Compound

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) that are modulators of sortilin activity. The invention also relates to pharmaceutical compositions containing these compounds and to the use of these compounds in the treatment or prevention of medical conditions in which modulation of sortilin activity is beneficial. Such medical conditions include neurodegenerative diseases, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss. [Background technology]

[0002] Sortilin (encoded by SORT1) is a type 1 membrane receptor of the vacuolar protein sorting 10 protein (VPS10P) family of sorting receptors and is abundantly expressed in the central nervous system, inner ear, and several peripheral tissues involved in metabolic control. 1、2、3、4 Sortilin has the amino acid sequence set forth in SEQ ID NO: 1 and contains a signal peptide, a propeptide, a Vps10p domain, a 10cc domain (10CCa + 10CCb), a transmembrane domain, and a large cytoplasmic tail. The luminal domain of sortilin contains six potential N-linked glycosylation sites, while the cytoplasmic tail allows for the recruitment of various adaptor proteins.

[0003] Sortilin binds to a vast number of ligands and membrane receptors, resulting in functions known to be important in cell signaling and sorting. For example, sortilin is involved in signal transduction by the pro-neurotrophins: the pro-form of nerve growth factor (proNGF), the pro-form of brain-derived neurotrophic factor (proBDNF), and the pro-form of neurotrophin 3 (proNT3). In complex with the protein p75NTR (p75 neurotrophin receptor), sortilin has been reported to form a receptor for pro-neurotrophin-mediated apoptotic effects that lead to degeneration and cell death in cells and animal models. 5、6、7 .

[0004] Previous studies have suggested a role for sortilin in cell sorting and signaling related to diseases such as diabetes and obesity (Huang et al 2013 Mol Biol Cell Oct;24(19):3115-22). 8 Sortilin promotes the translocation of GLUT4 to the plasma membrane and rescues it from degradation in lysosomes (Pan et al. Mol Biol Cell. 2017 Jun 15;28(12):1667-1675). 9 Sortilin levels have been found to be regulated by the level of inflammation associated with these diseases. The proinflammatory cytokine TNFα reduces both the mRNA and protein levels of sortilin in cultured mouse and human adipocytes, and in vivo when injected into mice (Kaddai et al. Diabetologia 52:932-40, 2009). 10 Sortilin can also affect cytokine secretion: targeting sortilin within immune cells has been proposed to attenuate inflammation and reduce atherosclerotic disease progression (Mortensen et al. J Clin Invest 124(12):5317-22,2014) 11 In addition, Patent Document 1 describes various scaffolds of small molecules that can bind to the active site of sortilin. Sortilin is involved in the regulation of glucose uptake (Shi & Kandror. Developmental Cell 9:99-108, 2005). 12 and lipid disorders (Gao et al. DNA and Cell Biology 36(12):1050-61, 2017) 13 be involved in.

[0005] Furthermore, plasma sortilin levels have been reported to be a potential biomarker for identifying patients suffering from either coronary heart disease or diabetes (Oh et al. t al.Cardiovascular Diabetology 16:92,2017) 14These patients who demonstrated increased sortilin levels in their plasma and were therefore identifiable as suffering from the above conditions, also exhibited improved glucose levels, suggesting sortilin as a therapeutic target for treating these conditions.

[0006] In view of the above, there is an unmet need for novel compounds that may be used in the treatment and prevention of medical conditions in which modulation of sortilin is effective, such as neurodegenerative diseases, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, inherited eye conditions, or hearing loss. The neurodegenerative disease may be selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and spinal cord injury; the inflammatory disease may be selected from inflammatory diseases and neuroinflammation; the cancer may be selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; and the hearing loss may be selected from noise-induced hearing loss, toxic hearing loss, presbycusis, sudden hearing loss, tinnitus, and sudden hearing loss. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] US Patent Application Publication No. 2016 / 0331746 [Patent Document 2] International Publication No. 2010 / 132601 [Patent Document 3] International Publication No. 2015 / 131100 Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (I):

[0009] [ka]

[0010] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; In formula (I), R 1 , R 2 and R 3 is selected from the group consisting of halo, H, (C1-C4) alkyl, halo(C1-C4) alkyl, (C2-C4) alkenyl, and halo(C2-C4) alkenyl. are each independently selected from; R 4 is H, (C1~C 10 ) Alkyl, halo (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, halo(C2-C 10 ) alkenyl, (C3-C8) aryl, halo(C3-C8) aryl, (C3-C8) heteroaryl, halo(C3-C8) heteroaryl, (C1-C6)-alkylene-(C3-C 20 )aryl, (C1-C6)-alkylene-(C3-C 20 ) heteroaryl, (C1-C6)-alkylene-(3- to 10-membered heterocyclic ring); The (C1-C6)-alkylene-(C3-C 20 )aryl, the aryl group in the (C1-C6)-alkylene-(C3-C 20 The heteroaryl group in the heteroaryl or the heterocyclic ring in the (C1-C6)-alkylene-(3- to 8-membered heterocyclic ring) is preferably a halo. , H, —OH, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; R 5 is H, (C1~C 10 ) alkyl and (C2-C 10 ) alkenyl; The alkyl and alkenyl groups are optionally substituted with halo, amido, and phenolic groups; and R 6is (C1~C 10 ) Alkyl, halo (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, halo(C2-C 10 ) selected from the group consisting of alkenyl and 3- to 10-membered heterocyclic rings; The heterocyclic ring may be selected from halo, —OH, (C1-C4) alkyl, halo(C1-C 10 ) optionally substituted by one or more substituents independently selected from alkyl, acetyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; Provided are compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, optical isomers, N-oxides, and / or prodrugs thereof.

[0011] It has been found that the compounds of formula (I) inhibit or antagonize sortilin and may therefore be useful in conditions where sortilin inhibition is effective. Such conditions include neurodegenerative diseases, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss. The neurodegenerative disease may be selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and spinal cord injury; the inflammatory disease may be selected from inflammatory diseases and neuroinflammation; the cancer may be selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; and the hearing loss may be selected from noise-induced hearing loss, toxic hearing loss, presbycusis, sudden hearing loss, tinnitus, and sudden hearing loss.

[0012] As used herein, the term "sortilin" may refer to full-length sortilin (also referred to as immature sortilin) ​​including a signal peptide, a propeptide, a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail having the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2, or may refer to mature sortilin including a Vps10p domain, a 10CC domain, a transmembrane domain, and a large cytoplasmic tail having the amino acid sequence set forth in SEQ ID NO: 3, or a naturally occurring fragment, homolog, or variant thereof. The terms "sortilin" or "sortilin molecule" are used interchangeably herein. It is understood that sortilin can interact with a proneurotrophin molecule to form a sortilin / proneurotrophin complex. This sortilin / proneurotrophin complex may or may not be able to interact with a p75NTR molecule to form a trimeric complex including sortilin, proneurotrophin, and p75NTR. It is understood that this trimeric complex may be involved in adverse biological responses, such as stimulating apoptosis in retinal and ganglion cells and regulating growth cone retraction of projecting axons. 5、7、15、16 .

[0013] As used herein, the term "pro-neurotrophin" refers to a larger precursor of a neurotrophin that undergoes proteolytic cleavage to obtain the mature form of the neurotrophin. Neurotrophins are a family of proteins, commonly referred to as growth factors, that induce the survival, development, and function of neurons. Pro-neurotrophins are biologically active and have distinct roles compared to their neurotrophin counterparts, such as inducing apoptosis. Examples of pro-neurotrophins include pro-NGF, pro-BDNF, pro-NT3, and pro-NT4. Pro-neurotrophins can also regulate synaptic plasticity. Mature neurotrophins induce synaptic strength, but their pro-forms may weaken synapses.

[0014] The compounds of the present invention may be sortilin inhibitors or antagonists. As used herein, the term "sortilin antagonist" refers to a substance that prevents, blocks, or otherwise weakens the effect of sortilin protein, which binds to proneurotrophins (e.g., proNGF, proNT3, proBDNF) and prevents the formation of a trimeric complex between sortilin, p75NTR, and proneurotrophins. The term "sortilin antagonist" also includes substances or drugs that prevent the formation of high-affinity trimeric complexes. In the latter scenario, it has been confirmed that a trimeric complex can be formed such that sortilin can bind to p75NTR (but not proNGF), and p75NTR can simultaneously bind to the NGF domain of proNGF. However, the resulting trimeric complex may have lower affinity for its receptor, and as a result, has significantly reduced ability to stimulate apoptosis by the above mechanism. Skeldal et al(J.Biol.Chem.2012 Dec 21;287(52):43798-809) 17 demonstrated that the apoptotic function of the trimeric complex is abolished when sortilin is absent from its intracellular domain. The term "sortilin antagonist" also includes substances or agents that prevent, block, or otherwise weaken the effect of the sortilin protein interacting with p75NTR. Preventing or only partially preventing the formation of the trimeric complex may completely prevent this interaction, while preventing the formation of the trimeric complex may result in a reduced biological effect. Skeldal et al. demonstrated that complex formation between sortilin and p75NTR depends on contact points in the extracellular domain of the receptor, and that this interaction is highly dependent on the extracellular membrane-proximal 23-amino acid sequence of p75NTR. Therefore, sortilin antagonists may interfere with this 23-amino acid sequence or a proximal sequence in the molecule.

[0015] R 1 , R 2 and R 3 are preferably each independently selected from the group consisting of halo, (C1-C2)alkyl and halo(C1-C2)alkyl.

[0016] In a preferred embodiment of the present invention, R 1 , R 2 and R 3 are each independently selected from F, CH3 and CF3. Most preferably, R 1 , R 2 and R 3 are the same. For example, in exemplary compounds of the present invention, R 1 , R 2 and R 3 Each may be F, CH3, or CF3.

[0017] In another preferred embodiment of the present invention, R 4 is H, (C1-C6) alkyl, halo(C1-C6) alkyl, (C3-C 10 )aryl, (C1-C3)-alkylene-(C3-C 10 )aryl, (C1-C3)-alkylene-(C3-C 10 ) heteroaryl and (C1-C3)-alkylene-(3- to 10-membered heterocyclic ring). 10 )aryl, the aryl group in the (C1-C3)-alkylene-(C3-C 10 The heteroaryl group in the heteroaryl or the heterocyclic ring in the (C1-C3)-alkylene-(3- to 10-membered heterocyclic ring) is selected from halo, H, —OH, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)a Optionally substituted by one or more substituents independently selected from alkoxy and halo(C1-C3)alkoxy.

[0018] The alkyl, haloalkyl, alkenyl, haloalkenyl groups and the alkyl, haloalkyl, alkoxy and haloalkoxy substituents may be straight or branched chain.

[0019] The substituents may be attached at any one of the aryl, heteroaryl, or heterocyclic rings. The one or more substituents may be attached to a carbon atom, a heteroatom, or a combination thereof. Preferably, there are no substituents or 1 to 3 substituents.

[0020] The heteroaryl or heterocyclic ring may contain one, two or more heteroatoms. Preferably, the heteroaryl or heterocyclic ring contains one or two heteroatoms. The heteroatoms may be selected from N, S or O. In groups where more than one heteroatom is present, the heteroatoms may be the same or different.

[0021] The heterocyclic ring may be aliphatic. The heterocyclic ring may be monocyclic, bicyclic, or tricyclic. Preferably, the heterocyclic ring is monocyclic or bicyclic. Preferably, the heterocyclic ring has 5 to 10 members, more preferably 5 to 9 members.

[0022] The aryl and heteroaryl groups may also be monocyclic, bicyclic, or tricyclic. Preferably, they are monocyclic or bicyclic. Preferably, the aryl and heteroaryl groups have a ring size of 5 to 10 members, more preferably 5 to 9 members.

[0023] In some preferred embodiments, R 4 teeth:

[0024] [ka]

[0025] is selected from the group consisting of:

[0026] R 4The chirality of the carbon in formula (I) bonded to is either (R) or (S). Preferably, when groups (ii) to (xii) are included in formula (I), the chirality of this carbon is (S); and when group (i) is included in formula (I), the chirality of this carbon is (S) or (R).

[0027] In another preferred embodiment of the present invention, R 5 is selected from the group consisting of H and (C1-C4) alkyl, wherein the alkyl group is optionally substituted with halo, amido, and phenol.

[0028] Preferably, R 5 teeth:

[0029] [ka]

[0030] is selected from the group consisting of:

[0031] In another preferred embodiment of the present invention, R 6 is selected from the group consisting of (C1-C3)alkyl, halo(C1-C3)alkyl, and a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halo, —OH, (C1-C4)alkyl, and acetyl.

[0032] Most preferably, R 6 teeth:

[0033] [ka]

[0034] is selected from the group consisting of:

[0035] Specific compounds of the present invention are listed below. (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1-methyl-1H-imidazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1,3-thiazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-4-carbamoyl-2-{[(2S)-pyrrolidin-2-yl]formamido}butanamido]-3-(1,3-thiazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl) -2-{[(2R)-morpholin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1-methyl-1H-amidazol-5-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-pyrrolidin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-carbamoyl-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1,3-thiazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(morpholin-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(pyridin-2-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-oxolan-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-oxolan-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-{[(2R)-4-acetylmorpholin-2-yl]formamido}-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3S)-morpholin-3-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3R)-morpholin-3-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-morpholin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(pyridin-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(pyridin-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(thiophen-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]formamido}propanamido]-3-methyl tylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3S)-pyrrolidin-3-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-piperazin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-piperazin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-[(2S)-2-{[(2S)-pyrrolidin-2-yl]formamido}propanamido]pentanamido]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-(2-{[(2S)-pyrrolidin-2-yl]formamido}acetamido)pentanamido]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-[(2S)-3-methyl-2-{[(2S)-pyrrolidin-2-yl]formamido}butanamido]pentanamido]hexanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-oxolan-2-yl]formamido}propanamido]-3-methylpentanamido]pentanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-oxolan-2-yl]formamido}propanamido]-3-methylpentanamido]pentanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5,5-trifluoropentanoic acid; and (2S)-2-[(2S,3S)-2-[(2S)-2-{[(2R)-4-acetylmorpholin-2-yl]formamido}-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5,5-trifluoropentanoic acid.

[0036] The compounds of formula (I) of the present invention are intended for use in the treatment or prevention of neurodegenerative diseases, inflammatory diseases, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, inherited eye conditions or hearing loss.

[0037] Preferably, said neurodegenerative disease is selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease and spinal cord injury.

[0038] Preferably, the inflammatory disease may be selected from inflammatory conditions and neuroinflammation.

[0039] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma and colon cancer.

[0040] Preferably, the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, presbycusis, sudden hearing loss, tinnitus and sudden hearing loss.

[0041] Thus, in embodiments, the compound for use according to the present invention may interfere with the interaction between a sortilin molecule and a proneurotrophin molecule, or may interfere with the interaction between a sortilin molecule and a p75NTR molecule. The sortilin molecule is mature sortilin. obtain.

[0042] Preferably, the compound of the present invention is a sortilin inhibitor. As used herein, the term "sortilin inhibitor" refers to a compound that binds to sortilin protein, thereby preventing its binding to proneurotrophin or p75NTR molecules, preventing the formation of the aforementioned trimeric complex, or resulting in the formation of a less active or inactive trimeric complex.

[0043] Preferably, the compounds of the invention prevent protein-protein interactions between sortilin molecules and proneurotrophin or p75NTR molecules, further preventing the formation of the apoptotic trimeric complex normally formed between sortilin, proneurotrophin and p75NTR receptors, or resulting in the formation of low affinity trimeric complexes that are biologically less active or inactive or minimally active.

[0044] Thus, the compound may bind to sortilin, proneurotrophin, or p75NTR molecules, and the antagonism may be due to direct blockade of protein-protein interactions or may be due to steric hindrance bound at a site on one of these proteins distant from the binding site.

[0045] According to a second aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0046] In a third aspect of the invention, there is provided a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use in therapy.

[0047] According to a fourth aspect of the invention there is provided a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use in the treatment or prevention of a neurodegenerative disease, an inflammatory disease, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition or hearing loss.

[0048] Preferably, said neurodegenerative disease is selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease and spinal cord injury.

[0049] Preferably, the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, presbycusis, sudden hearing loss, tinnitus and sudden hearing loss.

[0050] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma and colon cancer.

[0051] Preferably, said cardiovascular disease is selected from atherosclerosis, cardiomyopathy, heart attack, arrhythmia, and ischemic heart disease.

[0052] According to a fifth aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease, an inflammatory disease, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition or hearing loss.

[0053] According to a sixth aspect of the present invention there is provided a method for the treatment or prevention of a disease or condition responsive to sortilin modulation comprising administering a therapeutically effective amount of a compound according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

[0054] The compounds of the present invention may include isotopically labeled and / or isotopically enriched forms of said compounds. The compounds of the present invention herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the disclosed compounds include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as Cl.

[0055] The compounds of the present invention may be used per se or, if desired, as pharmaceutically acceptable salts (acid or base addition salts). The pharmaceutically acceptable addition salts described below are intended to include the therapeutically active, non-toxic acid and base addition salt forms that the compounds are capable of forming. Compounds with basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, 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, ascorbic acid, and the like. Compounds with acidic properties can be converted into their pharmaceutically acceptable base addition salts by treating the acid form with a suitable base.Exemplary base addition salt forms are 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 the solvates that compounds and their salts can form, such as hydrates, alcoholates, and the like.

[0056] Throughout this disclosure, a given chemical formula or name also encompasses all its pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and / or prodrugs.The compounds of the present invention should be understood to include any and all hydrates and / or solvates of the compound formula.Certain functional groups, such as hydroxy, amino, and similar groups, are believed to form complexes and / or coordination compounds with water and / or various solvents, resulting in various physical forms of the compounds.Therefore, the above formula should be understood to include and represent these various hydrates and / or solvates.

[0057] The compounds of the present invention also include tautomers. Tautomers result from the exchange of a single bond with an adjacent double bond, accompanied by the simultaneous migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and rings in which a proton can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution.

[0058] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as 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 are known in the art, such as by separation of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are intended to be included within the scope of the present invention. is contemplated as being within the scope of the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0059] In the case of compounds containing asymmetric carbon atoms, the present invention relates to D-isomers, L-isomers, and D,L mixtures. Furthermore, when two or more asymmetric carbon atoms are present, the present invention relates to diastereomers. When the compounds of the present invention contain asymmetric carbon atoms and occur as racemates, they can be separated into optically active isomers by known methods, for example, using optically active acids. However, it is also possible to use optically active starting materials from the beginning and then obtain the corresponding optically active or diastereomeric compounds as final products. [Brief explanation of the drawings]

[0060] [Figure 1A] FIG. 1A shows an X-ray image a) of the compound of Example 12 bound to h-Sortilin. [Figure 1B] FIG. 1B shows an X-ray image b) of the compound of Example 12 bound to h-Sortilin. DETAILED DESCRIPTION OF THE INVENTION

[0061] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvation into a biologically active compound of the present invention. When administered to a subject in need thereof, the prodrug may be inactive but is converted in vivo to an active compound of the present invention. Prodrugs are usually rapidly transformed in vivo to yield the parent compound of the present invention, for example, by hydrolysis in blood. Prodrug compounds usually offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), page 498 to (See 549.) Prodrugs of the compounds of the present invention may be prepared by modifying functional groups, such as hydroxy, amino, or mercapto groups present in the compounds of the present invention, in such a way that the modification is cleavable, either by routine manipulation or in vivo, to the parent compound of the present invention. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxy functional groups or phenylcarbamate derivatives of amino functional groups.

[0062] As used herein, the term "treatment" can include prevention of a named disease or condition, or amelioration or eradication of a disease once contracted. The term "prevention" refers to the prevention of a named disease or condition.

[0063] The methods defined herein include those in which a subject is identified as being in need of a particular, defined treatment. Identification of a subject as being in need of such treatment may be the judgment of the subject or a medical professional and may be subjective (e.g., opinion) or objective (e.g., measurable by testing or diagnostic methods).

[0064] In other aspects, the methods herein include those that further comprise monitoring the subject's response to the therapeutic management. Such monitoring can include periodic imaging or sampling of the subject's tissues, body fluids, cadavers, cells, proteins, chemical markers, genetic material, etc., for markers or indicators of the therapeutic regimen. In other methods, subjects are pre-screened or identified as needing such treatment by assessment of relevant markers or indicators of suitability for such treatment.

[0065] The present invention provides a method for monitoring the progress of a treatment, said method comprising the steps of: The method includes determining or measuring (e.g., screening, assaying) the level of a diagnostic marker (marker) (e.g., any target or cell type defined herein that is modulated by a compound herein) in a subject suffering from or susceptible to a disease or condition, said subject having been administered a therapeutic amount of a compound herein sufficient to treat the disease or condition. The level of the marker determined by the method can be compared to known levels of the marker in healthy controls or other affected patients to establish the disease status of the subject. In preferred embodiments, a second level of the marker in the subject is determined at a time later than the determination of the first level, and the two levels are compared to monitor the progress of the disease or the effectiveness of the treatment. In certain preferred embodiments, the subject's pre-treatment level of the marker is determined before initiating treatment according to the present invention; the pre-treatment level of the marker can then be compared to the level of the marker in the subject after initiating treatment to determine the effectiveness of the treatment.

[0066] The subject's marker level or activity may be determined at least once. Comparing the marker level with other measurements of marker levels, for example, obtained previously or later from the same patient, another patient, or a normal subject, is useful for determining whether treatment according to the present invention has the desired effect, thereby allowing for adjustment of dosage levels as needed. Determining the marker level may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or body fluid sample is first removed from the subject. Examples of suitable samples include blood, urine, tissue, oral or cheek cells, and hair samples containing hair roots. Other suitable samples will be known to those skilled in the art. Determining the protein and / or mRNA level (e.g., marker level) in the sample may be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence, real-time PCR, and the like.

[0067] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various administration methods. The compounds of the present invention may be administered together with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein may be administered by any suitable route, preferably oral, rectal, nasal, topical (including ophthalmic, buccal, and sublingual), sublingual, transdermal, intrathecal, transmucosal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. Other formulations may be conveniently provided in unit dosage form, for example, tablets and sustained-release capsules, and liposomes, and may be formulated by any method well known in the pharmaceutical arts. Pharmaceutical formulations are typically prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients include water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such formulations may contain other pharmaceutically active agents as well as conventional additives such as stabilizers, wetting agents, emulsifiers, flavorings, buffers, and the like. Typically, the amount of active compound is 0.1 to 95% by weight of the formulation for parenteral use, preferably 0.2 to 20% by weight of the formulation, and more preferably 1 to 50% by weight of the formulation for oral administration. The formulations can be further formulated by known methods such as granulation, compression, microencapsulation, spray coating, and the like. The formulations may be formulated in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections by conventional methods. Liquid formulations may be formulated by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated by conventional methods. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds disclosed herein may be incorporated into sustained release formulations.

[0068] The dosage level and frequency of administration of a particular compound will vary depending on various factors, including the potency of the particular compound used, the metabolic stability and duration of action of the compound, the patient's age, weight, general health, sex, diet, method and frequency of administration, excretion rate, drug combinations, the severity of the condition being treated, and the patient's medical history. Daily dosages range, for example, from about 0.001 mg to about 100 mg per kilogram of body weight, and may be administered in single or multiple doses, for example, from about 0.01 mg to about 25 mg each. Typically, such dosages are given orally, although parenteral administration may also be selected.

[0069] definition "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0070] The term "heteroatom" means O, N, or S.

[0071] The term “(C1~C n "(C1-C) alkyl" refers to a straight, branched, or cyclic or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3, or n carbon atoms. n For an alkyl group, it must be formed from at least three carbon atoms. nFor the moiety "(C1-C6)alkyl", all subgroups thereof are contemplated. For example, in the range (C1-C6)alkyl, all subgroups thereof are contemplated, such as (C1-C5)alkyl, (C1-C4)alkyl, (C1-C3)alkyl, (C1-C2)alkyl, (C1)alkyl, (C2-C6)alkyl, (C2-C5)alkyl, (C2-C4)alkyl, (C2-C3)alkyl, (C2)alkyl, (C3-C6)alkyl, (C3-C5)alkyl, (C3-C4)alkyl, (C3)alkyl, (C4-C6)alkyl, (C4-C5)alkyl, (C4)alkyl, (C5-C6)alkyl, (C6)alkyl, etc. Examples of "(C1-C6) alkyl" include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, branched or cyclic or partially cyclic pentyl and hexyl, and the like.

[0072] The term "halo-(C1-C n ") alkyl" refers to the above (C1-C) alkyl substituted with at least one halogen atom, preferably F, Cl, Br and I, more preferably F and Cl, most preferably F. n ) denotes alkyl.

[0073] When a term denotes a range, for example, "1 to 6 carbon atoms" in the definition of (C1-C6) alkyl, each integer is considered to be disclosed, ie, 1, 2, 3, 4, 5 and 6.

[0074] The term “(C2~C n The term "(C2-C6) alkenyl" refers to a straight, branched, or cyclic or partially cyclic alkyl group having at least one carbon-carbon double bond and having from 2 to 6 carbon atoms. The alkenyl group may contain a ring formed from 3 to 6 carbon atoms. The range "(C2-C6) nFor the moiety "(C2-C4)alkenyl," all subgroups thereof are contemplated. For example, the range "(C2-C4)alkenyl" includes (C2-C4)alkenyl, (C2-C3)alkenyl, (C2)alkenyl. Examples of "(C2-C4)alkenyl" include 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, etc.

[0075] The term "(C1-C4)alkoxy" means that the (C1-C4)alkyl group is as defined above. and the remainder of the compound is attached through the oxygen atom -O-((C1-C4) alkyl). Examples of "(C1-C4) alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy.

[0076] The term "halo-(C1-C4)alkoxy" denotes the above (C1-C4)alkoxy substituted by a halogen atom, preferably F, Cl, Br and I, more preferably F and Cl, most preferably F.

[0077] The term "halo" refers to a halogen atom, preferably F, Cl, Br and I, more preferably F and Cl, and most preferably F.

[0078] The term "3- to 10-membered heterocyclic ring" refers to a non-aromatic ring having from 3 to 10 ring atoms, with at least one ring atom being a heteroatom.

[0079] An "effective amount" refers to that amount of a compound of the present invention that confers a therapeutic effect on the treated subject. The therapeutic effect may be subjective (i.e., measurable by some test or marker) or objective (i.e., the subject gives an indication of or feels an effect).

[0080] As used herein, the term "administration" or "administering" refers to a route of administration of a compound disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intraocular, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration may vary depending on various factors, such as the components of a pharmaceutical composition containing a compound disclosed herein, the site of potential or actual disease, and the severity of the disease.

[0081] The terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "patient" refer to a human or another mammal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) suffering from or susceptible to a disease or disorder, and which may or may not have the disease or disorder. Preferably, the subject is a human.

[0082] The compounds of the present invention may be disclosed by name or by chemical structure. If a discrepancy exists between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0083] The present invention will now be further illustrated by the following non-limiting examples. The specific examples below are to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All references and publications cited herein are hereby incorporated by reference in their entirety.

[0084] Preparation of Compounds of the Invention The compounds of the present invention can be prepared according to the following general synthetic scheme by methods well known and appreciated in the art. For the steps of the general synthetic procedure, Scheme 1, suitable reaction conditions are well known in the art, and appropriate substitution of solvents and co-reagents is within the common general knowledge of one of ordinary skill in the art. Similarly, synthetic intermediates may be isolated and / or purified by various well-known techniques as needed or desired, and one of ordinary skill in the art will appreciate that it will often be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, one of ordinary skill in the art will appreciate that, depending on the circumstances, the moieties introduced will be readily apparent to those skilled in the art. Those skilled in the art will recognize that the order is important. The particular order of steps required to prepare compounds of formula (I) will depend on the particular compound being synthesized, the starting compound, and the relative barriers of the substituted moieties, as will be well understood by those skilled in the art. Unless otherwise specified, all substituents are as previously defined, and all reagents are well known and appreciated in the art.

[0085] Compounds of general formula (I) may be prepared by a variety of procedures, some of which are described below. One method particularly suitable for the preparation of small to medium sized peptides, well known and appreciated by those skilled in the art, is solid phase peptide synthesis (SPPS).

[0086] Suitable starting materials and protected amino acids of general formula AA-1, Int-1, Int-2, or Int-3 are commercially available or may be prepared by various methods. For example, as illustrated in the general synthetic procedure, Scheme 1, the carboxylic acid function of an appropriately substituted amino acid of general formula AA-1 can be chemoselectively protected as a suitable derivative, e.g., a methyl ester, using well-established procedures and reagents such as a mixture of methanol and thionyl chloride to obtain a compound of general formula Int-1. In a subsequent step, protection of the free amine function in Int-1 as an amide or carbamate, e.g., Fmoc, affords an intermediate of general structure Int-2. An intermediate of general formula Int-3 can be obtained by selective deprotection of the masked acid function present in Int-2, e.g., using acidic hydrolysis. When using SPPS, Int-3 can be attached to an appropriately functionalized resin, e.g., Wang resin, using an ester-forming reagent such as a mixture of diisopropylmethanediimine, 4-methylmorpholine, and N,N-dimethylpyridin-4-amine in dichloromethane to give a solid-supported intermediate of general formula Int-4.

[0087] General synthetic procedure

[0088] [ka]

[0089] If necessary, resin-bound intermediates Int-4 through Int-9 can be analyzed after cleavage from the resin. Alternatively, the corresponding steps on the solid support can be performed without analysis. The amine protecting group in Int-4 can be removed by treatment with a base such as piperazine, for example, if an Fmoc protecting group is used, to give Int-5. The free acid function present in a second N-protected amino acid, represented herein by a compound of general formula AA-2, can be coupled with the free amine present in an intermediate of general formula Int-5 using a classical amide coupling procedure, for example, a mixture of HATU and a base such as N-methylmorpholine in a suitable solvent system, such as a mixture of DCM-DMF, to give Int-6.

[0090] Similarly, a suitably protected amine moiety, AA-2, can be coupled with Int-5 to give Int-6. The primary amine protecting group can then be removed in a subsequent step, for example, using a base such as piperidine if an Fmoc protecting group is used, to give Int-7. Once again and as previously described, the free-based amine functionality present in Int-7 can be extended by the introduction of another suitably protected amino acid derivative of general formula AA-3, as exemplified in the general synthetic procedures, to give Int-8. Similarly, after selective removal of the amine protecting group in Int-8, the resulting Int-9 can be readily functionalized as an acyl derivative using classical amide coupling procedures, for example, using a mixture of HATU and a base such as N-methylmorpholine in a suitable solvent system such as a mixture of DCM-DMF, to give intermediates of general formula Int-10. The final compounds of general formula (I) are obtained by cleavage using, for example, acidic hydrolysis of the ester bond between the resin solid support and compounds of the general structure shown in Int-10 using a reagent such as trifluoroacetic acid.

[0091] Resin-bound intermediates were analyzed after cleavage from the resin. All analyses of intermediates were performed as free acids. be.

[0092] The products of each step can then be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.

[0093] Those skilled in the art will also appreciate that not all substituents in a compound of formula (I) will necessarily tolerate the particular reaction conditions used to synthesize the compound. These moieties may be introduced at a convenient point in the synthesis, or may be protected as needed or desired and then deprotected, as is well known in the art. Those skilled in the art will also appreciate that protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention. Methods for introducing or removing protecting groups used in the present invention are well known in the art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons, New York (2006). 18 reference. [Example]

[0094] Abbreviation approx.: about; aq: aqueous; br: broad; ca.: approximately (circa); CDI: 1,1'-carbonyldiimidazole; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl le; h: hour; min: minute; HATU: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V); HPLC: high-performance liquid chromatography; IPA: isopropanol; LC: liquid chromatography; m: multiplet; M: molar concentration, molecular ion; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: quartet; rt: room temperature (approximately 20°C); R T : retention time; s: singlet, solid; SPPS: solid phase peptide synthesis; t: triplet; TBAF: tetrabutylammonium fluoride; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC®: ultra performance liquid chromatography; UV: ultraviolet.

[0095] Other abbreviations shall convey their generally accepted meaning.

[0096] General experimental conditions All starting materials and solvents were obtained from either commercial sources or preparations according to literature references. Unless otherwise indicated, reaction mixtures were magnetically stirred and carried out at room temperature (approximately 20° C.).

[0097] Unless otherwise indicated, column chromatography was performed on an automated flash chromatography system such as a CombiFlash Rf system using pre-packed silica (40 μm) cartridges.

[0098] 1 H NMR spectra were recorded at 500 MHz on a Bruker AvanceIII-500 HD spectrometer equipped with a Bruker 5 mm SmartProbe™. Chemical shifts are expressed in parts per million (ppm) using either the central peak of the residual protic solvent as the reference or tetramethylsilane as an internal reference. Unless otherwise indicated, spectra were recorded at 298 K. The following abbreviations or combinations are used for NMR signal multiplicity: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0099] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC H-Class System equipped with an ACQUITY PDA Detector and an ACQUITY QDa Mass Detector, running one of the following analytical methods:

[0100] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 Series HPLC system coupled to an Agilent 1956, 6100, or 6120 Series single quadrupole mass spectrometer, running one of the following analytical methods:

[0101] Preparative HPLC purification was performed using either a Waters X-Select CSH C18, 5 μm, 19 × 50 mm column with a gradient of MeCN and water, both modified with 0.1% (v / v) formic acid, or a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm column with a gradient of MeCN and 10 mM aqueous ammonium bicarbonate. Fractions were collected following UV detection at a single wavelength measured by a variable wavelength detector.

[0102] Analysis method Method 1 - Acidic 3 minute method Column: Waters ACQUITY UPLC® CSH C18, 1.7 μm, 2.1 × 30 mm, 40°C Detection: UV at 254 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.1% (v / v) formic acid in water, B: 0.1% (v / v) formic acid in MeCN

[0103] [Table 1]

[0104] Method 2 - Basic Quarter Method Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6 × 30 mm, 40 °C Solvent: A: 10 mM ammonium bicarbonate aqueous solution, B: MeCN

[0105] [Table 2]

[0106] Intermediates (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (Int-11)

[0107] [ka]

[0108] Intermediate Int-11 was prepared according to the procedure described in US Pat. No. 6,269,999 to prepare methyl 5,5,5-trifluoropentanoate, followed by Fmoc protection and hydrolysis of the methyl ester as described in US Pat. No. 6,269,999.

[0109] 4-Acetyl-(2R)-2-morpholinecarboxylic acid (Int-15)

[0110] [ka]

[0111] (R)-2-(Methoxycarbonyl)morpholin-4-ium chloride (Int-13) Acetyl chloride (7.60 mL, 107 mmol) cooled to 0 °C was added to MeOH (40 (R)-2-(methoxycarbonyl)morpholin-4-ium chloride (Int-13, 3.64 g, 19.0 mmol, 98% yield, 95% purity) was obtained as an off-white solid. 1 H NMR(500MHz,DMSO-d6) δ 9.76(s,2H),4.56(dd,J=9.9,3.1Hz,1H),4.00(dt,J=12.7,3.3Hz,1H),3.88~3.80(m,1H) ,3.70(s,3H),3.39~3.30(m,1H),3.13~3.19(m,1H),3.11~3.05(m,1H),3.04~3.96(m,1H).

[0112] (R)-4-Acetylmorpholine-2-carboxylate methyl ester (Int-14) To a solution of (R)-2-(methoxycarbonyl)morpholin-4-ium chloride (Int-13, 998 mg, 5.49 mmol) and N-methylmorpholine (1.69 mL, 15.4 mmol) in DCM (18 mL) at 0 °C, acetyl chloride (469 μL, 6.59 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was filtered, and the filtrate was diluted with water (20 mL) and then basified to pH 8 by the addition of saturated aqueous NaHCO (approximately 10 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over MgSO, and concentrated to a dark orange oil. The crude product was purified by silica gel column chromatography (40 g column, 0-5% MeOH in DCM) to give (R)-methyl 4-acetylmorpholine-2-carboxylate (Int-14, 350 mg, 1.87 mmol, 34% yield, 95% purity) as a brown oil. 1 The H NMR spectrum shows rotamers. 1 H NMR (500MHz, 25℃, DMSO-d6, rotamer) δ 4.30(dd,J=7.5,3.4Hz,0.5H),4.20~4.09(m,1H),3.88(dt,J=11.5,3.4Hz,0.5H),3.79~3.70(m,1H),3.68(d,J=14.8Hz,3.5H),3.65~ 3.56(m,0.5H),3.56~3.46(m,1.5H),3.23(dddd,J=28.2,12.5,8.9,3.5Hz,1H),3.01(dd,J=13.0,8.8Hz,0.5H),2.01(d,J=8.1Hz,3H).

[0113] 1 H NMR(500MHz,90℃,DMSO-d6) δ 4.21~4.18(m,1H),3.87~3.84(m,1H),3.71(s,3H),3.66~3.59(m,1H),3.55(ddd,J=11 .6,8.6,3.0Hz,1H),3.29(td,J=10.3,9.6,5.1Hz,1H),3.01~2.99(m,2H),2.01(s,3H).

[0114] (R)-4-Acetylmorpholine-2-carboxylic acid (Int-15) To a solution of (R)-4-acetylmorpholine-2-carboxylic acid methyl ester (Int-14, 350 mg, 11.87 mmol) in water (2.5 mL) and THF (2.5 mL) cooled to 0 °C, LiOH (42.5 mg, 1.78 mmol) was added in portions. The reaction mixture was stirred for 3 h, then diluted with 1 M HCl (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were dried over MgSO and concentrated in vacuo to give a brown oil (40.0 mg). The aqueous phase was further extracted with 4:1 CHCl / IPA (30 mL × 3). The combined organic phases were dried over MgSO and concentrated in vacuo to give (R)-4-acetylmorpholine-2-carboxylic acid (Int-15, 202 mg, 1.10 mmol, 59% yield, 95% purity) as an off-white solid. 1 The H NMR spectrum shows rotamers. 1 H NMR (500MHz, 25℃, DMSO-d6, rotamer) δ 13.01(br s,1H),4.17(dt,J=10.7,3.3Hz,1H), 3.98(dd,J=9.2,3.4Hz,0.5H),3.88(dt,J=11.5,3.4Hz,0.5H),3.83~3.75(m,0.5H),3.70(dd,J=13.3,3.4Hz,0.5H),3.68~3.61(m,0.5H), 3.58(d,J=13.6Hz,0.5H),3.49(qd,J=11.8,11.2,2.8Hz,1.5H),3.27~3.15(m,1H),2.97(dd,J=13.3,9.2Hz,0.5H),2.01(d,J=10.0Hz,3H).

[0115] 1 H NMR (500 MHz, 90 °C, DMSO-d6) δ 4.15–3.93 (m, 1H), 3.93–3.76 (m, 1H), 3.65–3.46 (m, 2H), 3.32–3.17 (m, 1H), 3.13–2.82 (m, 2H), 2.01 (s, 3H). No COH peak was observed.

[0116] Example 1 (S)-5,5,5-trifluoro-2-((2S,3S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-tetrahydrofuran-2-carboxamido)propanamido)-3-methylpentanamido)pentanoic acid

[0117] [ka]

[0118] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (Int-16) Wang resin (loading: 1.0 mmol / g, 90.0 mg, 0.09 mmol) was swollen in DCM (1 mL) for 10 min, filtered, and washed with DCM (3 × 5 mL). (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (Int-11, 177 mg, 0.450 mmol) was added. To a mixture of 1H-benzo[d][1,2,3]triazol-1-ol hydrate (69.0 mg, 0.45 mmol), diisopropylmethanediimine (70.0 μL, 0.45 mmol), 4-methylmorpholine (49.0 μL, 0.45 mmol), and N,N-dimethylpyridin-4-amine (11.0 mg, 0.09 mmol) and DCM (5 mL) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). DCM (5 mL), (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (Int-11, 177 mg, 0.45 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (69.0 mg, 0.45 mmol), 4-methylmorpholine (49.0 μL, 0.45 mmol), diisopropylmethanediimine (69.7 μL, 0.45 mmol), and N,N-dimethylpyridin-4-amine (11.0 mg, 0.09 mmol) were added to the resin, and the suspension was gently stirred for an additional 12 h at room temperature. The mixture was filtered and washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3) to give Int-16. No analysis was performed at this stage and the resin was used directly in the next step.

[0119] Synthesis of (S)-2-((2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamido)-5,5,5-trifluoropentanoic acid [C-terminally attached to resin] (Int-18) Resin-bound (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (Int-16, 90.0 mg, 0.09 mmol) was swollen in DMF (1 mL) for 10 min and filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was sparged with nitrogen gas at room temperature for 20 min. The suspension was filtered, 20% piperidine in DMF (5 mL) was added, and the suspension was sparged with nitrogen gas at room temperature for 20 min. The suspension was filtered and washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). The resulting solid was used without further purification.

[0120] A mixture of DMF / DCM (1:1, 3 mL) was added, followed by (((9H-fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (Int-17, 127 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), and 4-methylmorpholine (40.0 μL, 0.36 mmol). The suspension was agitated with nitrogen gas at room temperature for 2 hours, then washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). DMF (3 mL) was added, followed by (((9H-fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (Int-17, 127 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), and 4-methylmorpholine (40.0 μL, 0.36 mmol). The suspension was agitated with nitrogen gas at room temperature for 15 hours, then washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3) to give Int-18. A small portion of the resin was added to 0.5 mL of TFA, and the suspension was left at room temperature for 1 hour. The suspension was concentrated in vacuo to give (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxycarbonyl)amino)-3-methylpentanamido)-5,5,5-trifluoropentanoic acid (77% purity) which was analyzed by UPLC. LCMS (Method 1, 1.67 min; M+H=507.4).

[0121] Synthesis of (5S,8S,11S)-5-(4-(tert-butoxy)benzyl)-8-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-3,6,9-trioxo-11-(3,3,3-trifluoropropyl)-2-oxa-4,7,10-triazadodecan-12-oic acid (Int-20) Resin-bound (S)-2-((2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamido)-5,5,5-trifluoropentanoic acid (Int-18, 90.0 mg, 0.09 mmol) was swollen in DMF (1 mL) for 10 min and filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was sparged with nitrogen gas at room temperature for 20 min. The suspension was filtered, 20% piperidine in DMF (5 mL) was added, and the suspension was sparged with nitrogen gas at room temperature for 20 min. The suspension was filtered and washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). The resulting solid was used without further purification.

[0122] A mixture of DMF / DCM (1:1, 3 mL) was added, followed by (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanoic acid (Int-19, 165 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), and 4-methylmorpholine (40.0 μL, 0.36 mmol). The suspension was agitated with nitrogen gas at room temperature for 2 hours, then washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). DMF (3 mL) was added, followed by (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanoic acid (Int-19, 165 mg, 0.36 mmol), 4-methylmorpholine (40.0 μL, 0.36 mmol), and HATU (137 mg, 0.36 mmol). The suspension was agitated with nitrogen gas at room temperature for 16 hours, then washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3) to give Int-20. A small portion of the resin was added to 0.5 mL of TFA, and the suspension was left at room temperature for 1 hour. The suspension was filtered and concentrated in vacuo to give (5S,8S,11S)-8-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-5-(4-hydroxybenzyl)-3,6,9-trioxo-11-(3,3,3-trifluoropropyl)-2-oxa-4,7,10-triazadodecanoic acid (69% purity), which was analyzed by UPLC. LCMS (Method 1, 1.58 min; M+H=670.5).

[0123] Synthesis of (S)-2-((2S,3S)-2-((S)-3-(4-(tert-butoxy)phenyl)-2-((S)-tetrahydrofuran-2-carboxamido)propanamido)-3-methylpentanamido)-5,5,5-trifluoropentanoic acid [C-terminally bound to resin] (Int-22) (5S,8S,11S)-5-(4-(tert-butoxy)benzyl)-8-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-3,6,9-trioxo-11-(3,3,3-trifluoropropyl)-2-oxa-4,7,10-triazadodecanoic acid (Int-20, 90.0 mg, 0.09 mmol) was swollen in DMF (1 mL) for 10 minutes and filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was sparged with nitrogen gas at room temperature for 20 minutes. The suspension was filtered, and 20% piperidine in DMF (5 mL) was added, and the suspension was sparged with nitrogen gas at room temperature for 20 minutes. The reaction mixture was filtered and washed with DMF (5 mL x 3), DCM (5 mL x 3), water (5 mL x 2) and DMF (5 mL x 3). The resulting solid was used without further purification.

[0124] A mixture of DMF / DCM (1:1, 3 mL) was added, followed by 4-methylmorpholine (33.0 μL, 0.30 mmol), HATU (114 mg, 0.30 mmol), and (S)-tetrahydrofuran-2-carboxylic acid (Int-21, 29.0 μL, 0.30 mmol). The suspension was agitated with nitrogen gas at room temperature for 2 hours, and then diluted with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3). The suspension was washed with DMF (3 mL), followed by 4-methylmorpholine (33.0 μL, 0.30 mmol), HATU (114 mg, 0.30 mmol), and (S)-tetrahydrofuran-2-carboxylic acid (Int-21, 29.0 μL, 0.30 mmol), and the suspension was gently stirred at room temperature for 12 hours. The suspension was filtered and washed with DMF (5 mL × 3), DCM (5 mL × 3), water (5 mL × 2), and DMF (5 mL × 3) to give Int-22. No analysis was performed at this stage, and the resin was used directly in the next step.

[0125] Synthesis of (S)-5,5,5-trifluoro-2-((2S,3S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-tetrahydrofuran-2-carboxamido)propanamido)-3-methylpentanamido)pentanoic acid (Example 1) A mixture of TFA / water (95:5, 1 mL) was added to resin-bound (S)-2-((2S,3S)-2-((S)-3-(4-(tert-butoxy)phenyl)-2-((S)-tetrahydrofuran-2-carboxamido)propanamido)-3-methylpentanamido)-5,5,5-trifluoropentanoic acid (Int-22, 80.0 mg, 0.08 mmol) and stirred at room temperature for 3 hours. The reaction mixture was filtered, and the resin was washed with DCM (20 mL × 3). The combined filtrate was concentrated in vacuo and azeotroped with toluene (15 mL × 3). The crude product was purified by preparative HPLC to give (S)-5,5,5-trifluoro-2-((2S,3S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-tetrahydrofuran-2-carboxamido)propanamido)-3-methylpentanamido)pentanoic acid (Example 1, 2.70 mg, 4.90 μmol, 6.5%, mp 115°C, m / z) as a white solid. 1 95% purity by H NMR was obtained. LCMS purity 95% (Method 1, 1.11 min; M+H=546.7). 1H NMR(500MHz,DMSO-d6) δ 12.83(s,1H),9.14(s,1H),8.28(s,1H),7.93(d,J=8.6Hz,1H),7.62(d,J=8.6Hz,1H),6.99~6.88(m,2H),6.66~6.56(m,2H), 4.49(td,J=8.8,4.4Hz,1H),4.26~4.23(m,1H),4.18(t,J=8.0Hz,1H),4.13(dd,J=8.1,4.6Hz,1H),3.84(q,J=6.9Hz,1H),3. 72(dt,J=8.1,6.5Hz,1H),2.90(dd,J=14.0,4.4Hz,1H),2.76(dd,J=14.0,9.1Hz,1H),2.29(ddd,J=50.1,23.9,9.6Hz,2H),2 .07~1.90(m,2H),1.86~1.77(m,1H),1.77~1.64(m,4H),1.52~1.35(m,1H),1.09(dt,J=14.9,7.9Hz,1H),0.94~0.76(m,6H).

[0126] [Table 3]

[0127] [Table 4]

[0128] Example 5 (S)-2-((S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-pyrrolidine-2-carboxamido)propanamido)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid

[0129] [ka]

[0130] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid (intermediate 24) Wang resin (loading: 1.0 mmol / g, 650 mg, 0.65 mmol) was swollen in DCM (30 mL) at room temperature for 10 min and filtered. DCM (30 mL) was added, followed by (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid (Int-23, 0.25 g, 0.65 mmol), DIC (0.31 mL, 2.00 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.30 g, 2.0 mmol), 4-methylmorpholine (0.21 mL, 2.00 mmol), and DMAP (79.0 mg, 0.65 mmol). The suspension was gently stirred at room temperature for 16 h. The suspension was filtered and washed with DMF (20 mL × 3), DCM (20 mL × 3), water (20 mL × 2), DMF (20 mL × 2), and DCM (20 mL × 2). A mixture of DCM / DMF (1:1, 30 mL) was added, followed by (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid (Int-23, 0.25 g, 0.65 mmol), DIC (0.31 mL, 2.00 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.30 g, 2.0 mmol), 4-methylmorpholine (0.21 mL, 2.00 mmol), and DMAP (79.0 mg, 0.65 mmol). The suspension was stirred at room temperature for 24 hours, then filtered and washed with DMF (5 mL x 2), DCM (5 mL x 2), water (5 mL x 2), DMF (5 mL x 2), DMF (20 mL x 2), and DCM (20 mL x 2) to give Int-24. A small portion of the resin was added to TFA (0.05 mL) and the suspension was left at room temperature for 1 hour. The suspension was filtered and concentrated in vacuo to give (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid (100% pure). was obtained and analyzed by LCMS: LCMS (Method 2, 1.53 min; M+Na=404.1).

[0131] Synthesis of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Int-26) (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid (Int-24, 100 mg, 100 μmol) was swollen in DMF (1 mL) for 10 minutes and then filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was agitated with nitrogen gas at room temperature for 20 minutes. The suspension was filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3). The resulting solid was used without further purification.

[0132] DCM (2.6 mL) and DMF (0.4 mL) were added, followed by (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanoic acid (Int-25, 155 mg, 0.40 mmol), HATU (152 mg, 0.40 mmol), and 4-methylmorpholine (44.0 μL, 0.40 mmol). The reaction was gently stirred under a nitrogen atmosphere at room temperature for 20 hours, then filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3) to give Int-26. A small portion of the resin was added to TFA (0.05 mL) and stirred at room temperature for 30 minutes. The suspension was filtered, washed with DCM (5 mL) and the combined filtrates were concentrated in vacuo to give (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (85% pure), analyzed by LCMS. (Method 2, 1.60 min; M+H=530.2).

[0133] Synthesis of (5S,8S,11S)-5-(4-(tert-butoxy)benzyl)-11-(3,3-dimethylbutyl)-1-(9H-fluoren-9-yl)-3,6,9-trioxo-8-(pyridin-2-ylmethyl)-2-oxa-4,7,10-triazadodecan-12-oic acid (Int-27) Resin-bound (S)-2-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Int-26, 50.0 mg, 50.0 μmol) was swollen in DMF (1 mL) for 10 minutes and then filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was agitated with nitrogen gas at room temperature for 20 minutes. The suspension was filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3). The resulting solid was used without further purification.

[0134] DCM (2.6 mL) and DMF (0.4 mL) were added, followed by (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanoic acid (Int-19, 92.0 mg, 0.20 mmol), HATU (76.0 mg, 0.20 mmol), and 4-methylmorpholine (22.0 μL, 0.20 mmol). The reaction was gently stirred under a nitrogen atmosphere at room temperature for 3 days, then filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3) to give Int-27. A small portion of the resin was added to TFA (0.05 mL) and stirred at room temperature for 30 minutes. The suspension was diluted with DCM (5 mL), filtered, and the filtrate concentrated in vacuo to give (5S,8S,11S)-11-(3,3-dimethylbutyl)-1-(9H-fluoren-9-yl) 5-(4-Hydroxybenzyl)-3,6,9-trioxo-8-(pyridin-2-ylmethyl)-2-oxa-4,7,10-triazadodecanoic acid (86% purity) was obtained and analyzed by LCMS (Method 2, 1.56 min; M+H=693.3).

[0135] Synthesis of (S)-2-((S)-2-((S)-3-(4-(tert-butoxy)phenyl)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)propanamido)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Int-29) Resin-bound (5S,8S,11S)-5-(4-(tert-butoxy)benzyl)-11-(3,3-dimethylbutyl)-1-(9H-fluoren-9-yl)-3,6,9-trioxo-8-(pyridin-2-ylmethyl)-2-oxa-4,7,10-triazadodecanoic acid (Int-27, 50.0 mg, 0.05 mmol) was swollen in DMF (5 mL) for 10 minutes and then filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin, and the suspension was agitated with nitrogen gas at room temperature for 20 minutes. The suspension was filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3). The resulting solid was used without further purification.

[0136] DCM (2.6 mL) and DMF (0.4 mL) were added, followed by (tert-butoxycarbonyl)-L-proline (Int-28, 43.0 mg, 0.20 mmol), HATU (76.0 mg, 0.20 mmol), and 4-methylmorpholine (22.0 μL, 0.20 mmol). The reaction was gently stirred under a nitrogen atmosphere for 20 hours. The suspension was filtered and washed with DMF (5 mL × 2), DCM (5 mL × 2), water (5 mL × 2), DCM (5 mL × 2), and DMF (5 mL × 3) to give Int-29. No analysis was performed at this stage; the resin was used directly in the next step.

[0137] Synthesis of (S)-2-((S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-pyrrolidine-2-carboxamido)propanamido)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Example 5) TFA (0.38 mL, 5.00 mmol) was added to resin-bound (S)-2-((S)-2-((S)-3-(4-(tert-butoxy)phenyl)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)propanamido)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Int-29, 50.0 mg, 50.0 μmol) and stirred at room temperature for 3 hours. The suspension was filtered, washed with DCM (5 mL × 3), and the filtrate was concentrated in vacuo and azeotroped with toluene (5 mL × 3). The crude product was purified by preparative HPLC to give (S)-2-((S)-2-((S)-3-(4-hydroxyphenyl)-2-((S)-pyrrolidine-2-carboxamido)propanamido)-3-(pyridin-2-yl)propanamido)-5,5-dimethylhexanoic acid (Example 5, 2.00 mg, 3.00 μmol, 7.0% yield) as a colorless solid. 1 97% purity was obtained by H NMR. LCMS purity was not confirmed due to a weak chromophore. (Method 2, 1.18 min; M+H=568.3). 1 H NMR(500MHz,DMSO-d6) δ 12.70(s,1H),9.21(s,1H),9.13(s,1H),8.57(d,J=8.5Hz,1H),8.46~8.43(m,2H),8.41~8. 38(m,1H),8.36(d,J=8.4Hz,1H),8.30(d,J=7.7Hz,1H),7.29(d,J=5.9Hz,1H),7.01(d,J=8. 5Hz,2H),6.64~6.61(m,2H),4.73~4.65(m,1H),4.50~4.43(m,1H),4.21~4.13(m,1H),4.07 ~4.01(m,1H),3.24~3.10(m,3H),3.07(dd,J=14.0,4.4Hz,1H),2.88(dd,J=14.1,4.0Hz,1H) ,2.82(dd,J=14.0,9.5Hz,1H),2.64~2.54(m,1H),2.26~2.16(m,1H),1.91~1.65(m,3H),1.64~1.54(m,1H),1.27~1.17(m,2H),0.86(s,9H).

[0138]

Table 5

[0139]

Table 6

[0140]

Table 7

[0141]

Table 8

[0142]

Table 9

[0143]

Table 10

[0144]

Table 11

[0145]

Table 12

[0146]

Table 13

[0147]

Table 14

[0148]

Table 15

[0149] Table 16

[0150] Table 17

[0151] Table 18

[0152]

Table 19

[0153] Table 20

[0154] Table 21

[0155] Table 22

[0156] Table 23

[0157] biological science Neurotensin scintillation proximity assay Data for exemplary compounds of the present invention tested in the Neurotensin (NTS) Scintillation Proximity Assay (SPA). IC 50 The data are shown in Table 6 below. NTS, a 13 amino acid neuropeptide, is a sortilin ligand. IC 50 is a measure of the amount of compound required to inhibit the binding of NTS to sortilin by 50%. Those skilled in the art will appreciate that IC 50 It will be appreciated that the lower the value, the less compound is needed to achieve the desired effect, and consequently the less chance of unwanted off-target effects.

[0158] Compound affinity was measured by binding to hSortilin in the SPA format [ 3 H]neurotensin was determined by measuring the displacement of [H]neurotensin. The total volume was 40 μl in 50 mM HEPES pH 7.4 assay buffer containing 100 mM NaCl, 2.0 mM CaCl, 0.1% BSA and 0.1% Tween®-20. Compounds were incubated at room temperature for 1 hour. After preincubation with 150 nM 6his-sortilin for 30 min, 5 nM 3 [H]neurotensin and Ni-chelating imaging beads (Perkin Elmer) were added, and after 6 hours the plates were read on a ViewLux with a 360 second exposure time. Compound dose-response evaluation was performed using eight drug concentrations (covering three decades). IC 50 Values ​​were calculated by nonlinear regression with a sigmoidal concentration response (variable slope) using CDD Vault software. All values ​​reported are the mean of at least two determinations.

[0159] The data in Table 6 below demonstrate that the compounds disclosed herein are sortilin inhibitors.

[0160] [Table 24]

[0161] [Table 25]

[0162] X-ray image of the compound of Example 12 bound to h-Sortilin material and method Sortilin, the luminal domain of sortilin, was obtained as previously described (Andersen et al., Acta Cryst. D, 2017). 19 Prior to crystallization, 12 μl of 4 mg / ml sSortilin in 50 mM Tris-HCl pH 8.0, 150 mM NaCl was mixed with 1.2 μl of two compounds INS1767 and INS1783 dissolved in DMSO at concentrations of 16.7 mM and 13.2 mM, respectively.

[0163] Sitting drops were set up by adding 2 μl of the sortilin ligand mixture to 2 μl of reservoir solution consisting of 100 mM Hepes pH 7.3, 400 mM malonate pH 7.3, 8% (vol / vol) glycerol, 22.5% (wt / vol) PEG 3350. The sitting drops were allowed to equilibrate by vapor diffusion with 500 μl of reservoir solution.

[0164] The crystals were mounted in litho loops without further cryoprotection and flash cooled in liquid nitrogen.

[0165] Diffraction data were collected at beamline P13 EMBL / DESY (Hamburg, Germany) and processed using the XDS package (Kabsch, W., Acta Cryst. D, 2010). 20 (Table 1).

[0166] The structure factor phases were analyzed using a search model implemented in the Phenix software package and The program was obtained by molecular replacement using the known structure of sortilin (PDB entry 3F6K) as the phaser (Afonine et al., Acta Cryst. D, 2012). 21The improved model was developed using Coot (Emsley P. et al., Acta Cryst. D, 2010). 22 and obtained through several model building cycles in maximum likelihood refinement using Phenix. The resulting X-ray images of the compound of Example 12 bound to h-Sortilin are shown in Figures 1A and 1B. The refinement statistics and agreement of the model with the standard geometry are shown in Table 7 below.

[0167] [Table 26]

[0168] [Table 27]

[0169] References 1. Tauris, J., et al., Proneurotrophin-3 May Induce Sortilin-Dependent Death In Inner Ear Neurons.Eur J Neuroscience (2020), 33(4), pp.622-31. 2. Goettsch, C., et al., Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Atherosclerosis, Thrombosis and Vascular Biology (2017), 38(1), pp.19-25. 3. Willnow, TE, et al., Sortilins:new players in lipoprotein metabolism. Current Opinion in Lipidology (2011), 22(2), pp.79-85. 4. Kjolby, M., et al., Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metabolism (2010), 12(3), pp.213-223. 5. Jansen, P., et al., Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nature Neuroscience (2007), 10(11), pp.1449-1457. 6. Tenk, H. K., et al., ProBDNF induces neuronal apoptosis via activation of a r eceptor complex of p75NTR and sortilin. J Neuroscience (2005), 10(11), pp.1449-1457. 7. Nykjaer, A., et al., Sortilin is essential for proNGF-induced neuronal cell death. Nature (2004), 427(6977), pp.843-848. 8. Huang, G. et al., Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin. Mol Biol Cell (2013), 24(19), pp.3115-3122. 9. Pan, X. et al., Sortilin and retromer mediate retrograde transport of Glut4 in 3T3-L1 adipocytes. Mol Biol Cell (2017), 28(12), pp.1667-1675. 10. Kaddai, V. et al. Involvement of TNF-α in abnormal adipocyte and muscle sortilin expression in obese mice and humans. Diabetologia (2009) 52, pp.932-940. 11. Mortensen, M. B. et al., Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis. J Clin Invest (2014), 124(12), pp.5317-5322. 12. Shi, J. & Kandror, K. V., Sortilin Is Essential and Sufficient for the Formation of Glut4 Storage Vesicles in 3T3-L1 Adipocytes. Developmental Cell (2005), 9, pp.99-108. 13. Gao, A. et al., Implications of Sortilin in Lipid Metabolism and Lipid Disorder Diseases. DNA and Cell Biology (2017), 36(12), pp.1050-1061. 14. Oh, T. J. et al., Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus. Cardiovascular Diabetology (2017), 16(92). 15. Santos, A. M. et al., Sortilin Participates in Light-dependent Photoreceptor Degeneration in Vivo. PLoS ONE (2012), 7(4), pp.e36243-e36243.16.Kuruvilla, R. et al., A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signalling. Cell (2004), 118(2), pp.243-255. 17. Skeldal, S. et al., Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis. J Biol Chem (2012), 21(287), pp. 43798-43809. 18. Wuts, P. G. M. and Greene, T. W, Greene’s Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons, New York (2006). 19. Andersen, KR et al., Introducing site-specific cysteines into nanobodies for mercury labeling allows de novo phasing of their crystal structures. Acta Crystallographia Section. D (2017), 73(1), pp.804-813. 20. Kabsch, W, XDS. Acta Crystallographia Section. D (2010), 66(2), pp.125-132. 21. Afonine, PV et al., Acta Crystallographia Section. D (2012), 68(4), pp.352-367. 22. Emsley, P. et al., Acta Crystallographia Section. D (2010), 66(4), pp.486-501.

[0170] Sequences referenced throughout this specification and forming part of the description

[0171] SEQ ID NO: 1 (full length sortilin-isoform 1) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCKAD LGALELWRTS DLGKSFKTIG 301 VKIYSFGLGG RFLFASVMAD KDTTRRIHVS TDQGDTWSMA QLPSVGQEQF 351 YSILAANDDM VFMHVDEPGD TGFGTIFTSD DRGIVYSKSL DRHLYTTTGG 401 ETDFTNVTSL RGVYITSVLS EDNSIQTMIT FDQGGRWTHL RKPENSECDA 451 TAKNKNECSL HIHASYSISQ KLNVPMAPLS EPNAVGIVIA HGSVGDAISV 501 MVPDVYISDD GGYSWTKMLE GPHYYTILDS GGIIVAIEHS SRPINVIKFS 551 TDEGQCWQTY TFTRDPIYFT GLASEPGARS MNISIWGFTE SFLTSQWVSY 601 TIDFKDILER NCEEKDYTIW LAHSTDPEDY EDGCILGYKE QFLRLRKSSM 651 CQNGRDYVVT KQPSICLCSL EDFLCDFGYY RPENDSKCVE QPELKGHDLE 701 FCLYGREEHL TTNGYRKIPG DKCQGGVNPV REVKDLKKKC TSNFLSPEKQ 751 NSKSNSVPII LAIVGLMLVT VVAGVLIVKK YVCGGRFLVH RYSVLQQHAE 801 ANGVDGVDAL DTASHTNKSG YHDDSDEDLL E

[0172] SEQ ID NO: 2 (full length sortilin-isoform 2) 1 MERPWGAADG LSRWPHGLGL LLLLQLLPPS TLSQDRLDAP PPPAAPLPRW 51 SGPIGVSWGL RAAAAGGAFP RGGRWRRSAP GEDEECGRVR DFVAKLANNT 101 HQHVFDDLRG SVSLSWVGDS TGVILVLTTF HVPLVIMTFG QSKLYRSEDY 151 GKNFKDITDL INNTFIRTEF GMAIGPENSG KVVLTAEVSG GSRGGRIFRS 201 SDFAKNFVQT DLPFHPLTQM MYSPQNSDYL LALSTENGLW VSKNFGGKWE 251 EIHKAVCLAK WGSDNTIFFT TYANGSCTDL GALELWRTSD LGKSFKTIGV 301 KIYSFGLGGR FLFASVMADK DTTRRIHVST DQGDTWSMAQ LPSVGQEQFY 351 SILAANDDMV FMHVDEPGDT GFGTIFTSDD RGIVYSKSLD RHLYTTTGGE 401 TDFTNVTSLR GVYITSVLSE DNSIQTMITF DQGGRWTHLR KPENSECDAT 451 AKNKNECSLH IHASYSISQK LNVPMAPLSE PNAVGIVIAH GSVGDAISVM 501 VPDVYISDDG GYSWTKMLEG PHYYTILDSG GIIVAIEHSS RPINVIKFST 551 DEGQCWQTYT FTRDPIYFTG LASEPGARSM NISIWGFTES FLTSQWVSYT 601 IDFKDILERN CEEKDYTIWL AHSTDPEDYE DGCILGYKEQ FLRLRKSSVC 651 QNGRDYVVTK QPSICLCSLE DFLCDFGYYR PENDSKCVEQ PELKGHDLEF 701 CLYGREEHLT TNGYRKIPGD KCQGGVNPVR EVKDLKKKCT SNFLSPEKQN 751 SKSNSVPIIL AIVGLMLVTV VAGVLIVKKY VCGGRFLVHR YSVLQQHAEA 801 NGVDGVDALD TASHTNKSGY HDDSDEDLLE

[0173] SEQ ID NO: 3 (mature sortilin) 1 MTFGQSKLYR SEDYGKNFKD ITDLINNTFI RTEFGMAIGP ENSGKVVLTA 51 EVSGGSRGGR IFRSSDFAKN FVQTDLPFHP LTQMMYSPQN SDYLLALSTE 101 NGLWVSKNFG GKWEEIHKAV CLAKWGSDNT IFFTTYANGS CTDLGALELW 151 RTSDLGKSFK TIGVKIYSFG LGGRFLFASV MADKDTTRRI HVSTDQGDTW 201 SMAQLPSVGQ EQFYSILAAN DDMVFMHVDE PGDTGFGTIF TSDDRGIVYS 251 KSLDRHLYTT TGGETDFTNV TSLRGVYITS VLSEDNSIQT MITFDQGGRW 301 THLRKPENSE CDATAKNKNE CSLHIHASYS ISQKLNVPMA PLSEPNAVGI 361 VIAHGSVGDA ISVMVPDVYI SDDGGYSWTK MLEGPHYYTI LDSGGIIVAI 401 EHSSRPINVI KFSTDEGQCW QTYTFTRDPI YFTGLASEPG ARSMNISIWG 451 FTESFLTSQW VSYTIDFKDI LERNCEEKDY TIWLAHSTDP EDYEDGCILG 501 YKEQFLRLRK SSVCQNGRDY VVTKQPSICL CSLEDFLCDF GYYRPENDSK 551 CVEQPELKGH DLEFCLYGRE EHLTTNGYRK IPGDKCQGGV NPVREVKDLK 601 KKCTSNFLSP EKQNSKSNSV PIILAIVGLM LVTVVAGVLI VKKYVCGGRF 651 LVHRYSVLQQ HAEANGVDGV DALDTASHTN KSGYHDDSDE DLLE

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof; In formula (I), R １ , R ２ and R ３ is halo, H, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkenyl, and halo(C ２ ~C ４ ) alkenyl; R ４ is H, (C １ ~C １０ ) alkyl, halo (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, halo(C ２ ~C １０ ) alkenyl, (C ３ ~C ８ ) aryl, halo (C ３ ~C ８ ) aryl, (C ３ ~C ８ ) Heteroaryl, halo(C ３ ~C ８ ) heteroaryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ ) aryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ ) heteroaryl, and (C １ ~C ６ )-alkylene-(3- to 10-membered heterocyclic ring); Said (C １ ~C ６ )-alkylene-(C ３ ~C ２０ ) an aryl group in aryl, １ ~C ６ )-alkylene-(C ３ ~C ２０ ) a heteroaryl group in the heteroaryl group or the above (C １ ~C ６ The heterocyclic ring in the )-alkylene-(3- to 10-membered heterocyclic ring) is selected from halo, H, —OH, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy and halo(C １ ~C ４ ) optionally substituted with one or more substituents independently selected from alkoxy; R ５ is H, (C １ ~C １０ ) alkyl and (C ２ ~C １０ ) alkenyl; The alkyl and alkenyl groups are optionally substituted with halo, amido and phenolic groups; and R ６ (C １ ~C １０ ) alkyl, halo (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, halo(C ２ ~C １０ ) selected from the group consisting of alkenyl and 3- to 10-membered heterocyclic rings; The heterocyclic ring may be selected from the group consisting of halo, —OH, (C １ ~C ４ ) alkyl, halo (C １ ~C １０ ) alkyl, acetyl, (C １ ~C ４ ) alkoxy, and halo (C １ ~C ４ ) optionally substituted by one or more substituents independently selected from alkoxy; The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

2. R １ , R ２ and R ３ Halo, (C １ ~C ２ ) alkyl and halo(C １ ~C ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, each independently selected from the group consisting of: alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

3. R １ , R ２ and R ３ , F, CH ３ and C.F. ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, each independently selected from:

4. R ４ is H, (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, (C ３ ~C ８ ) aryl, (C １ ~C ３ )-alkylene-(C ３ ~C １０ ) aryl, (C １ ~C ３ )-alkylene-(C ３ ~C １０ ) heteroaryl and (C １ ~C ３ )-alkylene-(3- to 10-membered heterocyclic ring); Said (C １ ~C ３ )-alkylene-(C ３ ~C １０ ) an aryl group in aryl, １ ~C ３ )-alkylene-(C ３ ~C １０ ) a heteroaryl group in the heteroaryl group or the above (C １ ~C ３ The heterocyclic ring in the )-alkylene-(3- to 10-membered heterocyclic ring) is selected from halo, H, —OH, (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy and halo(C １ ~C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, optionally substituted by one or more substituents independently selected from:

5. R ４ teeth, 【Chemistry 2】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

6. R ５ is H and (C １ ~C ４ ) alkyl; The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein the alkyl group is optionally substituted with halo, amide, and phenol.

7. R ５ teeth, 【Chemistry 3】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

8. R ６ (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkyl, and 3- to 8-membered heterocyclic rings; The heterocyclic ring may be selected from the group consisting of halo, —OH, (C １ ~C ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, optionally substituted by one or more substituents independently selected from alkyl and acetyl.

9. R ６ teeth, 【Chemistry 4】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

10. The compound of formula (I) (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(1-methyl-1H-amidazol-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(1,3-thiazol-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-4-carbamoyl-2-{[(2S)-pyrrolidin-2-yl]formamide}butanamide]-3-(1,3-thiazol-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2- {[(2S)-pyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-morpholin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(1-methyl-1H-amidazol-5-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-pyrrolidin-2-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-carbamoyl-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(1,3-thiazol-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(morpholin-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(pyridin-2-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-oxolan-2-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-oxolan-2-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-{[(2R)-4-acetylmorpholin-2-yl]formamide}-3-(4-hydroxyphenyl)propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3S)-morpholin-3-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3R)-morpholin-3-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-morpholin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(pyridin-4-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(pyridinyl 5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]-3-(thiophen-3-yl)propanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(3S)-pyrrolidin-3-yl]formamide}propanamide]-3-methylpentanamide]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-piperazin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-piperazin-2-yl]formamido}propanamido]-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-[(2S)-2-{[(2S)-pyrrolidin-2-yl]formamide}propanamide]pentanamide]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-(2-{[(2S)-pyrrolidin-2-yl]formamido}acetamido)pentanamido]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-[(2S)-3-methyl-2-{[(2S)-pyrrolidin-2-yl]formamido}butanamido]pentanamido]hexanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2R)-oxolan-2-yl]formamide}propanamide]-3-methylpentanamide]pentanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-2-[(2S)-3-(4-hydroxyphenyl)-2-{[(2S)-oxolan-2-yl]formamido}propanamido]-3-methylpentanamido]pentanoic acid; (2S)-2-[(2S,3S)-2-[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5,5-trifluoropentanoic acid; or 2. The compound of claim 1, which is (2S)-2-[(2S,3S)-2-[(2S)-2-{[(2R)-4-acetylmorpholin-2-yl]formamido}-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]-5,5,5-trifluoropentanoic acid, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, and a pharma- ceutically acceptable carrier, excipient, and / or diluent.

12. 12. A pharmaceutical composition according to claim 11 for use in therapy.

13. 12. A pharmaceutical composition according to claim 11 for use in the treatment or prevention of a neurodegenerative disease, an inflammatory disease, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition or hearing loss.

14. the neurodegenerative disease is selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease and spinal cord injury; The inflammatory disorder may be selected from inflammatory diseases and neuroinflammation; the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer; and 14. The pharmaceutical composition for use according to claim 13, wherein the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, presbycusis, idiopathic hearing loss, tinnitus and sudden hearing loss.

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