was washed with water (150 mL), 1 M HCl aqueous solution (150 mL), saturated NaHCO3 aqueous solution (150 mL), and brine (3 × 150 mL). After drying on MgSO4, the mixture was filtered and concentrated under vacuum to obtain 4-methylpentanal (6.14 g, 27 mmol, yield 70%, purity 44%) as a yellow liquid. UPLC (Method 5), (not applicable) min; M + H = not applicable. 1 H-NMR (400 MHz, DMSO) δ 9.71 (t, J = 1.7 Hz, 1H), 2.48-2.41 (m, 2H), 1.55 (ddd, J = 13.8, 12.8, 6.5 Hz, 1H), 1.46 (qd, J = 7.1, 0.6 Hz, 2H), 0.90 (d, J = 6.5 Hz, 6H)

[0150] Synthesis of sodium 1-hydroxy-4-methylpentane-1-sulfonate (Int 32-c) 4-methylpentanal (2.14 g) was diluted with ethanol (7.00 mL). To this mixture, a solution of sodium bisulfite (999 mg, 0.248 equivalents, 9.60 mmol) in water (1.60 mL) was added dropwise over 5 minutes at 45°C, and the mixture was stirred for 2 hours. The mixture was cooled to room temperature, filtered, and washed with ethanol (2 × 5 mL) to obtain sodium 1-hydroxy-4-methylpentane-1-sulfonate (1.28 g, 6.2 mmol, yield 65%, purity 99%) as a white solid. UPLC (Method 5), (not applicable) minutes; M + H = not applicable. 1 H-NMR (400 MHz, DMSO) δ 5.06 (s, 1H), 3.73 (d, J = 9.5 Hz, 1H), 1.75 (ddq, J = 13.1, 8.1, 2.7 Hz, 1H), 1.56-1.27 (m, 3H), 1.21-1.10 (m, 1H), 0.85 (dd, J = 6.6, 3.1 Hz, 6H)

[0151] The following intermediate 32-c-2 (Int 32-c-2) was prepared starting from the corresponding alkene using a method similar to that of Int 32-c. [Table 7]

[0152] [ka]

[0153] Synthesis of N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)isoquinoline-4-amine (Int 32-d-2) A mixture of isoquinolin-4-amine (147 mg, 98 wt%, 1 eq., 1.00 mmol) and sodium 1-hydroxy-4,4-dimethylpentane-1-sulfonate (220 mg, 99 wt%, 1 eq., 1.00 mmol) in MeOH (4.00 mL) was stirred at room temperature for 10 min, then methyldine(2,4,4-trimethylpentan-2-yl)-l4-azan (140 mg, 177 μL, 1 eq., 1.00 mmol) and TMS-N3 (121 mg, 140 μL, 95 wt%, 1 eq., 1.00 mmol) were added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0 - 100% EtOAc / isohexane) to give N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)pentyl)isoquinolin-4-amine (272 mg, 0.53 mmol, 53% yield, 82% purity) as a white solid. UPLC (method 5), 1.71 min; M+H = 423.6. 1 1H-NMR (400 MHz, DMSO) δ 8.​​​Synthesis of N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)isoquinoline-4-amine (Example 32) A mixture of N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)isoquinoline-4-amine (170 mg, 82 wt%, 1 equivalent, 330 μmol) was stirred in 3 M HCl (722 mg, 6.60 mL, 3.00 molar concentration, 60 equivalents, 19.8 mmol) in MeOH at 65°C for 16 hours. The crude product was vacuum concentrated and co-evaporated several times with MeOH. The product was loaded onto Celite and subsequently purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM). The pure fraction was recovered and evaporated. The crude product was loaded onto an SCX (1 g) column in MeOH. After washing the column with MeOH, the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum to obtain N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)isoquinoline-4-amine (74.0 mg, 0.24 mmol, yield 72%, purity 99%) as a yellow solid. UPLC (Method 5), 1.18 min; M+H=311.4. 1 H-NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.94 (dd, J = 8.1, 1.3 Hz, 1H), 7.73-7.66 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 4.95 (q, J = 7.2 Hz, 1H), 2.19-2.07 (m, 1H), 2.07-1.96 (m, 1H), 1.44 (td, J = 12.8, 4.6 Hz, 1H), 1.10 (td, J = 12.8, 4.4 Hz, 1H), 0.86 (s, 9H)

[0155] The following examples were prepared starting from the corresponding bisulfites and amines, in a manner similar to that of Example 32. [Table 8-1]

[0156] [Table 8-2]

[0157] [Table 8-3]

[0158] The following examples were prepared starting from the corresponding aldehydes and amines, in a manner similar to that of Example 32. [Table 9-1]

[0159] [Table 9-2]

[0160] Example 44 [ka]

[0161] Synthesis of N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-3-amine (Int 44-a) A mixture of quinoline-3-amine (123 mg, 1 equivalent, 850 μmol) and 3,3-dimethylbutanal (87.8 mg, 110 μL, 97 wt%, 1 equivalent, 850 μmol) in MeOH (3.00 mL) was stirred at room temperature for 10 minutes, and then methylidine (2,4, 4-Trimethylpentan-2-yl)-14-azan (126 mg, 158 μL, 95% by weight, 1 equivalent, 850 μmol) was added. After stirring for a further 5 minutes, TMS-N3 (100 mg, 115 μL, 94% by weight, 0.96 equivalents, 816 μmol) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was treated with saturated NaHCO3 aqueous solution (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous component was extracted with ethyl acetate (2 × 10 mL). The pooled organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% siRNA / isohexane) to obtain N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-3-amine (289 mg, 0.67 mmol, yield 79%, purity 95%) as a white solid. UPLC (Method 5), 2.19 min; M+H=409.5. 1 H-NMR (400 MHz, DMSO) δ 0.62 (s, 9H), 0.93 (s, 9H), 1.85 (d, J = 9.6 Hz, 6H), 1.90-2.10 (m, 3H), 2.26-2.36 (m, 1H), 5.11-5.21 (m, 1H), 6.89 (d, J = 9.4 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.34-7.47 (m, 2H), 7.68-7.75 (m, 1H), 7.79 (d, J = 8.1 Hz, 1H), 8.56 (d, J = 2.7 Hz, 1H)

[0162] Synthesis of N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)quinoline-3-amine (Example 44) A solution of N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-3-amine (146 mg, 1 equivalent, 357 μmol) in formic acid (0.5 mL) and water (1 drop) was heated at 50°C for 18 hours. The solvent was removed by vacuum. The crude product was chromatographed on silica gel (12 g). The product was purified using a Redisep Gold cartridge (0-10% MeOH / DCM) and dried in a vacuum desiccator at 45°C for 18 hours. N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)quinoline-3-amine (45.0 mg, 0.14 mmol, 40% yield, 94% purity) was obtained as a white solid. UPLC (Method 5), 1.24 min; M+H=297.4. 1 H-NMR (400 MHz, DMSO) δ 0.93 (s, 9H), 1.94-2.09 (m, 2H), 4.94-5.03 (m, 1H), 6.83 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.30-7.43 (m, 2H), 7.56-7.63 (m, 1H), 7.77 (dd, J = 1.3, 7.7 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 16.29 (s, 1H)

[0163] The following examples were prepared starting from the corresponding aldehydes and amines, in a manner similar to that of Example 44. [Table 10-1]

[0164] [Table 10-2]

[0165] Example 51 [ka]

[0166] Synthesis of N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyrazine-2-amine (Int 51-a) A mixture of pyrazine-2-amine (97.0 mg, 98% by weight, 1 equivalent, 1.00 mmol) and 3,3-dimethylbutanal (101 mg, 127 μL, 99% by weight, 1 equivalent, 1.00 mmol) in MeOH (4.00 mL) was stirred at room temperature for 10 minutes, after which methylizine (2,4,4-trimethylpentan-2-yl)-14-azan (140 mg, 177 μL, 1 equivalent, 1.00 mmol) and TMS-N3 (121 mg, 140 μL, 95% by weight, 1 equivalent, 1.00 mmol) were added. The mixture was stirred at 25°C for 16 hours. The reaction was stopped with saturated NaHCO3 aqueous solution (15 mL) and extracted with SiO2 (3 × 15 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% siRNA / isohexane), and the product was loaded onto an SCX (1.5 g) column in MeOH. After washing the column with MeOH, the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum to obtain N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyrazine-2-amine (84.0 mg, 0.23 mmol, yield 23%, purity 97%) as a white solid. UPLC (Method 5), 2.25 min; M+H=360.6. 1 H-NMR (400 MHz, DMSO) δ 8.02 (d, J = 1.5 Hz, 1H), 7.97 (dd, J = 2.9, 1.5 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 5.98 (td, J = 9.0, 4.3 Hz, 1H), 2.12 (d, J = 15.1 Hz, 1H), 1.96 (dd, J = 14.4, 8.9 Hz, 1H), 1.88 (d, J = 13.9 Hz, 5H), 1.81 (s, 3H), 0.92 (s, 9H), 0.61 (s, 9H)

[0167] Synthesis of N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)pyrazine-2-amine (Example 51) N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyrazine-2-amine (84.0 mg, 98 wt%, 1 equivalent, 229 μmol) was stirred at 65°C for 4 hours in 3 M HCl (501 mg, 4.58 mL, 3.00 molar concentration, 60 equivalents, 13.7 mmol) in CPME. The crude product was concentrated under vacuum and then loaded onto an SCX (1.5 g) column in MeOH. After washing the column with MeOH, the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum on Celite and purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM) to obtain N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)pyrazine-2-amine (21.0 mg, 84 μmol, yield 37%, purity 99%) as a yellow solid. UPLC (Method 5), 1.38 min; M+H=348.2. 1 H-NMR (400 MHz, DMSO) δ 8.01 (d, J = 1.5 Hz, 1H), 7.90 (dd, J = 2.9, 1.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 2.9 Hz, 1H), 5.41 (q, J = 6.7 Hz, 1H), 1.93 (d, J = 6.4 Hz, 2H), 0.90 (s, 9H)

[0168] The following Example 52 was prepared starting from the corresponding aldehyde and amine, in a manner similar to that of Example 51. [Table 11]

[0169] The following Example 53 was prepared starting from the corresponding bisulfite and amine, in a manner similar to that of Example 51. [Table 12]

[0170] Example 54 [ka]

[0171] Synthesis of N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-2-amine (Int 54-a) A mixture of quinoline-2-amine (169 mg, 98% by weight, 1 equivalent, 1.15 mmol) and 3,3-dimethylbutanal (115 mg, 144 μL, 1 equivalent, 1.15 mmol) in MeOH (3.00 mL) was stirred at room temperature for 10 minutes, after which methylizine (2,4,4-trimethylpentan-2-yl)-14-azan (170 mg, 213 μL, 95% by weight, 1 equivalent, 1.15 mmol) and TMS-N3 (139 mg, 160 μL, 95% by weight, 1 equivalent, 1.15 mmol) were added. The mixture was stirred at 25°C for 16 hours. The reaction was stopped with saturated NaHCO3 aqueous solution (15 mL) and extracted with dimethylethanol (3 × 15 mL). The combined organic layer was washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% siRNA / isohexane) to obtain N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-2-amine (275 mg, 0.64 mmol, yield 56%, purity 95%) as a white solid. UPLC (Method 5), 2.60 min; M+H=409.6. 1 H-NMR (400 MHz, DMSO) δ 7.87 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.65-7.57 (m, 1H), 7.56-7.44 (m, 2H), 7.17 (ddd, J = 8.1, 6.3, 1.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.44 (td, J = 9.1, 4.0 Hz, 1H), 2.30 (d, J = 15.1 Hz, 1H), 2.07-1.99 (m, 1H), 1.92 (s, 3H), 1.91 (s, 3H), 1.88-1.84 (m, 1H), 1.80 (d, J = 9.2 Hz, 1H), 0.96 (s, 9H), 0.54 (s, 9H)

[0172] Synthesis of N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)quinoline-2-amine (Example 54) A mixture of N-(3,3-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)quinoline-2-amine (175 mg, 99 wt%, 1 equivalent, 424 μmol) was stirred in HCl in water (928 mg, 4.24 mL, 6.00 molar concentration, 60 equivalents, 25.4 mmol) at 75°C for 5 hours. The crude product was concentrated under vacuum, diluted with MeCN, and evaporated again under vacuum. The residue was loaded onto Celite and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) to obtain N-(3,3-dimethyl-1-(1H-tetrazole-5-yl)butyl)quinoline-2-amine (42 mg, 0.13 mmol, yield 31%, purity 94%) as a green solid. UPLC (Method 5), 1.20 min; M+H=297.4. 1 H-NMR (500 MHz, DMSO) δ 8.09 (bs, 1H), 7.80-7.53 (m, 3H), 7.31 (bs, 1H), 7.00 (bs, 1H), 5.83 (bs, 1H), 2.12-2.01 (m, 2H), 0.96 (s, 9H)

[0173] The following examples were prepared starting from the corresponding aldehydes and amines, in a manner similar to that of Example 54. [Table 13-1]

[0174] [Table 13-2]

[0175] [Table 13-3]

[0176] [Table 13-4]

[0177] [Table 13-5]

[0178] Intermediate 70a~70d (Int 70a~Int 70d) [ka]

[0179] Synthesis of (E)-3-methyl-N-tritylbutan-1-imine (Int 70-a) A mixture of tritylamine (6.48 g, 1 equivalent, 25.0 mmol) and isovalenteraldehyde (3.23 g, 4.11 mL, 1.5 equivalents, 37.5 mmol) in toluene (25.0 mL) was refluxed for 18 hours using a Dean-Stark distillation apparatus. The reaction mixture was cooled to room temperature, MgSO4 was added, and the mixture was stirred for 15 minutes. After filtration and vacuum concentration, (E)-3-methyl-N-tritylbutan-1-imine (8.7 g, 25.0 mmol, 100% yield, 94% purity) was obtained as a yellow oil. UPLC (Method 5), 1.20 min; M+H=243.2. 1 H-NMR (400 MHz, CDCl3) δ 7.30-7.20 (m, 16H), 2.38-2.31 (m, 2H), 1.96 (dp, J = 13.5, 6.7 Hz, 1H), 0.93 (d, J = 6.7 Hz, 6H)

[0180] Synthesis of 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)-N-tritylbutan-1-amine(70-b) (E)-3-methyl-N-tritylbutan-1-imine (945 mg, 90% by weight, 1 equivalent, 2.60 mmol) dissolved in EtOH (8.00 mL) was stirred at room temperature, and then methylizine (2,4,4-trimethylpentan-2-yl)-14-azan (0.37 g, 0.47 mL, 98% by weight, 1.0 equivalent, 2.6 mmol) was introduced. After stirring at room temperature for 10 minutes, TMS-N3 (0.31 g, 0.36 mL, 94% by weight, 0.98 equivalents, 2.5 mmol) was added. The mixture was stirred at 25°C for 3 days. The reaction product was diluted with ethyl acetate (20 mL) and washed with saturated NaHCO3 solution (30 mL), followed by brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-20% siRNA / isohexane) to obtain 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)-N-tritylbutan-1-amine (1.17 g, 2.0 mmol, yield 79%) as a colorless gum. UPLC (Method 5), 2.82 min; M+H=not applicable. 1 H-NMR (400 MHz, DMSO) δ 0.53-0.61 (m, 3H), 0.63-0.90 (m, 12H), 1.27-1.69 (m, 11H), 3.39 (d, J = 7.9 Hz, 1H), 4.18 (s, 1H), 7.14-7.20 (m, 3H), 7.20-7.28 (m, 6H), 7.34-7.41 (m, 6H)

[0181] Synthesis of 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butan-1-amine (Int 70-c) Dissolve 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)-N-tritylbutan-1-amine (1.16 g, 89% by weight, 1 equivalent, 2.03 mmol) in DCM (10.0 mL), stir at 25°C, and then T FA (577 mg, 390 μL, 2.5 equivalents, 5.06 mmol) was added dropwise. The mixture was stirred for 1 hour and 15 minutes, and the reaction was stopped with saturated NaHCO3 (30 mL). The layers were separated, and the aqueous component was further extracted with DCM (25 mL). The pooled organic components were washed with brine (25 mL), passed through hydrophobic frit, and concentrated under vacuum. The crude product was loaded onto an SCX (approximately 6 g) column in MeOH. After washing the column with MeOH (200 mL), the product was eluted with 7 M ammonia in MeOH (150 mL). The resulting mixture was concentrated under vacuum to obtain 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butan-1-amine (499 mg, 1.8 mmol, yield 88%, purity 95%) as a colorless oil. UPLC (Method 5), (Not applicable) minutes; M+H=268.7. 1 H-NMR (400 MHz, DMSO) δ 0.72 (s, 9H), 0.91 (dd, J = 6.3, 8.8 Hz, 6H), 1.50-1.62 (m, 1H), 1.73-1.86 (m, 8H), 1.90 (d, J = 15.2 Hz, 1H), 2.06 (d, J = 15.2 Hz, 2H), 4.29 (dd, J = 5.0, 8.7 Hz, 1H)

[0182] Synthesis of 3-methyl-1-(1H-tetrazole-5-yl)butan-1-amine hydrochloride (Int 70-d) 3-Methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butan-1-amine (499 mg, 1 equivalent, 1.87 mmol) was dissolved in dichloromethane (1.00 mL), and then treated with 3M HCl (273 mg, 2.50 mL, 3.00 molar concentration, 4.02 equivalents, 7.50 mmol) in CPME. The reaction mixture was stirred at room temperature for 15 minutes. The solvent was removed by vacuum, and 3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butan-1-amine,HCl (559 mg, 1.7 mmol, yield 94%, purity 95%) was obtained as a white solid. UPLC (Method 5), (not applicable) min; M+H=268.7. 1 H-NMR (400 MHz, DMSO) δ 0.79 (s, 9H), 0.93 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 1.63-1.71 (m, 1H), 1.77-1.85 (m, 7H), 1.88-2.04 (m, 3H), 5.01 (d, J = 10.1 Hz, 1st hour), 8.75 (s, 3rd hour)

[0183] The following intermediates were prepared starting from the corresponding aldehydes using a method similar to that of intermediate 70-d. [Table 14]

[0184] Examples 74, 75, and 76 [ka]

[0185] Synthesis of N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (Int 74-a) 4-Chloro-6-fluoroquinazoline (255 mg, 1.5 equivalents, 1.40 mmol) and 4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentan-1-amine (275 mg, 1 equivalent, 931 μmol) were dissolved in DMSO (3.00 mL). DIPEA (301 mg, 405 μL, 2.5 equivalents, 2.33 mmol) was introduced, and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was diluted with DCM (20 mL), and then washed with 1 M HCl (20 mL), saturated NaHCO3 aqueous solution (20 mL), and then brine (3 × 25 mL). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% siRNA / isohexane) to obtain N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (377 mg, 0.81 mmol, yield 87%, purity 95%) as an orange solid. UPLC (Method 5), 2.19 min; M+H=442.2. 1 H-NMR (400 MHz, DMSO) δ 0.63 (s, 9H), 0.86 (s, 9H), 1.10-1.21 (m, 1H), 1.35-1.47 (m, 1H), 1.83 (s, 6H), 1.92-2.17 (m, 4H), 6.11 (q, J = 7.6 Hz, 1H), 7.72 (td, J = 2.7, 8.7 Hz, 1H), 7.80 (dd, J = 5.5, 9.2 Hz, 1H), 8.41 (dd, J = 2.8, 10.2 Hz, 1H), 8.50 (s, 1H), 8.80 (d, J = 8.1 Hz, 1H).19F NMR (376 MHz, DMSO) δ -113.01

[0186] Synthesis of N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (Example 74) N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (375 mg, 1 equivalent, 849 μmol) was dissolved in DCM (2 mL), and then 3 M hydrogen chloride (1.31 g, 12.0 mL, 3.00 molar concentration, 42.4 equivalents, 36.0 mmol) in CPME was added. The reaction mixture was heated at 70°C for 3 hours and then cooled to room temperature. Residue The solvent was decanted, and the resulting solid was vacuum concentrated. The crude product was loaded onto an SCX (0.5 g) column in MeOH. After washing the column with MeOH (100 mL), the product was eluted with 0.7 M ammonia in MeOH (150 mL). The resulting mixture was vacuum concentrated to obtain the product. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM) to obtain N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (90.0 mg, 0.26 mmol, 31%, purity 95%) as a yellow solid. UPLC (Method 5), 1.27 min; M+H=330.4. 1 H-NMR (400 MHz, DMSO) δ 0.85 (s, 9H), 1.18 (td, J = 5.1, 12.7 Hz, 1H), 1.34 (td, J = 4.9, 12.6 Hz, 1H), 1.94-2.11 (m, 2H), 5.66-5.73 19F NMR (376 MHz, DMSO) δ-113.81

[0187] Example 74, Enantiomeric resolution of N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (Examples 75 and 76) N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (140 mg, 0.43 mmol) was dissolved in MeOH under sonication and heating to a concentration of 6 mg / mL. This was filtered and then purified by chiral SFC on a Waters prep 100 equipped with PDA and QDA detectors at 40°C and 120 bar. The column was a Chiralpak IH 5 μm, 21 mm × 250 mm, with a flow rate of 65 mL / min of 20% MeOH (unbuffered), 80% CO2. The clean fraction was pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residue was redissolved in MeOH, transferred to a final vial, and evaporated on a Biotage V10. Next, the sample was dried for a further 18 hours in a vacuum oven at 30°C / 5 mmbar to obtain the first eluted isomer E1, N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (46 mg, 137 μmol, yield 30%, purity 98%) as a yellow film. LC-MS (Method 6), 1.38 min; M+H=330.2. 1 H-NMR (400 MHz, DMSO) δ 8.54 (d, J = 7.7 Hz, 1H), 8.43 (s, 1H), 8.32 (dd, J = 10.2, 2.8 Hz, 1H), 7.79 (dd, J = 9.2, 5.6 Hz, 1H), 7.71 (td, J = 8.8, 2.7 Hz, 1H), 5.70 (q, J = 7.8 Hz, 1H), 2.09 (qd, J = 12.5, 6.2 Hz, 2H), 1.37 (td, J = 12.3, 5.1 Hz, 1H), 1.22 (dd, J = 11.9, 4.9 Hz, 1H), 0.87 (s, 9H).19F NMR (376 MHz, DMSO) δ -113.81

[0188] The second eluted isomer was E2,N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine (43 mg, 129 μmol, yield 28%, purity 99%), obtained as a yellow film. LC-MS (Method 6), 1.38 min; M+H=330.2. 1 H-NMR (400 MHz, DMSO) δ 8.54 (d, J = 7.7 Hz, 1H), 8.43 (s, 1H), 8.32 (dd, J = 10.2, 2.8 Hz, 1H), 7.79 (dd, J = 9.2, 5.6 Hz, 1H), 7.71 (td, J = 8.8, 2.7 Hz, 1H), 5.70 (q, J = 7.8 Hz, 1H), 2.09 (qd, J = 12.5, 6.2 Hz, 2H), 1.37 (td, J = 12.3, 5.1 Hz, 1H), 1.22 (dd, J = 11.9, 4.9 Hz, 1H), 0.87 (s, 9H).19F NMR (376 MHz, DMSO) δ -113.81.Kira UPLC (Method 7), E2, N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine, 1.2 min, 99.32% EE.z, N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)-6-fluoroquinazoline-4-amine, 1.6 min, 97.4% EE. * The expected stereochemistry is unconfirmed.

[0189] Examples 80-96 below show the corresponding amine intermediates (Int 71d-73d) and salts Starting with aryl compounds, preparations were made in a manner similar to that of Examples 74, 75, and 76, and the same resolution method was used for the enantiomer pairs in Examples 93, 94, 95, and 96 (predicted stereochemistry is unconfirmed). [Table 15-1]

[0190] [Table 15-2]

[0191] [Table 15-3]

[0192] [Table 15-4]

[0193] [Table 15-5]

[0194] [Table 15-6]

[0195] [Table 15-7]

[0196] Examples 97 and 98 [ka]

[0197] Example 102, Enantiomeric Resolution of N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (Examples 97 and 98) N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine was dissolved in MeOH by sonication to a concentration of 10 mg / mL. This was filtered and purified by chiral SFC on a Waters prep 100 equipped with PDA and QDA detectors at 40°C and 120 bar. The column used was a Chiralpak IG 5 μm, 21 mm × 250 mm, with a flow rate of 65 mL / min of 25% MeOH (0.1% DEA), 75% CO2. The clean fraction was pooled, rinsed with MeOH, and concentrated to dryness using Genevac. The residue was redissolved in MeOH, transferred to a final vial, and evaporated on a Biotage V10. The isolated pure enantiomer was further dried in vacuum and in a desiccator to remove excess diethylamine, yielding the first eluted isomer E1, N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine,diethylamine (78.0 mg, 203 μmol, yield 29%, purity 100%) as a white solid. UPLC (Method 5), 1.13 min; M+H=312.4. Chiral Method 7, 1.12 min, 99% EE. 1 H-NMR (400 MHz, DMSO) δ 8.41 (d, J = 7.3 Hz, 2H), 8.24 (d, J = 8.5 Hz, 1H), 7.73 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.64 (dd, J = 8.4, 1.3 Hz, 1H), 7.46 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 5.72 (q, J = 7.9 Hz, 1H), 2.88 (q, J = 7.3 Hz, 4H), 2.09-1.88 (m, 2H), 1.31-1.17 (m, 2H), 1.14 (t, J = 7.2 Hz, 6H), 0.84 (s, 9H)

[0198] The second eluted isomer, E2, N-(4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine, diethylamine (82.0 mg, 0.21 mmol, yield 30%, purity 99%) (isomer 2), was also obtained as a white solid. UPLC (Method 5), 1.13 min; M+H=312.4. Chiral Method 7, 1.35 min, 97% EE. 1 H-NMR (400 MHz, DMSO) δ 8.42 (d, J = 8.1 Hz, 2H), 8.25 (d, J = 8.4 Hz, 1H), 7.73 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.64 (dd, J = 8.3, 1.3 Hz, 1H), 7.46 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 5.72 (q, J = 7.7 Hz, 1H), 2.90 (q, J = 7.3 Hz, 4H), 2.09-1.88 (m, 2H), 1.32-1.17 (m, 2H), 1.14 (t, J = 7.3 Hz, 6H), 0.84 (s, 9H)

[0199] The following single enantiomers, Examples 99 and 100, were obtained by a method similar to that of Examples 97 and 98. Expected stereochemistry is unconfirmed. [Table 16]

[0200] Example 101 [ka]

[0201] N-(4-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine(Int 101-b) synthesis 4-Methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentan-1-amine,trifluoroacetic acid (273 mg, 87 wt%, 1 equivalent, 600 μmol) was dissolved in DMSO (2.80 mL), then DIPEA (233 mg, 314 μL, 3 equivalents, 1.80 mmol) was added, followed by 4-chloroquinazoline (250 mg, 97 wt%, 2.46 equivalents, 1.47 mmol). The reaction mixture was stirred at 85°C for 60 hours. The reaction mixture was diluted with DCM (50 mL), then washed with 1 M HCl (30 mL), saturated NaHCO3 aqueous solution (30 mL), and then brine (3 × 50 mL). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% Âxy / isohexane) to obtain N-(4-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (158 mg, 323 μmol, yield 53%, purity 83%) as a brown gum. UPLC (Method 5), 1.73 min; M+H=410.5. 1 H-NMR (400 MHz, DMSO) δ 8.79 (d, J = 8.1 Hz, 1H), 8.49 (d, J = 8.6 Hz, 2H), 7.80 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.71 (dd, J = 8.4, 1.3 Hz, 1H), 7.54 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 6.21-6.12 (m, 1H), 2.23-2.03 (m, 3H), 1.95 (d, J = 15.1 Hz, 1H), 1.84 (d, J = 4.0 Hz, 6H), 1.58 (hept, J = 6.6 Hz, 1H), 1.42-1.31 (m, 1H), 1.25-1.18 (m, 1H), 0.86 (d, J = 3.7 Hz, 3H), 0.84 (d, J = 3.7 Hz, 3H), 0.63 (s, 9H)

[0202] Synthesis of N-(4-methyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (Example 101) A mixture of N-(4-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (158 mg, 83 wt%, 1 equivalent, 320 μmol) was stirred in HCl (969 mg, 8.86 mL, 3.00 molar concentration, 83 equivalents, 26.6 mmol) in MeOH for 16 hours at 65°C. The crude product was concentrated under vacuum, co-evaporated several times with MeOH, and loaded onto Celite. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM) to obtain N-(4-methyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine,HCl (125 mg, 0.37 mmol, 83%, purity 98%) as an off-white solid. This was loaded onto a column of SCX (750 mg) in MeOH. After washing the column with MeOH, the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum to obtain N-(4-methyl-1-(1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (21.0 mg, 70 μmol, 58% yield, 99% purity) as an off-white solid. UPLC (Method 5), 1.04 min; M+H=298.4. 1 H-NMR (400 MHz, DMSO) δ 8.49-8.38 (m, 3H), 7.77 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.68 (dd, J = 8.5, 1.3 Hz, 1H), 7.52 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 5.79-5.69 (m, 1H), 2.16-1.95 (m, 2H), 1.56 (dt, J = 13.3, 6.6 Hz, 1H), 1.36-1.17 (m, 2H), 0.86 (d, J = 4.5 Hz, 3H), 0.84 (d, J = 4.5 Hz, 3H)

[0203] The following examples were prepared in a manner similar to Example 101, starting from the corresponding amine intermediate Int 73d and heteroaryl chloride. [Table 17]

[0204] Example 104 [ka]

[0205] Synthesis of N-(3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyridine-4-amine (Int 104-b) 3-Methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butan-1-amine, Int 70-c (150 mg, 1 equivalent, 561 μmol), 4-bromopyridine hydrochloride (131 mg, 1.2 equivalents, 673 μmol), sodium tert-butoxide (172 mg, 3.2 equivalents, 1.79 mmol), and RuPhos (11.0 mg, 0.196 equivalents, 23.6 μmol) are combined with THF (3. It was taken up in 00 mL. After sparing for 2 minutes in N2, RuPhos G3 pre-catalyst (47.0 mg, 0.100 equivalents, 56.2 μmol) was added. N2 was injected into the mixture for 2 minutes, and then the mixture was heated at 75°C for 15 hours. The reaction mixture was cooled to room temperature, diluted with HCl (10 mL), and water (10 mL) was added. The layers were separated, and the organic layer was washed with saturated NaHCO3 aqueous solution (15 mL) and brine (15 mL). The organic layer was dried on magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) to obtain N-(3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyridine-4-amine (68.0 mg, 0.19 mmol, yield 33%, purity 94%) as a yellow gum. UPLC (method 5), 1.34 min; M+H=345.5. 1 H-NMR (400 MHz, DMSO) δ 0.65 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.53-1.64 (m, 1H), 1.75-1.80 (m, 6H), 1.80-2.04 (m, 4H), 5.09 (q, J = 7.6 Hz, 1H), 6.61-6.67 (m, 2H), 7.09 (d, J = 9.0 Hz, 1H), 8.04-8.10 (m, 2H)

[0206] Synthesis of N-(3-methyl-1-(1H-tetrazole-5-yl)butyl)pyridine-4-amine (Example 104) N-(3-methyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)butyl)pyridine-4-amine (68.0 mg, 1 equivalent, 197 μmol) was dissolved in DCM (0.5 mL), and then 3M HCl (273 mg, 2.50 mL, 3.00 molar concentration, 38.0 equivalents, 7.50 mmol) in CPME was added. The reaction mixture was heated at 70°C for 3 hours and then cooled to room temperature. The solid was recovered by filtration and washed with MTBE (10 mL). The crude product was loaded onto an SCX (0.5 g) column in MeOH. After washing the column with MeOH (50 mL), the product was eluted with 0.7 M ammonia in MeOH (30 mL). The resulting mixture was concentrated under vacuum to obtain the product, which was treated with MTBE (3 mL) and the solvent was removed under vacuum. The obtained solid was dried in a vacuum desiccator at 45°C for 15 hours. N-(3-methyl-1-(1H-tetrazole-5-yl)butyl)pyridine-4-amine (31.0 mg, 0.13 mmol, yield 64%, purity 95%) was obtained as a white solid. UPLC (Method 5), 0.75 min; M+H=233.3. 1 H-NMR (400 MHz, DMSO) δ 0.85 (dd, J = 1.6, 6.6 Hz, 3H), 0.92 (dd, J = 1.6, 6.6 Hz, 3H), 1.46-1.59 (m, 1H), 1.78-1.92 (m, 2H), 4.89 (q, J = 7.6 Hz, 1H), 6.86 (d, J = 6.6 Hz, 2H), 8.06 (d, J = 6.6 Hz, 2H), 8.62 (d, J (= 7.5 Hz, 1H)

[0207] The following Example 105 was prepared starting from an amine Int 70-c or Int 70-d and an aryl chloride, in a manner similar to that of Example 104. [Table 18]

[0208] Example 106 [ka]

[0209] 7-Bromo-N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentane Synthesis of -2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (Int 106-a) 4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentan-1-amine,trifluoroacetic acid (500 mg, 99% by weight, 1 equivalent, 1.21 mmol) was dissolved in DMSO (2.90 mL), and DIPEA (469 mg, 632 μL, 3 equivalents, 3.63 mmol) was added. 7-bromo-4-chloroquinazoline (601 mg, 98% by weight, 2 equivalents, 2.42 mmol) was introduced, and the reaction mixture was stirred at 85°C for 16 hours. The mixture was diluted with DCM (25 mL), and the solid was filtered. The mother liquor was diluted with DCM (50 mL), and then washed with 1 M HCl (30 mL), saturated NaHCO3 solution (30 mL), followed by brine (3 x 50 mL). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (solid loaded onto Celite, 0-40%, followed by 40-100% siRNA / n-heptane) to obtain the product, which was then polished with a minimal amount of n-heptane to obtain 7-bromo-N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (426 mg, 0.84 mmol, yield 69%, purity 99%) as a white solid.

[0210] UPLC (method 5), 2.45 min; M+H=500.0 / 502.1. 1 H-NMR (400 MHz, DMSO) δ 8.99 (d, J = 8.0 Hz, 1H), 8.56-8.42 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.9, 2.1 Hz, 1H), 6.10 (td, J = 8.2, 5.8 Hz, 1H), 2.21-2.01 (m, 3H), 1.96 (d, J = 15.0 Hz, 1H), 1.83 (s, 6H), 1.41 (td, J = 12.7, 4.8 Hz, 1H), 1.15 (td, J = 12.6, 4.1 Hz, 1H), 0.86 (s, 9H), 0.64 (s, 9H)

[0211] Synthesis of 4-((4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)amino)quinazoline-7-carbonitrile (Int 106-b) 7-Bromo-N-(4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)quinazoline-4-amine (120.0 mg, 1 equivalent, 238.8 μmol), XPhos Pd G3 (12.13 mg, 0.06 equivalents, 14.33 μmol), and potassium ferrocyanide trihydrate (50.43 mg, 0.5 equivalents, 119.4 μmol) were combined under a nitrogen atmosphere. A mixture of 1,4-dioxane (1600 μL) and water (800.0 μL) was introduced, and nitrogen was injected into the solvent for 2 minutes. The reaction mixture was stirred at 80°C for 18 hours. After cooling, the reaction mixture was filtered through a Celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with brine (5 mL), the organic layer was dried over MgSO4, filtered, and vacuum concentrated. The crude product was purified by chromatography on silica gel (dry load on Celite, 12 g cartridge, 0-40 ethyl acetate / heptane) to obtain 4-((4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)amino)quinazoline-7-carbonitrile (61.0 mg, 0.13 mmol, yield 56%, purity 99%) as an off-white solid. UPLC (Method 5), 2.40 min; M+H=449.5. 1H-NMR (400 MHz, DMSO) δ 9.18 (d, J = 7.9 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.60 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.92 (dd, J = 8.5, 1.7 Hz, 1H), 6.11 (q, J = 7.6 Hz, 1H), 2.10 (t, J = 15.7 Hz, 3H), 2.01-1.94 (m, 1H), 1.84 (s, 6H), 1.42 (td, J = 12.7, 4.8 Hz, 1H), 1.17 (dt, J = 12.8, 6.3 Hz, 1H), 0.86 (s, 9H), 0.65 (s, 9H)

[0212] Synthesis of 4-((4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)amino)quinazoline-7-carbonitrile (Example 106) 4-((4,4-dimethyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazole-5-yl)pentyl)amino)quinazoline-7-carbonitrin A mixture of ru and Int 105-b (60.0 mg, 99 wt%, 1 equivalent, 132 μmol) was stirred at 70°C for 1 hour in HCl (290 mg, 2.65 mL, 3.00 molar concentration, 60 equivalents, 7.94 mmol) in CPME. The crude product was concentrated under vacuum and co-evaporated with iPrOH. The crude product was loaded onto an SCX (0.5 g) column in MeOH. After washing the column with MeOH, the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum. The crude product was purified by chromatography on silica gel (solid loaded onto Celite, 4g cartridge, 0-20% MeOH / DCM) to obtain 4-((4,4-dimethyl-1-(1H-tetrazole-5-yl)pentyl)amino)quinazoline-7-carbonitrile (18.0 mg, 52.7 μmol, yield 39%, purity 98%) as a yellow solid.

[0213] UPLC (Method 6), 1.49 min; M+H=335.3. 1H-NMR (400 MHz, DMSO) δ 8.95 (d, J = 7.7 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.54 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.5, 1.7 Hz, 1H), 5.72 (q, J = 7.7 Hz, 1H), 2.12 (qd, J = 12.6, 6.2 Hz, 2H), 1.38 (td, J = 12.4, 5.0 Hz, 1H), 1.22 (td, J = 12.2, 5.0 Hz, 1H), 0.87 (s, 9H)

[0214] The following Example 107 was prepared in a manner similar to Example 106, starting from the amine Int 73-a and the corresponding heteroaryl chloride. [Table 19]

[0215] In the examples above, if the stereochemistry is not specified, the compound was prepared as a racemic mixture.

[0216] The following examples can be prepared in a manner similar to that of the previous examples. [Table 20-1]

[0217] [Table 20-2]

[0218] [Table 20-3]

[0219] Example 118 (S)-5,5-dimethyl-2-((2-methylquinazoline-4-yl)amino)hexanoic acid [ka]

[0220] Synthesis: 4-chloro-2-methylquinazoline (150 mg, 1 equivalent, 840 μmol), (S)-2-amino-5,5-dimethylhexanoic acid (176 mg, 99% by weight, 1.3 equivalents, 1.09 mmol), Pd2(dba)3 (16.0 mg, 99% by weight, 0.0206 equivalents, 17.3 μmol), JohnPhos (13.0 mg, 99% by weight, 0.0514 equivalents, 43.1 μmol), and sodium tert butoxide (196 mg, 99% by weight, 2.4 equivalents, 2.02 mmol) were combined and flushed with nitrogen for 5 minutes. 1,4-dioxane (5.00 mL) was added, and the reaction mixture was heated at 70°C for 4 hours. The reaction mixture was cooled to room temperature and the reaction was stopped with hydrogen chloride (72.9 mg, 2.00 mL, 1.00 mol concentration, 2.38 equivalents, 2.00 mmol). The mixture was then dissolved in DCM (15 mL). After dilution, the mixture was allowed to stand at room temperature for 2 days. The layers were separated. The aqueous component was extracted with DCM (10 mL), and the combined organic layer was washed with brine (20 mL), dried on MgSO4, filtered, and vacuum concentrated. The crude product was purified by chromatography on silica gel (solid load on Celite, 12 g cartridge, 0-20% DCM / MeOH) to obtain minimal product. The column was flushed with 0-20% DCM / MeOH and 1% AcOH as a modifier to obtain (S)-5,5-dimethyl-2-((2-methylquinazoline-4-yl)amino)hexanoic acid (13.0 mg, 41 μmol, 4.9%, purity 95%) as a yellow solid.

[0221] The product was analyzed by UPLC (CSH C18 column, 130 Å, 1.7 μm, 2.1 mm × 30 mm, 3-minute method, 0.1% formic acid, 2-100% MeCN / water): m / z 302.4 (M+H)+(ES+); 1.21 min, 100% purity, 210-400 nm.

[0222] 1H NMR in DMSO-d6 was consistent with the product structure with 95% purity.

[0223] 1H NMR (400 MHz, DMSO) δ 0.89 (s, 9H), 1.24-1.31 (m, 1H), 1.35-1.48 (m, 1H), 1.89 (q, J = 7.7 Hz, 2H), 2.41 (s, 3H), 4.65 (q, J = 7.3 Hz, 1H), 7.46 (td, J = 1.3, 7.5 Hz, 1H), 7.61 (dd, J = 1.3, 8.5 Hz, 1H), 7.73 (ddd, J = 1.3, 6.8, 8.2 Hz, 1H), 8.14 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 12.56 (s, 1H)

[0224] Example 119 (S)-2-((2-cyclopropylquinazoline-4-yl)amino)-5,5-dimethylhexanoic acid (as mesylate salt) [ka]

[0225] Synthesis: Step 1: 4-Chloro-2-cyclopropylquinazoline (283 mg, 1.1 equivalents, 1.38 mmol), (S)-2-amino-5,5-dimethylhexanoic acid (200 mg, 1 equivalent, 1.26 mmol), and sodium bicarbonate (317 mg, 3 equivalents, 3.77 mmol) were combined in THF (4.00 mL) and water (1.00 mL). The mixture was heated to 70°C for 4 hours and then cooled to room temperature. THF (4 mL) and water (1 mL) were added, and the mixture was filtered. Methanesulfonic acid (0.74 g, 0.50 mL, 6.1 equivalents, 7.7 mmol) was added to the filtrate, and the mixture was allowed to stand at room temperature for 15 hours. MTBE (5 mL) was added, and the layers were separated. The aqueous component was extracted with 2-MeTHF (10 mL). All layers were combined, and the solvent was removed by vacuum. The crude product was purified by chromatography on RP Flash C18 (12g cartridge, 20-60% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to obtain the product, which was then treated with TBME (5mL). The solvent was removed by vacuum, and the product was dried in a vacuum desiccator at 45°C for 18 hours.

[0226] (S)-2-((2-Cyclopropylquinazolin-4-yl)amino)-5,5-Dimethyl Tylhexanoic acid (33.0 mg, 96 μmol, 7.6%, purity 95%) was obtained as a white solid. This substance was then transferred directly to step 2.

[0227] The product was analyzed by UPLC (CSH C18 column, 130 Å, 1.7 μm, 2.1 mm × 30 mm, 3-minute method, 0.1% formic acid, 2-100% MeCN / water): m / z 328.4 (M+H)+(ES+); 1.32 min, 100% purity, 210-400 nm.

[0228] 1H NMR in DMSO-d6 was consistent with the structure of the product at 95% purity, containing 4 wt% formic acid.

[0229] 1H NMR (500 MHz, DMSO) δ 0.82-0.92 (m, 11H), 0.97-1.03 (m, 2H), 1.21-1.30 (m, 1H), 1.37-1.46 (m, 1H), 1.81-1.92 (m, 2H), 1.93-2.02 (m, 1H), 4.41 (q, J = 7.0 Hz, 1H), 7.41 (ddd, J = 1.2, 6.9, 8.2 Hz, 1H), 7.56-7.60 (m, 1H), 7.70 (ddd, J = 1.3, 6.9, 8.4 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 8.30-8.35 (m, 1H)

[0230] Step 2: (S)-2-((2-cyclopropylquinazolin-4-yl)amino)-5,5-dimethylhexanoic acid (33.0 mg, 1 equivalent, 101 μmol) was dissolved in MeOH (1.00 mL) and DCM (1 mL). Next, methanesulfonic acid (0.1 M in MeCN) (9.61 mg, 1.00 mL, 0.10 molar concentration, 0.992 equivalents, 100 μmol) was introduced. After stirring at room temperature for 30 minutes, the solvent was removed by vacuum. MTBE (2 mL) was added, and the solvent was removed by vacuum to obtain (S)-2-((2-cyclopropylquinazolin-4-yl)amino)-5,5-dimethylhexanoic acid, mesylic acid (40.0 mg, 90 μmol, 89%, purity 95%) as a white solid. 3 wt% DMSO and 0.7 wt% MeCN were added.

[0231] The product was analyzed by UPLC (CSH C18 column, 130 Å, 1.7 μm, 2.1 mm × 30 mm, 3-minute method, 0.1% formic acid, 2-100% MeCN / water): m / z 328.4 (M+H)+(ES+); 1.33 min, 100% purity, 210-400 nm.

[0232] 1H NMR in DMSO-d6 was consistent with the structure of the product at 95% purity, including 1.2 wt% MTBE.

[0233] 1H NMR (400 MHz, DMSO) δ 0.89 (s, 9H), 1.20-1.43 (m, 6H), 1.94 (q, J = 7.7 Hz, 2H), 2.21 (p, J = 6.6 Hz, 1H), 2.30 (s, 3H), 4.59 (q, J = 7.0 Hz,1H), 7.72-7.81 (m, 2H), 8.00-8.08 (m, 1H), 8.59 (d, J = 8.2 Hz, 1H), 9.94 (d, J = 6.5 Hz, 1H), 14.41 (s, 1H)

[0234] 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.

[0235] The affinity of a compound is expressed in the SPA format as follows: 3 This was identified by measuring the substitution of [H]-neurotensin binding to h-soltilin. A 5-point solution containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween-20 was used. Total volume of 40 μl in 0 mM HEPES pH 7.4 assay buffer. The compound was pre-incubated with 150 nM 6his-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 a range of three orders of magnitude). IC50 The values ​​were 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.

[0236] 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.

[0237] The affinity of the compound was determined using a Creoptix Wave instrument (Creoptix-Malvern Panalytical) to determine the affinity of 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] The data in Table 1 below demonstrates that the compounds disclosed herein bind to soltirin. [Table 21-1]

[0242] [Table 21-2]

[0243] [Table 21-3]

[0244] In the compound of the present invention, K is less than about 1.00E-4. d Having is advantageous. The obtained K d The data demonstrates that the embodiments of the present invention directly bind to the sorbitol protein.

[0245] 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 8 dissolved in 50% DMSO at a concentration of 14.86 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 placed on litho-loops without further freeze protection and instantaneously cooled with liquid nitrogen. Diffraction data is from beamline P13 EMB. The data was collected at L / DESY, Hamburg, and processed using the XDS package (Kabsch, W., Acta Cryst. D, 2010).

[0246] 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.

[0247] The details of the diffraction data are shown in Table 2 below (statistics for the highest resolution shell are shown in parentheses). [Table 22-1]

[0248] [Table 22-2]

[0249] X-ray images of Example 8, bound to h-soltilin, are shown in Figures 1 to 6. Figure 6 also shows the atomic contribution to the estimated binding affinity.

[0250] Figures 7A to 7C show electron density maps, which are observed by X-ray crystallography and are mapped to the molecular structure to illustrate the crystal structure.

[0251] Details of the electron density map are as follows: Figure 7A - 2fo-fc map. Density contour level = 1.5σ Figure 7B - Omit map. Density contour = 4.0σ Figure 7C - Polder map. Density contour = 6.0σ

[0252] The model includes three glycerol (GOL) molecules. Polder maps and omit maps were calculated separately for GOL and Example 8.

[0253] Embodiments of the present invention 1. Equation (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, [ka] and; R 2 is H or -CH3; R 3 C6~C 10 Selected from the group consisting of aryl and 5-membered to 10-membered heteroaryl rings, optionally including -OH, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, acetyl, cyano, and 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 5 R 6 Substituted with one or more substituents independently selected from; R 4 is H or -CH3; R 5 and R 6 Each is independently H or C1-C4 alkyl; and n is either 0 or 1.

[0254] 2.R 1 However, it is -CO2H; and / or R 2 H is; and / or R 4 However, it is -CH3; and / or The compound according to Embodiment 1, wherein n is 1.

[0255] 3.R 3 The compound according to Embodiment 1 or 2, wherein the group is selected from the group consisting of phenyl, naphthyl, a 5-membered ring or a 6-membered ring monocyclic heteroaryl, and a 9-membered ring or a 10-membered ring fused bicyclic heteroaryl, preferably selected from the group consisting of phenyl, naphthyl, a 6-membered ring monocyclic heteroaryl, and a 9-membered ring or a 10-membered ring fused bicyclic heteroaryl, and each group is optionally substituted.

[0256] 4.R 3 The compound according to Embodiment 3, wherein 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 C or N, preferably 1 to 3 ring atoms are N and the remaining ring atoms are C.

[0257] 5.R 3 The compound according to Embodiment 4, wherein one or two ring atoms in the five-membered or six-membered monocyclic heteroaryl group are nitrogen and the remaining ring atoms are carbon.

[0258] 6.R 3 The six-membered monocyclic heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl, preferably selected from the group consisting of pyridyl, pyrimidinyl, and pyrazinyl, and more preferably the following group: [ka] A compound according to any one of embodiments 3 to 5, wherein each group is optionally substituted.

[0259] 7.R 3The 9-membered or 10-membered ring fused bicyclic heteroaryl group is selected from the group consisting of indolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, azaindazolyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthylidinyl, pyridopyrimidinyl, and pyridopyramidinyl, preferably selected from the group consisting of azaindolyl, pyridopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, and quinazolinyl, and more preferably the following group: [ka] It is one of the following, and most preferably, [ka] A compound according to any one of embodiments 3 to 6, wherein each group is optionally substituted.

[0260] 8.R 3 The compound according to any of the preceding embodiments, wherein an optional substituent on is independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, phenyl, 6-membered heterocycloalkyl, -O-phenyl, and -O-CH2-phenyl, preferably independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, phenyl, morpholinyl, -O-phenyl, and -O-CH2-phenyl.

[0261] 9.R 3 but, (i) Phenyl and six-membered monocyclic heteroaryls that are optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, phenyl, -O-phenyl, -O-CH2-phenyl, and morpholinyl; and (ii) Naphthyl and 9-membered ring or 10-membered ring condensed bicyclic heteroaryl, which are optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and phenyl. A compound selected from the group consisting of the above, according to any of the prior embodiments.

[0262] 10.R 3 but, (i) Phenyls that are optionally substituted with one or more substituents independently selected from the group consisting of halo and -O-phenyl; (ii) A six-membered monocyclic heteroaryl ring that is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-C2 alkyl, C1-C2 alkoxy, phenyl, -O-phenyl, -O-CH2-phenyl, and morpholinyl; (iii) Naphthyl being optionally substituted with one or more halo atoms; and (iv) A 9-membered ring or 10-membered ring condensed bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and phenyl. A compound according to Embodiment 9, selected from the group consisting of the following.

[0263] 11.R 3 but, [ka] A compound selected from the group consisting of the above, according to any of the prior embodiments.

[0264] 12. The compound, (S)-2-anilino-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(2-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(1,3,5-triaza-4-naphthylamino)hexanoic acid; (S)-2-[5-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid (S)-2-(5-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(4-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(4-morpholino-2-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(2-quinoxalinylamino)hexanoic acid (S)-5,5-dimethyl-2-(5-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(3-methyl-2-pyradinylamino)hexanoic acid (S)-2-(2-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(6-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(2-methyl-4-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-4-pyrimidinylamino)hexanoic acid (S)-2-(2,6-dimethyl-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(8-methyl-4-quinazolinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-phenoxy-2-pyradinylamino)hexanoic acid (S)-2-(4-isoquinolylamino)-5,5-dimethylhexanoic acid (S)-2-(m-chlorophenylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(3-pyridylamino)hexanoic acid [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-2-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine;

[0265] [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine ; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyradinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-phenyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; N-2-pyrimidinyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-5-pyrimidinylamine; N-5-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-2-pyrazinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; N-3-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-2-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-3-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-pyridylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrimidinyl Min; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]aniline; N-2-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-3-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine;

[0266] [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][6-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][7-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1,3,7-triaza-4-naphthylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-bromo-4-quinazolinyl)amine;

[0267] [4-Methyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-phenyl-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; N-3-pyridyl[(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; N-3-pyridyl[(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyridylamine; [3-Methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyrimidinylamine; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-7-quinazoline carbonitrile;

[0268] 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-6-quinazoline carbonitrile; (S)-5,5-dimethyl-2-(o-phenoxyphenylamino)hexanoic acid; (S)-2-anilino-4,4-dimethylvaleric acid; (S)-2-anilino-2,5,5-trimethylhexanoic acid; (S)-5,5-dimethyl-2-(4-phenyl-2-pyrimidinylamino)hexanoic acid; (S)-2-[6-(benzyloxy)-2-pyradinylamino]-5,5-dimethylhexanoic acid; (S)-2-(6-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-(5-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-[4-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(6-phenoxy-4-pyrimidinylamino)hexanoic acid; (S)-2-(2,6-dimethoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid; Or the compounds described in any of the preceding embodiments, which are pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0269] 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.

[0270] 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.

[0271] 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, the neurodegenerative disorder is characterized by a misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal dementia, or frontotemporal dementia; Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder. Preferably, the inflammatory 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 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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[0276] Sequences that are referenced throughout this specification and form part of the description. Sequence ID No. 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

[0277] Sequence ID No. 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

[0278] Sequence ID 3 (mature soltirin) 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 3\01 THLRKPENSE CDATAKNKNE CSLHIHASYS ISQKLNVPMA PLSEPNAVGI 361 VIAHGSVGDA ISVMVPDVYI SDDGGYSWTK MLEGPHYYTI LDSGGIIVAI 401 EHSSRPINVI KFSTDEGQCW QTYTFTRDPI YFTGLASEPG ARSMNISIWG 451 FTESFLTSQW VSYTIDFKDI LERNCEEKDY TIWLAHSTDP EDYEDGCILG 50\0 YKEQFLRLRK SSVCQNGRDY VVTKQPSICL CSLEDFLCDF GYYRPENDSK 551 CVEQPELKGH DLEFCLYGRE EHLTTNGYRK IPGDKCQGGV NPVREVKDLK 601 KKCTSNFLSP EKQNSKSNSV PIILAIVGLM LVTVVAGVLI VKKYVCGGRF 651 LVHRYSVLQQ HAEANGVDGV DALDTASHTN KSGYHDDSDE DLLE

[0279] Sequence number 4 (mouse sortilin) >sp|Q6PHU5|SORT_MOUSE Sortilin OS=Mus musculus OX=10090 GN=Sort1 PE=1 SV=1 MERPRGAADGLLRWPLGLLLLLQLLPPAAVGQDRLDAPPPPAPPLLRWAGPVGVSWGLRA AAPGGPVPRAGRWRRGAPAEDQDCGRLPDFIAKLTNNTHQHVFDDLSGSVSLSWVGDSTG VILVLTTFQVPLVIVSFGQSKLYRSEDYGKNFKDITNLINNTFIRTEFGMAIGPENSGKV ILTAEVSGGSRGGRVFRSSDFAKNFVQTDLPFHPLTQMMYSPQNSDYLLALSTENGLWVS KNFGEKWEEIHKAVCLAKWGPNNIIFFTTHVNGSCKADLGALELWRTSDLGKTFKTIGVK IYSFGLGGRFLFASVMADKDTTRRIHVSTDQGDTWSMAQLPSVGQEQFYSILAANEDMVF MHVDEPGDTGFGTIFTSDDRGIVYSKSLDRHLYTTTGGETDFTNVTSLRGVYITSTLSED NSIQSMITFDQGGRWEHLRKPENSKCDATAKNKNECSLHIHASYSISQKLNVPMAPLSEP NAVGIVIAHGSVGDAISVMVPDVYISDDGGYSWAKMLEGPHYYTILDSGGIIVAIEHSNR PINVIKFSTDEGQCWQSYVFTQEPIYFTGLASEPGARSMNISIWGFTESFITRQWVSYTV DFKDILERNCEEDDYTTWLAHSTDPGDYKDGCILGYKEQFLRLRKSSVCQNGRDYVVAKQ PSVCPCSLEDFLCDFGYFRPENASECVEQPELKGHELEFCLYGKEEHLTTNGYRKIPGDK CQGGMNPAREVKDLKKKCTSNFLNPTKQNSKSNSVPIILAIVGLMLVTVVAGVLIVKKYV CGGRFLVHRYSVLQQHAEADGVEALDSTSHAKSGYHDDSDEDLLE

Claims

1. Equation (I): 【Chemistry 1】 Compounds of, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof, wherein, R １ teeth, 【Chemistry 2】 And; R ２ is H or -CH ３ And; R ３ is selected from the group consisting of C ６ to C １０ aryl and 5- to 10-membered heteroaryl, and optionally, -OH, halo, C １ to C ４ alkyl, C １ to C ４ alkoxy, C １ to C ４ hydroxyalkyl, C １ to C ４ haloalkyl, C １ to C ４ haloalkoxy, C １ to C ４ hydroxyalkoxy, acetyl, cyano, C ６ to C １０ aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, -O-(C ６ to C １０ aryl), and -O-CH ２ -(C ６ to C １０ aryl) and is substituted with one or more substituents independently selected therefrom; R ４ is H or -CH ３ and; as well as n is either 0 or 1. Compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

2. R １ However, -CO ２ H is; and / or R ２ H is; and / or R ４ However, -CH ３ and / or n is 1, The compound according to claim 1.

3. R ３ The compound according to claim 1 or 2, wherein the group is selected from the group consisting of phenyl, naphthyl, a five-membered ring or a six-membered ring monocyclic heteroaryl, and a nine-membered ring or a ten-membered ring fused bicyclic heteroaryl, preferably selected from the group consisting of phenyl, naphthyl, a six-membered ring monocyclic heteroaryl, and a nine-membered ring or a ten-membered ring fused bicyclic heteroaryl, and more preferably selected from the group consisting of a ten-membered ring fused bicyclic heteroaryl, and each group is optionally substituted.

4. R ３ The aforementioned 5-membered ring or 6-membered ring monocyclic heteroaryl group and the aforementioned 9-membered ring or 10-membered ring condensation The compound according to claim 3, wherein each ring atom in the bicyclic heteroaryl group is independently C or N, preferably 1 to 3 ring atoms are N and the remaining ring atoms are C.

5. R ３ The compound according to claim 4, wherein one or two ring atoms in the five-membered ring or six-membered ring monocyclic heteroaryl group are N and the remaining ring atoms are C.

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

7. R ３ The aforementioned nine-membered or ten-membered ring fused bicyclic heteroaryl group is selected from the group consisting of indolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, azaindazolyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthylidinyl, pyridopyrimidinyl, and pyridopyramidinyl, preferably selected from the group consisting of azaindolyl, pyridopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, and quinazolinyl, and more preferably the following group: 【Chemistry 4】 It is one of the following, and most preferably, 【Transformation 5】 The compound according to any one of claims 3 to 6, wherein each group is optionally substituted.

8. R ３ The optional substituents on are halo, cyano, and C. １ ~C ４ Alkyl, C １ ~ C ４ Alkoxy, C １ ~C ４ Haloalkyl, phenyl, six-membered heterocycloalkyl, -O-phenyl, and -O-CH ２ - Independently selected from the group consisting of phenyl, preferably halo, cyano, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, phenyl, morpholinyl, -O-phenyl, and -O-CH ２ - Independently selected from the group consisting of phenyl, more preferably halo, cyano, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Haloalkyl, phenyl, morpholinyl, -O-phenyl, and -O-CH ２ - A compound independently selected from the group consisting of phenyl, according to any one of claims 1 to 7.

9. R ３ but, (i) Hello, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, phenyl, -O-phenyl, -O-CH ２ Phenyl and six-membered monocyclic heteroaryl compounds optionally substituted with one or more substituents independently selected from the group consisting of phenyl and morpholinyl; and (ii) Halo, Cyano, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ A group independently selected from the group consisting of haloalkyl and phenyl, preferably halo, cyano, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, 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 haloalkyls and phenyls. A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. R ３ but, (i) Phenyls that are optionally substituted with one or more substituents independently selected from the group consisting of halo and -O-phenyl; (ii) Hello, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, phenyl, -O-phenyl, -O-CH ２ - A six-membered monocyclic heteroaryl ring, optionally substituted with one or more substituents independently selected from the group consisting of phenyl and morpholinyl; (iii) Naphthyl being optionally substituted with one or more halo atoms; and (iv) halo, cyano, C １ -C ３ alkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkyl, and phenyl, preferably selected independently from the group consisting of halo, cyano, C １ -C ２ alkyl, C １ -C ２ alkoxy, C １ -C ２ haloalkyl, and phenyl, and optionally substituted with one or more substituents selected independently from the group consisting of a 9-membered or 10-membered ring-fused bicyclic heteroaryl A compound according to claim 9, selected from the group consisting of the following.

11. R ３ but, 【Transformation 6】 Selected from the group consisting of, Preferably, R ３ is 【Transformation 7】 A compound according to any one of claims 1 to 10, selected from the group consisting of the following.

12. The aforementioned compound, (S)-2-anilino-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(2-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(1,3,5-triaza-4-naphthylamino)hexanoic acid; (S)-2-[5-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid (S)-2-(5-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(4-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(4-morpholino-2-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(2-quinoxalinylamino)hexanoic acid (S)-5,5-dimethyl-2-(5-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(3-methyl-2-pyradinylamino)hexanoic acid (S)-2-(2-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(6-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(2-methyl-4-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-4-pyrimidinylamino)hexanoic acid (S)-2-(2,6-dimethyl-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(8-methyl-4-quinazolinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-phenoxy-2-pyradinylamino)hexanoic acid (S)-2-(4-isoquinolylamino)-5,5-dimethylhexanoic acid (S)-2-(m-chlorophenylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(3-pyridylamino)hexanoic acid [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-2-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrazinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-phenyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; N-2-pyrimidinyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-5-pyrimidinylamine; N-5-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; N-2-pyrazinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; N-3-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-2-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-3-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-pyridylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrimidinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]aniline; N-2-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-3-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][6-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][7-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1,3,7-triaza-4-naphthylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-bromo-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-phenyl-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2 -Quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; N-3-pyridyl[(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine; N-3-pyridyl[(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyrimidinylamine; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-7-quinazoline carbonitrile; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-6-quinazoline carbonitrine; (S)-5,5-dimethyl-2-(o-phenoxyphenylamino)hexanoic acid; (S)-2-anilino-4,4-dimethylvaleric acid; (S)-2-anilino-2,5,5-trimethylhexanoic acid; (S)-5,5-dimethyl-2-(4-phenyl-2-pyrimidinylamino)hexanoic acid; (S)-2-[6-(benzyloxy)-2-pyradinylamino]-5,5-dimethylhexanoic acid; (S)-2-(6-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-(5-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-[4-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(6-phenoxy-4-pyrimidinylamino)hexanoic acid; (S)-2-(2,6-dimethoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-((2-methylquinazoline-4-yl)aminohexanoic acid; (S)-2-((2-cyclopropylquinazoline-4-yl)amino)-5,5-dimethylhexanoic acid; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof, Preferably, the compound is: (S)-2-anilino-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(2-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyridylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyradinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(2-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(5-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-pyrimidinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(4-quinazolinylamino)hexanoic acid; (S)-5,5-dimethyl-2-(1,3,5-triaza-4-naphthylamino)hexanoic acid; (S)-2-[5-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid (S)-2-(5-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(4-methoxy-2-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(4-morpholino-2-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(2-quinoxalinylamino)hexanoic acid (S)-5,5-dimethyl-2-(5-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(3-methyl-2-pyradinylamino)hexanoic acid (S)-2-(2-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-2-(6-methoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(2-methyl-4-pyrimidinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-4-pyrimidinylamino)hexanoic acid (S)-2-(2,6-dimethyl-4-pyrimidinylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(8-methyl-4-quinazolinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-methyl-2-pyradinylamino)hexanoic acid (S)-5,5-dimethyl-2-(6-phenoxy-2-pyradinylamino)hexanoic acid (S)-2-(4-isoquinolylamino)-5,5-dimethylhexanoic acid (S)-2-(m-chlorophenylamino)-5,5-dimethylhexanoic acid (S)-5,5-dimethyl-2-(3-pyridylamino)hexanoic acid [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; N-2-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-1-naphthylamine; N-phenyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrazinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-phenyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; N-2-pyrimidinyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-isoquinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-5-pyrimidinylamine; N-5-pyrimidinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; N-2-pyrazinyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](1-methyl-1H-1,7-diazaiden-5-yl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-2-quinolylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-3-quinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-quinolylamine; N-2-pyrimidinyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; N-3-pyridyl[4-methyl-1-(2H-tetraazole-5-yl)pentyl]amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-3-isoquinolylamine; N-2-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; N-3-pyridyl[3,3-dimethyl-1-(2H-tetraazole-5-yl)butylamine]amine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-3-pyridylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyrimidinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-2-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]aniline; N-2-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl) pliers [Lu]amine; N-3-pyridyl[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [3,3-dimethyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methoxy-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](6-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-fluoro-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](6-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][6-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl][7-(trifluoromethyl)-4-quinazolinyl]amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-1,3,7-triaza-4-naphthylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-methyl-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](7-bromo-4-quinazolinyl)amine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl](7-methoxy-4-quinazolinyl)amine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl](2-phenyl-4-quinazolinyl)amine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-isoquinolylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-2-quinolylamine; [(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4 -Quinazolinylamine; [(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; N-3-pyridyl[(S)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine; N-3-pyridyl[(R)-4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamine; [4-methyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [4,4-dimethyl-1-(2H-tetraazole-5-yl)pentyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-quinazolinylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyridylamine; [3-methyl-1-(2H-tetraazole-5-yl)butyl]-4-pyrimidinylamine; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-7-quinazoline carbonitrile; 4-[4,4-dimethyl-1-(2H-tetraazole-5-yl)pentylamino]-6-quinazoline carbonitrine; (S)-5,5-dimethyl-2-(o-phenoxyphenylamino)hexanoic acid; (S)-2-anilino-4,4-dimethylvaleric acid; (S)-2-anilino-2,5,5-trimethylhexanoic acid; (S)-5,5-dimethyl-2-(4-phenyl-2-pyrimidinylamino)hexanoic acid; (S)-2-[6-(benzyloxy)-2-pyradinylamino]-5,5-dimethylhexanoic acid; (S)-2-(6-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-(5-methoxy-2-pyradinylamino)-5,5-dimethylhexanoic acid; (S)-2-[4-(benzyloxy)-2-pyrimidinylamino]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-(6-phenoxy-4-pyrimidinylamino)hexanoic acid; (S)-2-(2,6-dimethoxy-4-pyrimidinylamino)-5,5-dimethylhexanoic 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 characterized by a misfolded TAR DNA-binding protein 43, such as amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal lobar degeneration, or frontotemporal dementia; Preferably, the mental disorder is selected from bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorder. Preferably, the inflammatory 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 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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