Modulators of sortilin activity

Abstract

The present invention relates to compounds of formula (I) that are modulators of sortilin activity. The invention also relates to pharmaceutical compositions comprising 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 present invention also relates to pharmaceutical compositions comprising 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 disorders, inflammatory disorders, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss. [Background technology]

[0002] Sortilin (encoded by SORT1) is a member of the vacuolar protein sorting 10 protein (VPS10P) family of sorting receptors. It is a type 1 membrane receptor for β-lactamase, and is abundantly expressed in the central nervous system, the inner ear, and some peripheral tissues involved in metabolic regulation. 1,2,3,4 Sortilin has the amino acid sequence according to 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 has six potential N-linked glycosylation sites, while the cytoplasmic tail allows the recruitment of various adaptor proteins.

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

[0004] Previous studies have suggested a role for sortilin in cell sorting and signaling associated with diseases such as diabetes and obesity (Huang et al 2013 Mol Biol Cell Oct; 24(19): 3115-22) 8 Sortilin promotes the translocation of GLUT4 to the plasma membrane and to the lysosomes. (Pan et al Mol Biol Cell. 2017 Jun 15; 28(12): 1667-1675) 9 Sortilin levels are modulated by the level of inflammation associated with these diseases. It has been shown that the pro-inflammatory cytokine TNFα reduces both sortilin mRNA and protein levels in cultured mouse and human adipocytes, and in vivo when injected into mice (Kaddai et al. Diabetologia 52: 932-40, 2009). 10 Sortilin may also affect cytokine secretion, which may contribute to inflammation. Targeting sortilin in immune cells has been proposed to attenuate IL-1 and reduce atherosclerotic disease progression (Mortensen et al. J Clin Invest 124(12): 5317-22, 2014). 11 In addition, Patent Document 1 discloses a compound capable of binding to the active site of sortilin. Sortilin is a small molecule that regulates glucose uptake (Shi & Kandror. Developmental Cell 9: 99-108, 2005). 12 and the development of dyslipidemia (Gao et al. DNA and Cell Biology 36(12): 1050-61, 2017) 13 is involved in.

[0005] Furthermore, plasma sortilin levels have been reported as a potential biomarker for identifying patients with either coronary heart disease or diabetes mellitus (Oh et al. Cardiovascular Diabetology 16:92, 2017). 14 showed elevated sortilin levels in plasma, Thus, patients who were identifiable as having the above conditions also presented with elevated glucose levels, which supports the use of sortilin as a therapeutic target for treating these conditions. This proposes the following. [Prior art documents] [Patent documents]

[0006] [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

[0007] In view of the above, there is an unmet need for novel compounds that can be used to treat and prevent medical conditions that benefit from the modulation of Sortilin, such as neurodegenerative disorders, inflammatory disorders, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss. The neurodegenerative disorder may be 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 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, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss. [Brief description of the drawings]

[0008] [Figure 1]FIG. 1 is an X-ray image of Example 3 bound to h-Sortilin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In a first aspect, the present invention provides a compound of formula (I)

[0010] [ka]

[0011] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, wherein R 1 , R 2 , and R 3 are each independently selected from the group consisting of halo, H, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C2-C4)alkenyl, and halo-(C2-C4)alkenyl; R 4 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 Heteraryl, (C1-C6)-alkylene-(C3-C 20 )-aryl, (C1-C6)-alkylene-(C3-C 20 )-heteroaryl, (C1-C6)-alkylene-(3-10 membered heterocyclic ring); In this case, (C1-C6)-alkylene-(C3-C 20 )-aryl, (C1-C6)-alkylene-(C3-C 20the heteroaryl group of the (C1-C6)-heteroaryl, or the heterocyclic ring of the (C1-C6)-alkylene-(3-8 membered heterocyclic ring) is optionally substituted with one or more substituents independently selected from halo, H, -OH, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C1-C4)alkoxy, and halo-(C1-C4)alkoxy; R 5 is selected from the group consisting of H, (C1-C4) alkyl, halo-(C1-C4) alkyl, (C2-C4) alkenyl, and halo-(C1-C4) alkenyl; and R 6 is selected from the group consisting of (C1-C6)alkyl, halo-(C1-C6)alkyl, (C2-C6)alkenyl, halo-(C2-C6)alkenyl, (C3-C8)aryl, halo-(C3-C8)aryl, (C3-C8)heteroaryl, and halo-(C3-C8)heteroaryl.

[0012] Surprisingly, it has been found that the compounds of formula (I) inhibit or antagonize sortilin and therefore can be useful in conditions where inhibition of sortilin is beneficial.Such conditions include neurodegenerative disorders, inflammatory disorders, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss.Neurodegenerative disorders can be selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and spinal cord injury, inflammatory disorders can be selected from inflammatory disease and neuroinflammation, cancer can be selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer, and hearing loss can be selected from noise-induced hearing loss, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0013] As used herein, the term "Sortilin" may refer to full-length Sortilin (also referred to as immature Sortilin) ​​having an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2, including the signal peptide, the propeptide, the Vps10p domain, the 10CC domain, the transmembrane domain, and the large cytoplasmic tail, or it may refer to mature Sortilin having an amino acid sequence according to SEQ ID NO: 3, including the Vps10p domain, the 10CC domain, the transmembrane domain, and the large cytoplasmic tail, 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 interact with a p75NTR molecule to form a trimeric complex including Sortilin, Proneurotrophin, and p75NTR. It is understood that this trimeric complex may be responsible for adverse biological responses such as stimulation of apoptosis in retinal and ganglion cells and inhibition of growth cone retraction of projecting axons.

[0014] As used herein, the term "pro-neurotrophin" refers to a precursor of a neurotrophin that is larger than the neurotrophin and undergoes proteolytic cleavage to generate the mature form of the neurotrophin. Neurotrophins are a family of proteins that induce the survival, development, and function of neurons and are commonly referred to as growth factors. Pro-neurotrophins are biologically active and have different roles compared to their neurotrophin counterparts, such as inducing apoptosis. Examples of pro-neurotrophins include proNGF, proBDNF, proNT3, and proNT4. Pro-neurotrophins can also regulate synaptic plasticity. While mature neurotrophins induce synaptic strength, in their precursor form, they can weaken synapses.

[0015] The compounds of the present invention may be sortilin inhibitors or antagonists. As used herein, the term "sortilin antagonist" refers to a substance that interferes with, blocks, or otherwise attenuates the effect of sortilin protein binding 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 agents that interfere with the formation of high affinity trimeric complexes. In the latter scenario, it is recognized that a trimeric complex may be formed in that sortilin can bind to p75NTR (but not to proNGF) and at the same time, p75NTR can bind to the NGF domain of proNGF. However, the resulting trimeric complex may have a lower affinity for its receptor and, as a result, is greatly reduced in its ability to stimulate apoptosis via the mechanism described above. Skeldal et al. al(J. Biol. Chem. 2012 Dec 21; 287(52): 43798-809) 15 Sortilin is a demonstrated that the apoptotic function of the trimeric complex is abolished when the Sortilin antagonist does not have the p75NTR domain. The term "Sortilin antagonist" also includes substances or agents that interfere with, block, or otherwise attenuate the effect of the Sortilin protein interacting with p75NTR. This interaction may be completely prevented, in which case the formation of the trimeric complex is prevented, or this interaction may be only partially prevented, in which case the trimeric complex may form but may have reduced biological efficacy. Skeldal et al. We have shown that sortilin interaction depends on contact points in the extracellular domain of the receptor, and that this interaction is critically dependent on an extracellular juxtamembrane 23 amino acid sequence of p75NTR. Thus, sortilin antagonists may interfere with this 23 amino acid sequence or a proximal sequence in the molecule.

[0016] In a first aspect of the present invention, R 1 , R 2, and R 3 is preferably each independently selected from the group consisting of halo, (C1-C2)alkyl, and halo-(C1-C2)alkyl.

[0017] 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 identical. For example, in exemplary compounds of the invention, R 1 , R 2 , and R 3 may each be F, CH3, or CF3.

[0018] 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 20 (C1-C3)-alkylene-(C3-C4)-heteroaryl, and (C1-C3)-alkylene-(3-10 membered heterocyclic ring). 10 )-aryl, (C1-C3)-alkylene-(C3-C 10 The heteroaryl group of the (C1-C3)-heteroaryl, or the heterocyclic ring of the (C1-C3)-alkylene-(3-8 membered heterocyclic ring) is optionally substituted with one or more substituents independently selected from halo, -OH, (C1-C4)alkyl, halo-(C1-C4)alkyl, (C1-C4)alkoxy, and halo-(C1-C4)alkoxy.

[0019] The alkyl, haloalkyl, alkenyl, haloalkenyl groups, and the alkyl, haloalkyl, alkoxy, and haloalkoxy substituents can be straight or branched.

[0020] The substituents may be attached to any position of the aryl, heteroaryl, or heterocyclic ring. One or more of the substituents may be attached to a carbon atom, a heteroatom, or a combination thereof. There may be no substituents or there may be 1 to 3 substituents. is preferred.

[0021] The heteroaryl or heterocyclic ring may contain one, two, three 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 the case of groups in which more than one heteroatom is present, the heteroatoms may be the same or they may be different.

[0022] The heterocyclic ring may be aliphatic. It may be monocyclic, bicyclic, or tricyclic. Preferably, the heterocyclic ring is monocyclic or bicyclic. Preferably, the heterocyclic ring has 5 to 7 ring members.

[0023] The aryl and heteroaryl groups may also be monocyclic, bicyclic, or tricyclic, preferably monocyclic or bicyclic, and preferably have a ring size of 5 to 9 members.

[0024] In some preferred embodiments, R 4 is selected from the following:

[0025] [ka]

[0026] R 4 The chirality of the carbon in formula (I) bonded to is either (R) or (S). Preferably, when the above groups (i) to (xii) and (ix) to (xx) are included in formula (I), the chirality of this carbon is (S), and in group (xiii), it can be (S) or (R).

[0027] In another preferred embodiment of the present invention, R 5 is selected from the group consisting of H, (C1-C3)-alkyl, and (C1-C3)haloalkyl.

[0028] Preferably, R 5 is selected from the group consisting of H and CH3.

[0029] In another preferred embodiment of the present invention, R 6 is selected from the group consisting of (C1-C4)alkyl, halo-(C1-C4)alkyl, (C3-C8)heteroaryl, and halo-(C3-C8)heteroaryl.

[0030] Most preferably, R 6 is selected from the group consisting of CH3, pyrazine, and morpholine. do.

[0031] Particular compounds of the invention are those listed below. (S)-2-(2-acetamidoacetamido)-5,5-dimethylhexanoic acid; (S)-5,5-Dimethyl-2-(2-(pyrazine-2-carboxamido)acetamido)hexanoic acid; (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid; (2S)-5,5-Dimethyl-2-{2-[(pyrazin-2-yl)formamido]acetamido}hexanoic acid; (2S)-2-[(2S,3S)-2-acetamido-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]hexanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]pentanoic acid; (2S)-2-[(2S)-2-acetamido-3-phenylpropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(4-fluorophenyl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-3-(3,5-difluorophenyl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-imidazol-5-yl)propanamido]-5,5-dimethylhexanoic acid; (S)-5,5-Dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-imidazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-{[(3S)-morpholin-3-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-{[(3R)-morpholin-3-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-{[(2S)-morpholin-2-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-{[(2R)-morpholin-2-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-4-yl)-2-(N-methylacetamido)propanamido]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-5-yl)-2-(N-methylacetamido)propanamido]hexanoic acid; (2S)-5,5-Dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-4-yl)-2-(2-oxopyrrolidin-1-yl)propanamido]hexanoic acid; (2S)-2-[(2S)-3-(1,2-dimethyl-1H-imidazol-5-yl)-2-(N-methylacetamido)propanamido-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-3-(1,2-dimethyl-1H-imidazol-4-yl)-2-(N-methylacetamido)propanamido-5,5-dimethylhexanoic acid; (2S)-2-[(2R)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1,3-thiazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(thiophen-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-2-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(morpholin-4-yl)propanamido]-5,5-dimethylhexanoic acid; and (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid.

[0032] The compounds of formula (I) are intended for use in the treatment or prevention of neurodegenerative disorders, inflammatory disorders, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, inherited eye conditions, or hearing loss.

[0033] Preferably, the neurodegenerative disorder is selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and spinal cord injury.

[0034] Preferably, the inflammatory disorder may be selected from inflammatory diseases and neuroinflammation.

[0035] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0036] Preferably, the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0037] Thus, in one embodiment, a compound for use according to the invention may disrupt the interaction between a Sortilin molecule and a proneurotrophin molecule, or may disrupt the interaction between a Sortilin molecule and a p75NTR molecule. The Sortilin molecule may be mature Sortilin.

[0038] 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 a sortilin protein, thereby preventing the sortilin protein from binding to proneurotrophins or p75NTR molecules, preventing the formation of the above-mentioned trimeric complex or resulting in the formation of a trimeric complex with reduced activity or inactive.

[0039] Preferably, the compounds of the invention prevent protein-protein interactions between sortilin molecules and proneurotrophins or p75NTR molecules, and further prevent the formation of the apoptotic trimeric complexes normally formed between sortilin, proneurotrophins and the p75NTR receptor, or result in the formation of low affinity trimeric complexes with reduced or inactive or minimal biological activity.

[0040] Thus, the compound may be a sortilin, a pro-neutrophin, or can bind to the p75NTR molecule. Antagonism may be due to direct blockade of protein-protein interactions, or it may be due to steric hindrance when binding to a site other than the binding site of one of these proteins.

[0041] 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 pharma- ceutically acceptable carriers, excipients and / or diluents.

[0042] 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.

[0043] 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 disorder, an inflammatory disorder, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition, or hearing loss.

[0044] Preferably, the neurodegenerative disorder is selected from frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and spinal cord injury.

[0045] Preferably, the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

[0046] Preferably, the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, glioblastoma, and colorectal cancer.

[0047] Preferably, the cardiovascular disease is selected from atherosclerotic disease, cardiomyopathy, heart attack, arrhythmia, and coronary artery disease.

[0048] According to a fifth aspect of the invention there is provided the use of a compound according to the first aspect of the invention for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder, an inflammatory disorder, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition, or hearing loss.

[0049] According to a sixth aspect of the 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.

[0050] The compounds of the present invention may include isotopically labeled and / or isotopically enriched forms of the 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 may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine; 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Cl, etc.

[0051] The compounds of the present invention may be used as such or, where appropriate, as their pharma- ceutically acceptable salts (acid or base addition salts). The pharma-ceutically acceptable addition salts mentioned below are intended to include the therapeutically active, non-toxic acid and base addition salt forms that the compounds are capable of forming. Compounds having basic properties can be converted to their pharma-ceutically 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, phosphoric acid, and 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 other organic acids. Compounds having an acidic property can be converted to their pharma-ceutically acceptable base addition salts by treating the acid form with an appropriate base. Exemplary base addition salt forms are sodium salts, potassium salts, calcium salts, and salts with pharma-ceutically acceptable amines, such as ammonia, alkylamines, benzathine, and amino acids, such as arginine and lysine. The term addition salt, as used herein, also includes solvates that the compounds and their salts can form, such as hydrates, alcoholates, and the like.

[0052] Throughout this disclosure, any chemical formula or chemical name is intended to include all its pharma-ceutically acceptable salts, solvates, hydrates, N-oxides, and / or prodrug forms. It is understood that the compounds of the present invention include any hydrates and / or solvates of the compound formula. It is understood that certain functional groups, such as hydroxyl groups, amino groups, etc., form complexes and / or coordination compounds with water and / or various solvents in the various physical forms of the compound. Therefore, it is understood that the above formula includes and represents various hydrates and / or solvates.

[0053] The compounds of the present invention also include tautomers. Tautomers arise by the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomers include prototropic tautomers, which are protonated isomeric states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of 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 can be in equilibrium or sterically fixed in one form by appropriate substitution.

[0054] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, can also exist in the compounds described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0055] In the case of compounds containing one asymmetric carbon atom, the present invention relates to the D-form, the L-form and D,L mixtures, and also to the diastereomeric forms, if two or more asymmetric carbon atoms are present. Compounds of the present invention which contain asymmetric carbon atoms and are obtained in principle as racemates can be separated into optically active isomers in known manner, for example by using optically active acids. However, it is also possible to use optically active starting materials from the beginning, to obtain the corresponding optically active or diastereomeric compounds as final products.

[0056] The term "prodrug" refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent compound of the invention. Prodrug compounds usually offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Silverman, RB, The Organic Chemistry, 1999, 143:131-132). (See, for example, The Mysteries of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), pages 498-549.) A prodrug of a compound of the present invention is a compound of the present invention. Prodrugs can be prepared by modifying functional groups such as hydroxy, amino or mercapto groups in a way that the modifications are cleaved, either routinely or in vivo, to the parent compounds of the invention. Examples of prodrugs include, but are not limited to, acetate, formate and succinate derivatives of hydroxy functional groups or phenylcarbamate derivatives of amino functional groups.

[0057] As used herein, the term "treatment" can include prevention of the described disorder or condition, or amelioration or elimination of the disorder once it has developed. The term "prevention" refers to the prevention of the described disorder or condition.

[0058] The methods provided herein include methods where a subject is identified as being in need of a particular described treatment. Identifying 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 a test or diagnostic method).

[0059] In other aspects, the methods herein include methods further comprising monitoring the subject's response to administration of the treatment. Such monitoring may include periodic imaging or sampling of the subject's tissues, bodily fluids, specimens, cells, proteins, chemical markers, genetic material, etc. as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as in need of such treatment by assessment for relevant markers or indicators of suitability of such treatment.

[0060] The present invention provides a method for monitoring the progress of a treatment. The method includes determining the level of a diagnostic marker (e.g., any target or cell type as described herein modified by a compound as described herein) or diagnostic measurement (e.g., screening, assay) in a subject suffering from or susceptible to a disorder or a symptom thereof as described herein, the subject being administered a therapeutic amount of a compound as described herein sufficient to treat the disease or a symptom thereof. The level of the Marker determined in this manner can be compared to known levels of the Marker, either in healthy normal controls or in other affected patients, to establish the disease status of the subject. In a preferred embodiment, 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, a pre-treatment level of the Marker in the subject is determined before starting a treatment according to the present invention, and this pre-treatment level of the Marker can then be compared to the level of the Marker in the subject after the start of treatment to determine the effectiveness of the treatment.

[0061] The level of the Marker or the activity of the Marker in the subject may be determined at least once. Comparing the level of the Marker with other measurements of the Marker level, e.g., obtained earlier or later from the same patient, another patient, or a normal subject, may be useful in determining whether the treatment according to the invention has had the desired effect, thereby allowing for adjusting dosage levels accordingly. The determination of the level of the Marker 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 of skill in the art. The determination of the protein level 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. Examples of methods include real-time PCR.

[0062] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It is understood that the compounds of the present invention may be administered together with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein may be administered by any suitable route, preferably by oral, rectal, nasal, topical (including ocular, 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 forms, such as tablets and sustained release capsules, and liposomes, and may be prepared by any method known in the art of pharmacy. Pharmaceutical formulations are usually prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. Such formulations may also contain other pharmacologically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, and the like. Usually, the amount of active compound is 0.1-95% by weight of the preparation, preferably 0.2-20% by weight in preparations for parenteral use, and more preferably 1-50% by weight in preparations for oral administration. The preparations may further be prepared by known methods such as granulation, compression, microencapsulation, spray coating, and the like. The preparations may be prepared by conventional methods into the dosage forms of tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable medium. Tablets and granules may be coated by conventional methods. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds disclosed herein can be incorporated into sustained release formulations.

[0063] The dosage level and frequency of administration of a particular compound will vary depending on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, the age, weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the condition being treated, and the treatments the patient is undergoing. Daily dosages may range, for example, from about 0.001 mg to about 100 mg per kg of body weight, administered in single or multiple doses, for example, at doses of about 0.01 mg to about 25 mg each. Typically, such dosages are given orally, although parenteral administration may be selected.

[0064] definition "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes examples of when the event or circumstance occurs as well as examples of when the event or circumstance does not occur.

[0065] The term "heteroatom" means O, N, or S.

[0066] "(C1~C n The term "(C1-C)alkyl" refers to a linear, branched, or cyclic or partially cyclic alkyl group having 1 to n carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 n For a "(C1-C) alkyl" group to contain a cyclic moiety, it must be formed from at least three carbon atoms. n For the portion of the range "(C1-C6)alkyl," all subgroups thereof are contemplated. For example, the range (C1-C6)alkyl includes (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, All subgroups of (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.

[0067] "Hello-(C1~C n The term "alkyl" refers to any of the above C1-C alkyl groups substituted with at least one halogen atom. n alkyl; the halogen atoms are preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0068] When a term denotes a range, for example "1 to 6 carbon atoms" in the definition of (C1-C6)alkyl, each integer, i.e., 1, 2, 3, 4, 5, and 6, is considered to be disclosed.

[0069] "(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. Alkenyl groups can include rings formed from 3 to 6 carbon atoms. n For portions of the range of "(C2-C4)alkenyl," all subgroups thereof are contemplated. For example, the range of "(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, and the like.

[0070] The term "(C1-C4)alkoxy" refers to -O-((C1-C4)alkyl), where the (C1-C4)alkyl group is as defined above and is attached to the remainder of the compound via an oxygen atom. Examples of "(C1-C4)alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy.

[0071] The term "halo-(C1-C4)alkoxy" refers to the above-mentioned (C1-C4)alkoxy substituted with a halogen atom, the halogen atom being preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0072] The term "halo" refers to halogen atoms, preferably F, Cl, Br, and I, more preferably F and Cl, and most preferably F.

[0073] The term "3- to 10-membered heterocyclic ring" refers to a non-aromatic ring system having 3 to 10 ring atoms, with at least one ring atom being a heteroatom.

[0074] By "effective amount" is meant an amount of a compound of the invention that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0075] As used herein, the term "administration" or "administering" refers to the route of administration of the compounds 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 a variety of factors, including the components of the pharmaceutical composition comprising the compounds disclosed herein, the potential or actual disease site, and the severity of the disease.

[0076] The terms "subject" and "patient" are used interchangeably herein. They refer to a human or another mammal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that may be afflicted with or susceptible to a disease or disorder, but may or may not have the disease or disorder. Preferably, the subject is a human.

[0077] The compounds of the invention may be disclosed by name or by chemical structure. If there is a discrepancy between the name of a compound and its associated chemical structure, the chemical structure shall take precedence.

[0078] The present invention will now be further described by the following non-limiting examples. The following specific examples are merely illustrative, and should not be construed as limiting the remainder of the disclosure in any way. 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.

[0079] Preparation of the Compounds of the Invention The compounds of the present invention can be prepared according to the following general synthetic schemes by methods known and recognized in the art. Appropriate reaction conditions for the steps of these schemes are known in the art, and appropriate substitution of solvents and co-reagents is within the common general knowledge of one skilled in the art. Similarly, one skilled in the art will recognize that synthetic intermediates may be isolated and / or purified by various known techniques, if necessary or optional, and that in many cases, various intermediates can be used directly in the next synthetic step with little or no purification. Furthermore, one skilled in the art will also recognize that in some circumstances, the order in which moieties are introduced is not critical. As one skilled in the art will appreciate, the specific order of steps required to prepare a compound of formula (I) will vary depending on the particular compound being synthesized, the starting compound, and the relative propensity of the moieties to be substituted. Unless otherwise specified, all substituents are as previously defined, and all reagents are known and recognized in the art.

[0080] Compounds of general formula (I) may be prepared by a variety of procedures, some of which are described below: One method that is particularly suitable for the preparation of small to medium sized peptides is solid phase peptide synthesis (SPPS), as known and appreciated by those skilled in the art.

[0081] Suitable starting materials and protected amino acids of general formula AA-1, AA-2, Int-1, Int-2, or Int-3 may be commercially available or prepared by various methods. For example, as shown in Scheme 1, the carboxylic acid function of an appropriately substituted amino acid of general formula AA-1 may be chemoselectively protected as a suitable derivative, for example 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 of Int-1, for example as an amide or carbamate, such as Fmoc, gives an intermediate of general structure Int-2. Intermediates of general formula Int-3 may be obtained by selective deprotection of the masked acid function present in Int-2, for example using acidic hydrolysis. When using SPPS, Int-3 can be coupled to an appropriately functionalized resin, such as 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.

[0082] General synthesis procedure 1

[0083] [ka]

[0084] If required, the resin-bound intermediates Int-4 to Int-7 can be analyzed after cleavage from the resin. Alternatively, the corresponding steps on the solid support can be performed without analysis. The protecting group of the amine of Int-4 can be removed by treatment with a base such as piperidine, for example when the Fmoc protecting group is used, to give Int-5. The free acid function present on the second N-protected amino acid, represented herein by a compound of general formula AA-2, can be coupled to the free amine present on the intermediate of general formula Int-5 using traditional amide coupling procedures, for example a mixture of HATU and a base such as N-methylmorpholine in a suitable solvent system such as a DCM-DMF mixture, to give Int-6. Advantageously, the N-protecting groups of AA-2 and Int-6 can be converted to the desired substituted R 6 Cleavage of the ester bond between the solid support and a compound of the general structure depicted in Int-6 by acidic hydrolysis, for example with a reagent such as trifluoroacetic acid, provides the desired compound of general formula (I).

[0085] Alternatively, AA-2 can be introduced into Int-6 with a suitable protecting group on the amine moiety, which can be removed in a subsequent step, for example by using a base such as piperidine when the Fmoc protecting group is used, to obtain Int-7. The free base amine functionality present in Int-7 can be easily functionalized as an acyl derivative using traditional amide coupling procedures, for example a mixture of HATU and a base such as N-methylmorpholine in a suitable solvent system such as a DCM-DMF mixture, to obtain intermediates of general formula Int-8. The final compounds of general formula (I) can be obtained by cleaving the ester bond between the resin solid support and the compound of the general structure shown in Int-8, for example by using acidic hydrolysis with a reagent such as trifluoroacetic acid.

[0086] Compounds of general formula (I) may also be obtained as shown in general scheme 2 below. Those skilled in the art will appreciate that the amine function of a compound of general formula Int-1 may be coupled with a free carboxylic acid function present in a compound of general formula AA-2, as described above and by way of example, using a mixture of coupling reagents such as HATU and N-methylmorpholine and a base in a suitable solvent system such as DCM, DMF or a mixture thereof, to obtain an intermediate of general formula Int-9. Subsequently, chemoselective cleavage of the ester type protecting group present in a compound of general formula Int-9 is carried out by basic hydrolysis in an aqueous medium, such as LiOH in a mixture of water and acetonitrile, to obtain the intermediate of the desired general formula A compound of formula (I) can be obtained.

[0087] General synthesis procedure 2

[0088] [ka]

[0089] The products of each step may be subsequently recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.

[0090] Resin-bound intermediates were analyzed after cleavage from the resin. All analyses of intermediates were of the free acid.

[0091] Those skilled in the art will also understand that not all of the substituents of the compounds of formula (I) will tolerate certain reaction conditions used in the synthesis of the compounds. As known to those skilled in the art, these moieties may be introduced at any convenient point in the synthesis or may be protected and subsequently deprotected as necessary or optional. Those skilled in the art will understand that the protecting groups may be removed at any convenient point during the synthesis of the compounds of the invention. Methods for introducing or removing the protecting groups used in the present invention are known to those skilled in the art and are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons, New York (2006) 16 Please refer to. EXAMPLES

[0092] Abbreviation approx: approximately; aq: aqueous; br: broad; ca.: approximately; CDI: 1,1'-carbonyldiimidazole; d: doublet; DCM: dichloromethane; DIC: N,N'-diisopropylcarbodiimide; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMF: dimethylformamide; eq.: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Fmoc: fluorenylmethoxycarbonyl; Boc: tert-butoxycarbonyl; h: 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

[0093] Other abbreviations are intended to indicate their generally accepted meaning.

[0094] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to the literature. Unless otherwise noted, reaction mixtures were stirred magnetically and reactions were carried out at room temperature (approximately 20° C.).

[0095] Column chromatography was carried out using prepacked silica (40 μm) cartridges on an automated flash chromatography system such as the CombiFlash® Rf system unless otherwise noted.

[0096] 1 H NMR spectra were obtained using a Bruker 5mm 400 or 500 MHz spectrometer. Recorded on a Bruker Avance AV-I-400 instrument equipped with a SmartProbe™, a Bruker Avance AV-II-400 instrument, or a Bruker Avance III-500HD spectrometer. Chemical shifts are expressed in parts per million (ppm) relative to the central peak of the residual protic solvent as reference or to tetramethylsilane as an internal standard. Spectra were recorded at 298 K unless otherwise noted. For NMR signal multiplicities, the following abbreviations or combinations thereof are used: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet, and t = triplet.

[0097] Analysis method 1~3: Analytical UPLC-MS experiments were performed to identify retention times and associated mass ions using a Waters ACQUITY UPLC H-Class system equipped with an ACQUITY PDA Detector and an ACQUITY QDa Mass Detector, running one of the analytical methods described below.

[0098] To identify retention times and associated mass ions, analytical LC-MS experiments were performed using an Agilent 1200 series HPLC system coupled with an Agilent 1956, 6100, or 6120 series single quadrupole mass spectrometer, running one of the analytical methods described below.

[0099] Preparative HPLC purification was performed using a Waters X-Select CSH C18, 5 μm, 19×50 mm column with a gradient of acetonitrile and water, both modified with 0.1% v / v formic acid, or on a Waters X-Bridge BEH C18, 5 μm, 19×50 mm column with a gradient of acetonitrile and 10 mM ammonium bicarbonate (aqueous). Fractions were collected after detection by UV at a single wavelength measured by a variable wavelength detector.

[0100] Method 1: Acid 3-minute method Column: Waters ACQUITY UPLC CSH C18, 1.7 μm, 2.1 × 30 mm, 40 °C Detection: UV, 254 nm unless otherwise noted, MS by electrospray ionization. Eluent A: 0.1% by volume formic acid in water, Eluent B: 0.1% by volume formic acid in acetonitrile gradient:

[0101] [Table 1]

[0102] Method 2: Basic 3-minute method Column: Waters ACQUITY UPLC BEH C18, 1.7 μm, 2.1 × 30 mm, 40 °C Eluent A: 10 mM ammonium bicarbonate (aqueous solution), Eluent B: acetonitrile (Other parameters are the same as Method 1)

[0103] Method 3: Basic 4-minute method Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6 × 30 mm, 40 °C Detection: UV, 254 nm unless otherwise noted, MS by electrospray ionization. Eluent A: 10 mM ammonium bicarbonate (aqueous solution), Eluent B: MeCN

[0104] [Table 2]

[0105] Analysis methods 4~8: Method 4: LCMS_SC_BASE Instrumentation: Agilent 1260 Binary Pump: G1312B, Degasser; Autosampler, ColCom, DAD: Agilent G1315C, 210, 220, and 220-320 nm, PDA 210-320 nm, MSD: Agilent LC / MSD G6130B ESI, Positive / Negative 100-1000; Column: Waters XSelect™ CSH C18, 30×2.1 mm, 3.5 μm, Temperature: 25° C., Flow rate: 1 mL / min, Gradient: t0=5% B, t1.6 min=98% B, t3 min=98% B, Post time: 1.4 min Eluent A: 10 mM ammonium bicarbonate aqueous solution (pH = 9.0), Eluent B: acetonitrile Nitrile

[0106] Method 5: SC_ACID Instrument: Agilent 1260 binary pump, degasser; autosampler, ColCom, DAD: Agilent G1315D, 210, 220, and 220-320 nm, PDA: 210-320 nm, MSD: Agilent LC / MSD G6130B ESI, positive / negative 100-1000, ELSD Alltech 3300 gas flow 1.5 ml / min, gas temperature: 40°C Column: Waters XSelect™ C18, 30×2.1 mm, 3.5 μm, Temperature: 40° C. Flow rate: 1 mL / min, gradient: t0 = 5% B, t1.6 min = 98% B, t3 min = 98% B, post time: 1.3 min Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile

[0107] Method 6: UPLC_AN_BASE Equipment: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN, SO: UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: Gas pressure 40 psi, Drift tube temperature: 50°C Column: Waters XSelect CSH C18, 50×2.1 mm, 2.5 μm, temperature: 25° C., flow rate: 0.6 mL / min, gradient: t0=5% B, t2.0 min=98% B, t2.7 min = 98%B, post time: 0.3 min Eluent A: 10 mM ammonium bicarbonate aqueous solution (pH = 9.5), Eluent B: acetonitrile

[0108] Method 7: UPLC_AN_ACID Equipment: Waters IClass; Binary pump: UPIBSM, SM: UPISMFTN, SO: UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: Gas pressure 40 psi, Drift tube temperature: 50°C Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, temperature: 40 °C, flow rate: 0.6 mL / min, gradient: t0 = 5% B, t2.0 min = 98% B, t2.7 min = 98% B, post time: 0.3 min Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile

[0109] Method 8: PREP_ACID-AS4A Instrument: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100 x 30 mm, 10 μ); Flow rate: 55 ml / min Column temperature: room temperature Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile Linear gradient: t=0 min 20% B, t=2 min 20% B, t=8.5 min 60% B, t=10 min 100% B, t=13 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI positive / negative) Mass range: 100-1000; Fractions collected based on MS and DAD

[0110] Example 1 (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid

[0111] [ka]

[0112] Synthesis of methyl (S)-2-amino-5,5-dimethylhexanoate hydrochloride (2) Thionyl chloride (2.75 mL, 37.7 mmol) was added dropwise to a mixture of 5,5-dimethyl-L-norleucine (AA-1, 2.0 g, 12.6 mmol) in methanol (10 mL). The mixture was stirred at 50° C. for 1 h. The solvent was evaporated under vacuum to give methyl (S)-2-amino-5,5-dimethylhexanoate hydrochloride (2; 2.59 g, 12.4 mmol, 98% yield) as a slightly yellow solid. LCMS (Method 8, 0.987 min; M+H=174.2; calculated 174.2).

[0113] Synthesis of (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid (Example 1) HATU (110 mg, 0.289 mmol) was added to a mixture of acetylglycine 3 (33.8 mg, 0.289 mmol) and triethylamine (0.121 ml, 0.866 mmol) in dichloromethane (1 ml). The mixture was stirred for 30 min. The intermediate methyl (S)-2-amino-5,5-dimethylhexanoate hydrochloride (2, 50 mg, 0.238 mmol) was added and the mixture was stirred overnight. The mixture was concentrated in vacuum. The residue was dissolved in water (1 ml) and acetonitrile (1 ml). Lithium hydroxide (69.1 mg, 2.89 mmol) was added. The mixture was stirred overnight at 40° C. Concentrated in vacuum and purified by preparative HPLC (Method 8). The product-containing fractions were combined and lyophilized to give the title compound, Example 1 (27.6 mg, 0.107 mmol, 37% yield, 98.5% purity). LCMS (Method 6, 0.953 min; M+H=259.1; calculated 259.1). 1 H-NMR(400MHz,DMSO)δ12.68(br,1H),8.12-8.01(m,2H),4.14(td,J=8.1,5.0Hz,1H),3 .73-3.69(m,2H),1.84(s,3H),1.66(m,1H),1.56(m,1H),1.26-1.10(m,2H),0.85(s,9H)

[0114] Example 2 (2S)-5,5-Dimethyl-2-{2-[(pyrazin-2-yl)formamido]acetamido}hexanoic acid

[0115] [ka]

[0116] Synthesis of (pyrazine-2-carbonyl)glycine (5) CDI (324 mg, 2.000 mmol) was added to a suspension of pyrazine-2-carboxylic acid (4, 248 mg, 2 mmol) in tetrahydrofuran (dry) (3 ml). The mixture was heated at 60° C. for 1 h, cooled to room temperature, and triethylamine (300 μL, 2.152 mmol) and glycine (AA-2, 150 mg, 2 mmol) were added. The mixture was concentrated, and water (10 mL) and EtOAc (25 mL) were added. The layers were separated, washed with brine (10 mL), and the organic layer was dried over Na2SO4 and concentrated to give a white solid (402 mg). The crude product was purified by column chromatography (12 g SiO2; 10% methanol (7 M NH3) in DCM) to give (pyrazine-2-carbonyl)glycine (5, 82 mg, 0.453 mmol, 22% yield). LCMS (Method 4, 0.162 min; M+H=182.0; calculated value 182.1)

[0117] Synthesis of (2S)-5,5-dimethyl-2-{2-[(pyrazin-2-yl)formamido]acetamido}hexanoic acid (Example 2) HATU (110 mg, 0.289 mmol) was added to a solution of (pyrazine-2-carbonyl)glycine (5, 52.3 mg, 0.289 mmol) and TEA (0.121 ml, 0.866 mmol) in dichloromethane (2 ml). The mixture was stirred for 30 min. The intermediate methyl (S)-2-amino-5,5-dimethylhexanoate hydrochloride (2, 50 mg, 0.238 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo and lithium hydroxide (69.1 mg, 2.89 mmol), acetonitrile (1 mL) and water (2 mL) were added. The mixture was stirred overnight at 40° C. The mixture was concentrated in vacuo and purified by preparative HPLC (Method 8). The fractions were combined and lyophilized to give the title compound (2S)-5,5-dimethyl-2-{2-[(pyrazin-2-yl)formamide]acetamido}hexanoic acid (Example 2, 12.4 mg, 0.038 mmol, 16% yield, 99.1% purity). LCMS (Method 6, 0.729 min; M+H=323.2; calculated 323.2). 1 H-NMR(400MHz,DMSO)δ9.19(d,J=1.6Hz,1H),9.01(t,J=5.9Hz,1H),8.90(d,J=2.5Hz,1H),8.82-8.71(m,1H),7.98(d,J=7.5Hz,1H), 7.68(br,1H),4.03(td,J=7.4,5.1Hz,1H),3.96(d,J=5.9Hz,2H),1.66(m,1H),1.54(m,1H),1.14(dd,J=9.8,7.4Hz,2H),0.82(s,9H)

[0118] Example 3 (2S)-2-[(2S)-2-acetamido-3-phenylpropanamido]-5,5-dimethylhexanoic acid

[0119] [ka]

[0120] Synthesis of acetyl-L-phenylalanine (6) Aqueous sodium hydroxide (1M) (1.5 ml, 1.5 mmol) was added dropwise to a stirred solution of L-phenylalanine (AA-2, 248 mg, 1.5 mmol) in water (3 ml) until the pH was 12. Acetic anhydride (0.235 ml, 2.490 mmol) was added dropwise. If a precipitate formed, more aqueous sodium hydroxide (1 M) was added to maintain the pH > 8. The mixture was stirred for 3 h. The pH was adjusted to pH 2 with 5 M aqueous hydrochloric acid and the precipitated product was collected by filtration and dried in vacuo to give acetyl-L-phenylalanine (6, 274 mg, 1.322 mmol, 88% yield). LCMS (Method 5, 1.465 min; M+H = 208.1; calculated 208.1).

[0121] Synthesis of (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid (Example 3) HATU (110 mg, 0.289 mmol) was added to a mixture of acetyl-L-phenylalanine (6, 59.8 mg, 0.289 mmol) and triethylamine (0.121 ml, 0.866 mmol) in dichloromethane (1 ml). The mixture was stirred for 30 min. The intermediate methyl (S)-2-amino-5,5-dimethylhexanoate hydrochloride (2, 50 mg, 0.238 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo and lithium hydroxide (69.1 mg, 2.89 mmol), acetonitrile (1 ml) and water (1 ml) were added. The mixture was stirred overnight at 40° C. The mixture was concentrated in vacuo and purified by preparative HPLC (Method 8). The fractions were combined and lyophilized to give the title compound (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid (Example 3, 20.7 mg, 0.059 mmol, 24% yield, 95.75% purity). LCMS (Method 7, 1.274 min; M+H=349.2; calculated 349.2). 1H-NMR(400MHz,DMSO)δ12.58(s,1H),8.20(d,J=7.8Hz,1H),8.08(d,J=8.6Hz,1H),7 .27(s,2H),7.26-7.22(m,2H),7.18(m,1H),4.56(ddd,J=10.2,8.4,3.9Hz,1H),4.1 4(td,J=8.1,5.0Hz,1H),3.00(dd,J=13.9,3.9Hz,1H),2.70(dd,J=13.9,10.2Hz,1H ),1.73(s,3H),1.72-1.66(m,1H),1.66-1.51(m,1H),1.30-1.08(m,2H),0.86(s,9H)

[0122] Example 4 (2S)-2-[(2S)-2-acetamido-3-(4-fluorophenyl)propanamido]-5,5-dimethylhexanoic acid

[0123] [ka]

[0124] Example 4 was prepared in a manner similar to Example 3, starting from the corresponding amino acid analogous to AA-3.

[0125] (2S)-2-[(2S)-2-acetamido-3-(4-fluorophenyl)propanamido]-5,5-dimethylhexanoic acid (Example 4, 28.6 mg, 27% yield, 100% purity). LCMS (Method 7, 1.308 min; M+H=367.2; calculated 367.2). 1H-NMR(400MHz,DMSO)δ12.57(s,1H),8.21(d,J=7.7Hz,1H),8.08(d,J=8.7Hz,1H),7. 29(dd,J=8.6,5.7Hz,2H),7.08(t,J=8.9Hz,2H),4.55(ddd,J=10.1,8.5,4.1Hz,1H),4 .14(td,J=8.1,5.0Hz,1H),2.97(dd,J=13.9,4.2Hz,1H),2.68(dd,J=13.9,10.1Hz,1 H),1.74(s,3H),1.72-1.64(m,1H),1.64-1.49(m,1H),1.28-1.11(m,2H),0.86(s,9H)

[0126] Example 5 (2S)-2-[(2S)-3-(3,5-difluorophenyl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid

[0127] [ka]

[0128] Example 5 was prepared in a manner similar to Example 3, starting from the corresponding amino acid analogous to AA-3.

[0129] (2S)-2-[(2S)-3-(3,5-difluorophenyl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid (Example 5, 27.8 mg, 30% yield, 98.13% purity). LCMS (Method 7, 1.308 min; M+H=367.2; calculated 367.2). 1H-NMR(400MHz,DMSO)δ12.64(s,1H),8.22(d,J=7.8Hz,1H),8.10(d,J=8.6Hz,1H), 7.05(tt,J=9.5,2.4Hz,1H),7.01-6.97(m,2H),4.60(td,J=9.8,4.2Hz,1H),4.14( td,J=8.1,4.9Hz,1H),3.00(dd,J=13.9,4.2Hz,1H),2.74(dd,J=13.7,10.0Hz,1H) ,1.75(s,3H),1.74-1.64(m,1H),1.63-1.47(m,1H),1.26-1.12(m,2H),0.86(s,9H)

[0130] Example 6 (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid

[0131] [ka]

[0132] Synthesis of tert-butyl (S)-2-amino-5,5-dimethylhexanoate (11) H2SO4 (0.62 g, 0.33 mL, 2.0 equiv, 6.3 mmol) was added to a stirred suspension of (S)-2-amino-5,5-dimethylhexanoic acid (AA-1, 0.50 g, 1 equiv, 3.1 mmol) and 4A molecular sieves in tert-butyl acetate (10, 8.7 g, 10 mL, 24 equiv, 75 mmol) while maintaining the temperature below 5° C. The reaction was then allowed to reach room temperature and stirred for 20 h.

[0133] The reaction was added dropwise to a vigorously stirred solution of sodium bicarbonate (2.6 g, 10.0 equiv., 31 mmol) in water (20 mL) and the resulting mixture was extracted with EtOAc (2×20 mL), dried (MgSO4), filtered and evaporated in vacuo to give a light brown gum. This gum was azeotroped with toluene to give the title compound (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid (11, 0.54 g, 2.4 mmol, 76%, 95%) as a cream-colored solid. UPLC (CSH C18 column, 130 Å, 1.7 μm, 2.1 mm×30 mm, 3 min method, 0.1% formic acid, 2-100% MeCN / water): m / z 216.4 (M+H). + (ES+);0.86 min. 1 H NMR(500MHz,DMSO-d6)δ7.50(s,2H),3.71(app.t,J=5.8Hz,1H),1.71-1.62(m,2H),1.45(s,9H),1.33-1.24(m,1H),1.16-1.06(m,1H),0.86(s,9H)

[0134] Synthesis of tert-butyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate (13) HOBt (0.34 g, 1.1 equiv, 2.2 mmol) was added to a stirred solution of acetyl-L-tryptophan (12, 0.50 g, 1 equiv, 2.0 mmol) and tert-butyl (S)-2-amino-5,5-dimethylhexanoate (11, 0.46 g, 1.05 equiv, 2.1 mmol) in DMF (5 mL). The reaction was cooled to 0° C. and EDC (0.41 g, 1.05 equiv, 2.1 mmol) and 4-methylmorpholine (0.41 g, 0.45 mL, 2.0 equiv, 4.1 mmol) were added, allowed to reach room temperature, and stirred for 16 h.

[0135] The reaction was quenched with water (20 mL), extracted with EtOAc (2×20 mL), washed with water (2×10 mL) and brine (5 mL), dried (MgSO4), filtered, evaporated in vacuo and purified by chromatography on silica gel (40 g FlashPure column, 0-100% EtOAc / isohexane) to give the title compound tert-butyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate (13, 0.56 g, 1.2 mmol, 62%, 99% pure), 3318-07-1, as a colorless foam. LCMS (XBridge BEH C18, 130 Å, 2.5 μm, 2.1 mm×30 mm, 3 min, 0.1% ammonium hydroxide, 5-100% MeCN / water): 3318-07-1, m / z 444.0(M+H) + (ES+); 2.18 min, purity 99.5% from 210 to 400 nm. 1 H NMR(500MHz,DMSO-d6)δ10.79(d,J=2.4Hz ,1H),8.23(d,J=7.4Hz,1H),8.02(d,J=8.4Hz,1H),7.62(d,J=7.9Hz,1H),7.34-7.29(m,1 H),7.13(d,J=2.0Hz,1H),7.05(ddd,J=8.1,7.0,1.2Hz,1H),6.97(ddd,J=8.0,6.9,1.1Hz ,1H),4.64-4.56(m,1H),4.11-4.03(m,1H),3.10(dd,J=14.7,4.3Hz,1H),2.87(dd,J=14. 7,9.7Hz,1H),1.75(s,3H),1.70-1.52(m,2H),1.40(s,9H),1.21-1.14(m,2H),0.86(s,9H)

[0136] Synthesis of (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid (Example 6) tert-Butyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate 13 (480 mg, 1 equiv, 1.08 mmol) was dissolved in ice / cold 2,2,2-trifluoroacetic acid (50 mL), the ice bath was removed and stirred for 45 min. TFA was evaporated under vacuum at 25° C., azeotroped with toluene (50 mL), then dissolved in DCM (10 mL) and adsorbed onto Celite. The DCM was evaporated under vacuum and the material was purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate) to give the title compound (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid (Example 6, 218 mg, 0.56 mmol, 51%, 99%) as a white solid. UPLC (CSH C18 column, 130 Å, 1.7 μm, 2.1 mm×30 mm, 3 min method, 0.1% formic acid, 2-100% MeCN / water) m / z 388.9 (M+H)+(ES+); 1.27 min, 100% purity 210-400 nm. LCMS (XBridge BEH C18, 130 Å, 2.5 μm, 2.1 mm × 30 mm, 3 min method, 0.1% ammonium hydroxide, 5-100% MeCN / water): 3318-14-1, m / z 388.0 (M+H) + (ES+); 1.05 min, 99% purity at 260 nm ± 80 nm. 1H NMR(500MHz,DMSO-d6)δ10.78(s,1H),8.10(d,J=8.3Hz,1H),7.86(d,J=7.2Hz,1H),7.58(d,J=7.9Hz,1H), 7.31(dt,J=8.1,1.0Hz,1H),7.12(d,J=2.2Hz,1H),7.05(ddd,J=8.1,6.9,1.2Hz,1H),6.97(ddd,J=8.0,7.0 , 1.1Hz, 1H), 4.54-4.46(m, 1H), 4.01-3.93(m, 1H), 3.12(dd, J=14.8, 4.3Hz, 1H), 2.86(dd, J=14.8, 9.6Hz, 1H), 1.76(s, 3H), 1.74-1.65(m, 1H), 1.61-1.50(m, 1H), 1.19-1.11(m, 2H), 0.83(s, 9H), no CO2H protons observed.

[0137] Example 7 (S)-5,5-Dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid

[0138] [ka]

[0139] Synthesis of (pyrazine-2-carbonyl)-L-phenylalanine (7) CDI (324 mg, 2.000 mmol) was added to a suspension of pyrazine-2-carboxylic acid (4, 248 mg, 2 mmol) in tetrahydrofuran (dry) (3 ml). The mixture was heated at 60° C. for 1 h, cooled to room temperature, TEA (300 μL, 2.152 mmol) and L-phenylalanine (330 mg, 2 mmol) were added, and the mixture was stirred for 2 h. The solvent was evaporated, water and ethyl acetate were added, separated and extracted twice more with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuo to give (pyrazine-2-carbonyl)-L-phenylalanine (7, 80 mg, 0.295 mmol, 14.75% yield). ) was obtained. LCMS (Method 4, 1.379 min; (M+H) += 272.0; calculated value 272.1)

[0140] Synthesis of (S)-5,5-dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid (Example 7) HATU (224 mg, 0.59 mmol) was added to the intermediate (S)-2-amino-5,5-dimethylhexanoic acid (2, 94 mg, 0.59 mmol), intermediate (7, pyrazine-2-carbonyl)-L-phenylalanine (1 mL) in N,N-dimethylformamide (1 mL). To a mixture of 5,5-dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid (Example 7, 14 mg, 0.034 mmol, 5.75% yield) was added 1.60 mg, 0.590 mmol) and diisopropylethylamine (0.206 mL, 1.18 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was purified by preparative HPLC (Method 8). The product-containing fractions were combined and lyophilized to give the title compound (S)-5,5-dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid (Example 7, 14 mg, 0.034 mmol, 5.75% yield). LCMS (Method 6, 0.958 min; M+H=413.2; calculated 413.2). 1 H-NMR(400MHz,DMSO)δ12.77(br,1H),9.12(d,J=1.5Hz,1H),8.88(d,J=2.5Hz,1H), 8.81-8.71(m,1H),8.69(d,J=8.6Hz,1H),8.44(d,J=7.8Hz,1H),7.31-7.10(m,5H), 4.90-4.79(m,1H),4.26-4.10(m,1H),3.17(dd,J=13.9,4.6Hz,1H),3.08(dd,J=13. 8,8.5Hz,1H),1.80-1.66(m,1H),1.66-1.56(m,1H),1.30-1.12(m,2H),0.84(s,9H)

[0141] Example 8 (2S)-5,5,5-trifluoro-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]pentanoic acid

[0142] [ka]

[0143] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (14) (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid 14 was prepared by preparing methyl 5,5,5-trifluoropentanoate according to the procedure set out in US Pat. No. 5,233,636, followed by Fmoc protection and methyl ester hydrolysis as described in US Pat. No. 5,233,636.

[0144] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid [resin-bound to C-terminus] (Resin-15) Wang resin (loading amount: 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 (14, 177 mg, 0.450 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (69.0 mg, 0.45 mmol), diisopropylmethandiimine (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) were added and the mixture was stirred at room temperature for 18 h. 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). DCM (5 mL), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid (14, 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 at room temperature for another 12 h. The 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) to give the resin-bound intermediate Resin-15. No analysis was performed at this stage, and the resin was used directly in the next step.

[0145] Synthesis of (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5,5-trifluoropentanoic acid [resin-bound to C-terminus] (Resin-17) (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoropentanoic acid, resin bound (Resin-15, 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 and 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 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.

[0146] A mixture of DMF / DCM (1:1, 3 mL) was added, followed by (((9H-fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (16, 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 h, then filtered and 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 (16, 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 h, then filtered and washed with DMF (5 mL×3), DCM (5 mL×3), water (5 mL×2), and DMF (5 mL×3) to give the resin-bound intermediate Resin-17. A small amount of the resin was added to 0.5 mL of TFA, and the suspension was left at room temperature for 1 h. The suspension was concentrated in vacuo to give (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5,5-trifluoropentanoic acid (77% purity, Method 1, 1.67 min; M+H=507.4).

[0147] Synthesis of (S)-5,5,5-trifluoro-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]pentanoic acid (Resin-18) (S)-2-((2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5,5-trifluoropentanoic acid, resin bound (Resin-17, 30.0 mg, 0.030 mmol) was swollen in DMF at room temperature for 10 min and filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin and nitrogen gas was passed through the suspension for 20 min. The suspension was filtered, 20% piperidine in DMF (5 mL) was added and nitrogen gas was passed through the suspension for 20 min. The suspension was filtered and washed with DMF (5 mL x 3), DCM (5 mL x 3), water, and DMF (5 mL x 3). The resulting solid was used without further purification. To the resulting resin was added DMF (5 mL), pyrazine-2-carboxylic acid 4 (19 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and 4-methylmorpholine (15 mg, 0.15 mmol). Nitrogen gas was passed through the suspension for 2 h. The suspension was filtered, washed with DMF (5 mL x 3), DCM (5 mL x 3), water (5 mL x 2), and DMF (5 mL x 3), and DMF (10 mL) was added. Pyrazine-2-carboxylic acid (4, 19 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and 4-methylmorpholine (15 mg, 0.15 mmol) were added. Nitrogen gas was passed through the suspension for 15 h. The reaction suspension was filtered and washed with DMF (5 mL x 3), DCM (5 mL x 3), water (5 mL x 2), DMF (5 mL x 2), and DCM (5 mL x 2) to give the resin-bound intermediate Resin-18 (15 mg, 0.030 mmol).

[0148] A mixture of TFA / water (95:5, 1 mL) was added to the resin-bound intermediate Resin-18 (15 mg, 0.030 mmol) and stirred at room temperature for 3 h. The reaction mixture was filtered and the resin was washed with DCM (20 mL x 3). The combined filtrate was concentrated in vacuo and azeotroped with toluene (15 mL x 3). The crude product was purified by preparative HPLC. This afforded the title compound (S)-5,5,5-trifluoro-2-((2S,3S)-3- Methyl-2-(pyrazine-2-carboxamido)pentanamide) pentanoic acid (Example 8, 6.3 mg, 16 μmol, 54% yield) was obtained as a white solid. LCMS purity 100% (Method 2, 0.56 min; MH=389.2), NMR purity 100% [ 1 H NMR(500MHz,DMSO-d6)δ12.84(br s,1H),9.20(s,1H),8.91(d,J=2.5Hz,1H),8.77(t,J=2.1Hz,1H),8.56(d,J=7.7Hz,1H),8.48(d,J=9.0Hz,1H),4.49(dd,J=9.1,6.9Hz,1H), 4.35-4.26(m,1H),2.39-2.21(m,2H),2.01-1.77(m,3H),1.57-1.45(m ,1H),1.17-1.06(m,1H),0.93(d,J=6.8Hz,3H),0.85(t,J=7.4Hz,3H)]

[0149] Example 9 (S)-5,5-Dimethyl-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]hexanoic acid

[0150] [ka]

[0151] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid [resin-bound to C-terminus] (Resin-20) Wang resin (loading amount: 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 (19, 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) and the suspension was gently stirred at room temperature for 16 h. The suspension was filtered and washed with DMF (20 mL x 3), DCM (20 mL x 3), water (20 mL x 2), DMF (20 mL x 2), and DCM (20 mL x 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 (19, 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, 2.00 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 h, then filtered and diluted 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 and DCM (20 mL x 2) to give resin-bound Resin-20. A small amount of the resin was added to TFA (0.05 mL) and the suspension was left at room temperature for 1 h. 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), which was analyzed by LCMS (Method 3, 1.53 min; M+Na=404.1).

[0152] Synthesis of (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5-dimethylhexanoic acid [resin-bound to C-terminus] (Resin-21) (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5-dimethylhexanoic acid, resin bound (Resin-20, 600 mg, 600 μmol) was swollen in DMF (1 mL) for 10 min and filtered. 20% piperidine in DMF (30 mL) was added to the swollen resin and the suspension was agitated with nitrogen gas at room temperature for 20 min. The suspension was filtered and washed with DMF (20 mL x 2), DCM (20 mL x 2), water (20 mL x 2), DCM (20 mL x 2), and DMF (20 mL x 3). The suspension was filtered and 20% piperidine in DMF (30 mL) was added and nitrogen gas was passed through the suspension for 20 min. The suspension was filtered and washed with DMF (20 mL x 3), DCM (20 mL x 3), water (20 mL x 2), and DMF (20 mL x 3). The resulting solid was used without further purification.

[0153] DCM (2.6 mL) and DMF (0.4 mL) were added, followed by (((9H-fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (16, 850 mg, 2.40 mmol), HATU (910 mg, 2.40 mmol), and 4-methylmorpholine (0.26 mL, 2.40 mmol). The reaction was gently stirred at room temperature under nitrogen for 16 hours, then filtered and washed with DMF (20 mL x 2), DCM (20 mL x 2), water (20 mL x 2), DCM (20 mL x 2), and DMF (20 mL x 3). (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-isoleucine (16, 850 mg, 2.40 mmol), HATU (910 mg, 2.40 mmol), and 4-methylmorpholine (0.26 mL, 2.40 mmol) were added. Nitrogen gas was passed through for 15 h. The reaction suspension was filtered and washed with DMF (20 mL x 3), DCM (20 mL x 3), water (20 mL x 2), DMF (20 mL x 2), and DCM (20 mL x 2) to give the resin-bound intermediate Resin-21. A small amount of the resin was added to TFA (0.05 mL) and stirred at room temperature for 30 min. The suspension was filtered, washed with DCM (5 mL) and the combined filtrates were concentrated in vacuo to give (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5-dimethylhexanoic acid (96% purity), which was analyzed by LCMS (Method 2, 1.17 min; M+H=496.56).

[0154] [Table 3]

[0155] Synthesis of (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-(pyrazine-2-carboxamido)pentanamide)hexanoic acid (Example 9) (S)-2-((2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylpentanamide)-5,5-dimethylhexanoic acid, resin bound (Resin-21, 39.0 mg, 0.08 mmol) was swollen in DMF at room temperature for 10 min and filtered. 20% piperidine in DMF (5 mL) was added to the swollen resin and nitrogen gas was passed through the suspension for 20 min. The suspension was filtered, 20% piperidine in DMF (5 mL) was added and nitrogen gas was passed through the suspension for 20 min. The suspension was filtered and washed with DMF (5 mL x 3), DCM (5 mL x 3), water, and DMF (5 mL x 3). The resulting solid was used without further purification. To the resulting resin was added DMF (5 mL), pyrazine-2-carboxylic acid (4, 40.0 mg, 0.32 mmol), HATU (0.12 mg, 0.32 mmol), and 4-methylmorpholine (38.0 μL, 0.32 mmol). Nitrogen gas was passed through the suspension for 2 h. The suspension was filtered, washed with DMF (5 mL x 3), DCM (5 mL x 3), water (5 mL x 2), and DMF (5 mL x 3), and DMF (10 mL) was added. Pyrazine-2-carboxylic acid (4, 40.0 mg, 0.32 mmol), HATU (0.12 mg, 0.32 mmol), and 4-methylmorpholine (38.0 μL, 0.32 mmol) were added. Nitrogen gas was passed through the suspension for 15 h. The reaction suspension was filtered and washed with DMF (5 mL x 3), DCM (5 mL x 3), water (5 mL x 2), DMF (5 mL x 2), and DCM (5 mL x 2) to give the resin-bound intermediate Resin-22 (39 mg, 0.030 mmol).

[0156] A mixture of TFA / water (95:5, 1 mL) was added to the resin-bound intermediate Resin-22 (39.0 mg, 0.08 mmol) and stirred at room temperature for 3 h. The reaction mixture was filtered and the resin was washed with DCM (20 mL x 3). The combined filtrate was concentrated in vacuo and azeotroped with toluene (15 mL x 3). The crude product was purified by preparative HPLC. This afforded the title compound (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-(pyrazine-2-carboxamido)pentanamide)hexanoic acid (Example 9, 13.71 mg, 33 μmol, 41% yield, 90% purity) as a white solid. LCMS purity 100% (Method 1, 1.39 min; M+H=379.3); NMR purity 90% [ 1 H NMR(500MHz,DMSO-d6)δ12.55(br s,1H),9.20(d,J=1.5Hz,1H),8.91(d,J=2.5Hz,1H),8.79-8. 75(m,1H),8.47(d,J=9.3Hz,1H),8.43(d,J=7.6Hz,1H),4.54(dd,J=9.3,7.0Hz,1H),4.14(td,J=8.0,5.0Hz,1H), 1.93-1.85 (m, 1H), 1.70-1.45 (m, 3H), 1.24-1.05 (m, 3H), 0.92 (d, J=6.8Hz, 3H), 0.86-0.80 (m, 12H), 0.5% TBME included]

[0157] Example 10 (S)-2-((S)-2-acetamido-3-(1-methyl-1H-imidazol-5-yl)propanamido)-5,5-dimethylhexanoic acid

[0158] [ka]

[0159] Example 10 was prepared in a manner similar to Example 9.

[0160] (S)-2-((S)-2-acetamido-3-(1-methyl-1H-imidazol-5-yl)propanamido)-5,5-dimethylhexanoic acid (4.4% yield, 97% LCMS purity). LCMS purity 97% (Method 1, 0.57 min; M+H=353.3); NMR purity 90% [ 1 H NMR(500MHz,DMSO-d6)δ12.64(br s,1H),8.33(d,J=8.0Hz,1H),8.10(d,J=8.6Hz,1H),7.54(s,1H),6.67(s,1 H),4.65(dd,J=8.2,6.5Hz,1H),4.11(td,J=8.2,4.9Hz,1H),3.57(s,3H),2 .86(dd,J=15.1,6.5Hz,1H),2.74(dd,J=15.1,7.9Hz,1H),1.81(s,3H),1.6 5-1.55(m,1H),1.52-1.43(m,1H),1.09-1.05(m,2H),0.82(s,9H),4%IPA content]

[0161] Example 11 Synthesis of (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoic acid

[0162] [ka]

[0163] Example 11, the same compound as Example 6, was further prepared in a manner similar to Example 9.

[0164] (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoic acid (yield 3.0%, LCMS purity 100%). LCMS purity 100% (Method 1, 1.18 min; M+H=388.3). NMR purity 98% [ 1H NMR(500MHz,DMSO-d6)δ10.79-10.75(m,1H),8.12(d,J=8.2Hz,1H),7.79(s,1H),7.57(d,J=7.9Hz ,1H),7.31(d,J=8.1Hz,1H),7.13-7.11(m,1H),7.06-7.02(m,1H),6.99-6.94(m,1H),4.50-4.42( m, 1H), 3.92-3.87(m, 1H), 3.13(dd, J=14.7, 4.3Hz, 1H), 2.86(dd, J=14.7, 9.7Hz, 1H), 1.76(s, 3H), 1.74-1.65(m, 1H), 1.59-1.50(m, 1H), 1.16-1.08(m, 2H), 0.83(s, 9H), 2% DCM content, no CO2H peak observed.

[0165] Example 12 Synthesis of (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-((R)-morpholine-2-carboxamido)pentanamide)hexanoic acid

[0166] [ka]

[0167] Example 12 was prepared in a manner similar to Example 9.

[0168] (S)-5,5-Dimethyl-2-((2S,3S)-3-methyl-2-((R)-morpholine-2-carboxamido)pentanamide)hexanoic acid (yield 3%, LCMS purity was Unconfirmed due to weak chromophore. Method 1, 0.67 min, M+H=386.2). NMR purity 97%[ 1H NMR(500MHz,DMSO-d6)δ8.03(br s,1H),7.28(d,J=9.2Hz,1H),4.25-4.18(m,1H),4.03-3.94(m,1H),3.88-3.82(m,2H ),3.56-3.46(m,1H),2.99-2.93(m,1H),2.72-2.58(m,2H),2.48-2.42(m,1H),1.78- 1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.58-1.48 (m, 1H), 1.46-1.38 (m, 1H), 1.18-1.11 (m, 2H), 1.06-0.95 (m, 1H), 0.85-0.82 (m, 11H), 0.82-0.78 (m, 4H), NH and CO2H peaks not observed.

[0169] Example 13 Synthesis of (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-((S)-morpholine-2-carboxamido)pentanamide)hexanoic acid

[0170] [ka]

[0171] Example 13 was prepared in a manner similar to Example 9.

[0172] (S)-5,5-Dimethyl-2-((2S,3S)-3-methyl-2-((S)-morpholine-2-carboxamido)pentanamide)hexanoic acid (20% yield, LCMS purity unconfirmed due to weak chromophore. Method 1, 0.66 min, M+H=386.2). NMR purity 95%[ 1H NMR(500MHz,DMSO-d6)δ9.72-8.66(m,1H),8.09(br s,1H),7.27(d,J=9.2Hz,1H),4.26(dd,J=9.2,6.9Hz,1H),4.04-3.96(m,1H),3.87-3.79(m,2H) ,3.50(td,J=10.9,3.2Hz,1H),3.01(dd,J=12.5,2.8Hz,1H),2.71-2.62(m,2H),2.48-2.41(m,1 H), 1.78-1.70(m,1H), 1.69-1.61(m,1H), 1.58-1.49(m,1H), 1.45-1.36(m,1H), 1.18-1.11(m,2H), 1.05-0.95(m,1H), 0.83(d,J=2.0Hz,9H), 0.83-0.78(m,6H), 3% acetonitrile, no CO2H peak observed.

[0173] Example 14 Synthesis of (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-((R)-morpholine-3-carboxamido)pentanamide)hexanoic acid

[0174] [ka]

[0175] Example 14 was prepared in a manner similar to Example 9.

[0176] (S)-5,5-Dimethyl-2-((2S,3S)-3-methyl-2-((R)-morpholine-2-carboxamido)pentanamide)hexanoic acid (7.2% yield, LCMS purity unconfirmed due to weak chromophore. Method 1, 0.67 min, M+H=386.2). 95% NMR purity 95% [ 1H NMR(500MHz,DMSO-d6)δ9.16-8.74(m,1H),8.12(br s,1H),7.25(d,J=9.2Hz,1H),4.26(dd,J=9.2,6.9Hz,1H),4.04-3.97(m,1H),3.86-3.78(m,2H) ,3.50(td,J=10.9,3.2Hz,1H),3.01(dd,J=12.1,2.8Hz,1H),2.71-2.60(m,2H),2.45(dd,J=12.4 , 10.2Hz,1H), 1.77-1.69(m,1H), 1.69-1.61(m,1H), 1.60-1.49(m,1H), 1.44-1.36(m,1H), 1.18-1.11(m,2H), 1.05-0.95(m,1H), 0.83(s,9H), 0.83-0.79(m,6H), 2% acetonitrile, no CO2H peak observed.

[0177] Example 15 Synthesis of (S)-5,5-dimethyl-2-((2S,3S)-3-methyl-2-((S)-morpholine-3-carboxamido)pentanamide)hexanoic acid

[0178] [ka]

[0179] Example 15 was prepared in a manner similar to Example 9.

[0180] (S)-5,5-Dimethyl-2-((2S,3S)-3-methyl-2-((S)-morpholine-3-carboxamide)pentanamide)hexanoic acid (15% yield, method 1, 0.66 min, M+H=386.2). NMR purity 87% [ 1 H NMR(500MHz,DMSO-d6)δ8.17-8.07(m,1H),7.78(d,J=9.2Hz,1H ),4.27(dd,J=9.2,6.6Hz,1H),4.08-4.01(m,1H),3.70(dd,J=10.9,3.6Hz,1H),3.55(dt, J=11.2,3.7Hz,2H),3.46(dd,J=10.9,7.7Hz,1H),2.91-2.82(m,1H),2.78-2.61(m,3H),1 .79-1.71(m,1H), 1.71-1.61(m,1H), 1.61-1.49(m,1H), 1.49-1.39(m,1H), 1.22-1.11(m,2H), 1.08-0.99(m,1H), 0.85(s,2H), 0.84(s,9H), 0.82(t,J=7.9Hz,4H), no CO2H peak observed.

[0181] Example 16 Synthesis of (S)-2-((2S,3S)-2-acetamido-3-methylpentanamido)-5,5-dimethylhexanoic acid

[0182] [ka]

[0183] Example 16 was prepared in a manner similar to Example 9.

[0184] (S)-2-((2S,3S)-2-acetamido-3-methylpentanamide)-5,5-dimethylhexanoic acid (yield 30%, LCMS purity = 100%, method 3, 1.09 min, M+H = 315.2). NMR purity 98% [ 1 H NMR(500MHz,DMSO-d6)δ12.46(br s,1H),8.06(d,J=7.3Hz,1H),7.85(d,J=9.1Hz,1H),4.23(dd,J=9.0,7.5Hz,1H),4.12-4.03(m,1H),1.84(s,3H),1.74-1.62(m,2 H),1.61-1.50(m,1H),1.47-1.38(m,1H),1.25-1.13(m,2H),1.13-1.02(m,1H),0.85(s,9H),0.83(s,3H),0.80(t,J=7.4Hz,3H)]

[0185] Example 17 (2S)-2-[(2S)-3-(1-tert-butyl-1H-indol-3-yl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid

[0186] [ka]

[0187] tert-Butyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate 13 (480 mg, 1.08 mmol) was dissolved in ice / cold 2,2,2-trifluoroacetic acid (50 mL), the ice bath was removed and stirred for 45 min. The TFA was evaporated under vacuum at 25° C. and azeotroped with toluene (50 mL), subsequently dissolved in DCM (10 mL) and adsorbed onto Celite. The DCM was evaporated under vacuum and the material was purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% MeCN / 10 mM ammonium bicarbonate) to give the title compound (2S)-2-[(2S)-3-(1-tert-butyl-1H-indol-3-yl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid (Example 17, 4 mg, 0.009 mmol, 0.8%) as a light brown solid. LCMS purity 98% (Method 1; 1.61 min; M+H=444.2). 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.15(d,J=7.7Hz,1H),8.03(d,J=8.3Hz,1H),7.65-7. 57(m,2H),7.28(s,1H),7.07(ddd,J=8.4,6.9,1.3Hz,1H),6.99(app.t,J=7.4Hz,1H),4.63-4 .55(m,1H),4.16-4.09(m,1H),3.08(dd,J=14.7,5.1Hz,1H),2.84(dd,J=14.8,8.8Hz,1H),1. 77(s,3H),1.73-1.65(m,1H),1.64(s,9H),1.61-1.49(m,1H),1.24-1.11(m,2H),0.85(s,9H)

[0188] Example 18 (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid

[0189] [ka]

[0190] Synthesis of (2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanoic acid (26) AcO (0.16 mL, 1.6 mmol) was added dropwise to a mixture of 1-methyl-L-tryptophan (0.30 g, 1.4 mmol) and sodium carbonate (0.44 g, 4.1 mmol) in EtOAc (10 mL) and water (10 mL) with vigorous stirring, followed by Stirred for 2 h. The reaction was adjusted to pH 3 with 2M HCl, extracted with EtOAc (20 mL), washed with brine (10 mL), dried (MgSO4), filtered and evaporated in vacuo to give (2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanoic acid (26, 0.31 g, 1.1 mmol, 83%) as an off-white solid. LCMS purity 97% (Method 1; 0.98 min; M+H=261.1). 1 H NMR(500MHz,DMSO-d6)δ12.59(s,1H),8.13(d,J=7.8Hz,1H),7.54(d,J=7.8,Hz,1H),7.37(d,J=8.2Hz,1H),7.13(dd,J=8.1,6.9Hz,1H),7.10(s,1 H),7.02(dd,J=8.0,6.9Hz,1H),4.44(td,J=8.2,5.2Hz,1H),3.72(s,3H),3.13(dd,J=14.6,5.3Hz,1H),2.98(dd,J=14.6,8.5Hz,1H),1.80(s,3H)

[0191] Synthesis of tert-butyl (2S)-2-((2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate (27) HOBt (97 mg, 0.63 mmol) was added to a stirred solution of Nα-acetyl-1-methyl-L-tryptophan (0.15 g, 0.58 mmol) and tert-butyl (2S)-2-amino-5,5-dimethylhexanoate (0.13 g, 0.61 mmol) in DMF (1 mL). The reaction was cooled to 0° C. and EDC (0.12 g, 0.61 mmol) and 4-methylmorpholine (0.13 mL, 1.2 mmol) were added, allowed to reach room temperature, and stirred for 4 h. The reaction was quenched with water (20 mL), extracted with EtOAc (2×20 mL), washed with water (2×10 mL) and brine (5 mL), dried (MgSO4), filtered, evaporated in vacuo and purified by chromatography on silica gel (24 g FlashPure column, 0-100% EtOAc / isohexane) to give tert-butyl (2S)-2-((2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate (27, 0.17 g, 0.36 mmol, 63%) as a colorless gum. LCMS purity 100% (Method 2, 1.83 min; M+H=458.1). 1 H NMR(500MHz,DMSO-d6)δ8.23(d,J=7.4Hz,1H),8.02(d,J=8.3Hz,1H),7.66-7.62(m,1H),7. 37-7.34(m,1H),7.14-7.10(m,1H),7.09(s,1H),7.03-6.99(m,1H),4.58(td,J=8.8,4.6Hz, 1H),4.08(td,J=7.4,5.7Hz,1H),3.72(s,3H),3.09(dd,J=14.6,4.6Hz,1H),2.87(dd,J=14 .7,9.3Hz,1H),1.76(s,3H),1.69-1.52(m,2H),1.40(s,9H),1.21-1.16(m,2H),0.86(s,9H)

[0192] Synthesis of (S)-2-((S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido)-5,5-dimethylhexanoic acid (Example 18) tert-Butyl (2S)-2-((2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido)-5,5-dimethylhexanoate (165 mg, 361 μmol) was dissolved in an ice / cold mixture of formic acid (5 mL) and water (0.5 mL). The ice bath was then removed and the reaction stirred for 20 h. The solvent was evaporated under vacuum, azeotroped with toluene, and treated with ether to give the title compound (2S)-2-((2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido)-5,5-dimethylhexanoic acid (Example 18, 142 mg, 0.35 mmol, 96%) as an off-white solid. 98% purity LCMS (Method 1; 1.39 min; M+H=402.5). 1 H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.17(d,J=7.7Hz,1H),8.02(d,J=8.3Hz,1H), 7.62(d,J=7.9Hz,1H),7.35(d,J=8.2Hz,1H),7.12(t,J=7.6Hz,1H),7.09(s,1H ),7.01(t,J=7.4Hz,1H),4.57(td,J=8.6,4.8Hz,1H),4.16(td,J=8.1,5.3Hz,1 H),3.71(s,3H),3.09(dd,J=14.7,4.8Hz,1H),2.87(dd,J=14.7,9.0Hz,1H),1. 76(s,3H),1.73-1.65(m,1H),1.63-1.53(m,1H),1.26-1.11(m,2H),0.86(s,9H)

[0193] Biological Data 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 the table below. NTS, a 13 amino acid neuropeptide, is a ligand for sortilin. IC50 is a measure of the amount of compound required to inhibit the binding of NTS to sortilin by 50%. One of skill in the art would recognize the IC 50It is recognized that the lower the value, the less compound is needed to achieve the desired effect, thereby reducing the probability of unwanted off-target effects.

[0194] Compound affinity was determined by measuring the displacement of [3H]-neurotensin or [125I]-neurotensin binding to h-sortilin in an SPA format. Total volume of 40 μl in 50 mM HEPES pH 7.4 assay buffer containing 100 mM NaCl, 2.0 mM CaCl2, 0.1% BSA, and 0.1% Tween-20. Compounds were pre-incubated with 150 nM 6his-sortilin for 30 min at room temperature, followed by addition of 5 nM [3H]-neurotensin or [125I]-neurotensin and Ni-chelating imaging beads (Perkin Elmer), and after 6 h, plates were read on a ViewLux with an exposure time of 360 s. Compound dose-response evaluation was performed at eight drug concentrations (covering three orders of magnitude). IC 50 Values ​​were calculated by nonlinear regression with a sigmoidal concentration response (variable slope) using CDD Vault software. All values ​​reported are the average of at least two specific values.

[0195] The data in the table below demonstrate that the compounds disclosed herein are sortilin inhibitors.

[0196] [Table 4]

[0197] X-ray data Materials and Methods Sortilin, the luminal domain of sortilin, was obtained as previously reported (Andersen et al., Acta Cryst. D, 2017). 17 Before crystallization, add 50 mM Tris-HCl 12 μl of 4 mg / ml sSortilin in pH 8.0, 150 mM NaCl was mixed with 1.2 μl of two compounds INS1767 and INS1783 at concentrations of 16.7 mM and 13.2 mM, respectively, dissolved in DMSO.

[0198] Sitting drops were set up by adding 2 μl of the sortilin ligand mixture to 2 μl of reservoir solution composed of 100 mM Hepes pH 7.3, 400 mM malonate pH 7.3, 8% v / v glycerol, 22.5% w / v PEG 3350. Sitting drops were left with 500 μl of reservoir solution and allowed to equilibrate by vapor diffusion.

[0199] The crystals were loaded into litho-loops without further cryoprotection and flash frozen in liquid nitrogen. Cooled.

[0200] Diffraction data were collected at beamline P13 EMBL / DESY, Hamburg, and analyzed using the XDS package (Kabsch, W., Acta Cryst. D, 2010). 18 (Table 1 ).

[0201] Phases for the structure factors were obtained by molecular replacement using the known structure of sortilin (PDB entry 3F6K) as a search model and the program Phaser implemented in the Phenix software package (Afonine et al., Acta Cryst. D, 2012). 1 9 The refined model was constructed using multiple cycles of model building in Coot (Emsley P. et al., Acta Cryst. D, 2010) 20and maximum likelihood refinement using Phenix. An X-ray image of the compound of Example 3 bound to h-Sortilin is shown in Figure 1. Refinement statistics and basis size and model agreement are shown in the table below.

[0202] [Table 5]

[0203] 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 M Etabolic 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 receptor 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. 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. 16. Wuts, PGM and Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons, New York (2006). 17. 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. 18. Kabsch, W, XDS. Acta Crystallographia Section. D (2010) , 66(2), pp. 125-132.19. Afonine, PV et al., Acta Crystallographia Section. D (2012) , 68(4), pp. 352-367. 20. Emsley, P. et al., Acta Crystallographia Section. D (2010) , 66(4), pp. 486-501.

[0204] Sequences referenced throughout this specification and forming part of the description 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

[0205] 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

[0206] 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, During the ceremony, R １ , R ２ , and R ３ are each independently halo, H, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkenyl, and halo-(C ２ ~C ４ ) alkenyl; 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 ２０ ) aryl, halo-(C ３ ~C ２０ ) aryl, (C ３ ~C ８ ) heteroaryl, halo-(C ３ ~C ２０ ) heteroaryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-aryl, (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-heteroaryl, and (C １ ~C ６ )-alkylene-(3- to 10-membered heterocyclic ring); In this case (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-aryl, the aryl group of (C １ ~C ６ )-alkylene-(C ３ ~C ２０ )-heteroaryl, or (C １ ~C ６ The heterocyclic ring of the 3- to 8-membered alkylene-(3- to 8-membered heterocyclic ring) is optionally selected from halo, H, —OH, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, and halo-(C １ ~C ４ ) substituted with one or more substituents independently selected from alkoxy; R ５ is H, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkenyl, and halo-(C １ ~C ４ ) alkenyl; and R ６ (C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkyl, (C ２ ~C ６ ) alkenyl, halo-(C ２ ~C ６ ) alkenyl, (C ３ ~C ２０ ) aryl, halo-(C ３ ~C ２０ ) aryl, (C ３ ~C ２０ ) heteroaryl, and halo-(C ３ ~C ２０ ) heteroaryl; 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 each independently represents 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, wherein the compound is selected from the group consisting of:

3. R １ , R ２ , and R ３ each independently represents 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, selected from:

4. R ４ But, H, (C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkyl, (C ３ ~C １０ ) aryl, (C １ ~C ３ )-alkylene-(C ３ ~C １０ )-aryl, (C １ ~C ３ )-alkylene-(C ３ ~C ２０ )-heteroaryl, and (C １ ~C ３ )-alkylene-(3- to 10-membered heterocyclic ring); In this case (C １ ~C ３ )-alkylene-(C ３ ~C １０ )-aryl, the aryl group of (C １ ~C ３ )-alkylene-(C ３ ~C １０ )-heteroaryl, or (C １ ~C ３ The heterocyclic ring of the -alkylene-(3- to 8-membered heterocyclic ring) is optionally selected from halo, —OH, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, and halo-(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, substituted with one or more substituents independently selected from:

5. R ４ but, 【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 But, H, (C １ ~C ３ )-alkyl, and (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, wherein the compound is selected from the group consisting of: haloalkyl.

7. R ５ H and CH 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 However, (C １ ~C ４ ) alkyl, halo-(C １ ~C ４ ) alkyl, (C ３ ~C ８ ) heteroaryl, and halo-(C ３ ~C ８ ) heteroaryl, or a pharma- ceutically acceptable salt, solvate, hydrate, or tautomer thereof. , optical isomers, N-oxides, and / or prodrugs.

9. R ６ But, CH ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and / or prodrug thereof, selected from the group consisting of: pyrazine, and morpholine.

10. The compound of formula (I) (S)-2-(2-acetamidoacetamido)-5,5-dimethylhexanoic acid; (S)-5,5-Dimethyl-2-(2-(pyrazine-2-carboxamido)acetamido)hexanoic acid; (S)-2-((S)-2-acetamido-3-phenylpropanamido)-5,5-dimethylhexanoic acid; (2S)-5,5-Dimethyl-2-{2-[(pyrazin-2-yl)formamido]acetamido}hexanoic acid; (2S)-2-[(2S,3S)-2-acetamido-3-methylpentanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]hexanoic acid; (2S)-5,5,5-trifluoro-2-[(2S,3S)-3-methyl-2-[(pyrazin-2-yl)formamido]pentanamide]pentanoic acid; (2S)-2-[(2S)-2-acetamido-3-phenylpropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(4-fluorophenyl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-3-(3,5-difluorophenyl)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-imidazol-5-yl)propanamido]-5,5-dimethylhexanoic acid; (S)-5,5-dimethyl-2-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)hexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-imidazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-{[(3S)-morpholin-3-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-{[(3R)-morpholin-3-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-{[(2S)-morpholin-2-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S,3S)-3-methyl-2-{[(2R)-morpholin-2-yl]formamido}pentanamide]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-4-yl)-2-(N-methylacetamido)propanamido]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-5-yl)-2-(N-methylacetamido)propanamido]hexanoic acid; (2S)-5,5-dimethyl-2-[(2S)-3-(1-methyl-1H-imidazol-4-yl)-2-(2-oxopyrrolidin-1-yl)propanamido]hexanoic acid; (2S)-2-[(2S)-3-(1,2-dimethyl-1H-imidazol-5-yl)-2-(N-methylacetamido)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-3-(1,2-dimethyl-1H-imidazol-4-yl)-2-(N-methylacetamido)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2R)-2-acetamido-3-(1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(1,3-thiazol-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamidopropanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(thiophen-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-2-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-3-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(pyridin-4-yl)propanamido]-5,5-dimethylhexanoic acid; (2S)-2-[(2S)-2-acetamido-3-(morpholin-4-yl)propanamido]-5,5-dimethylhexanoic acid; or 2. The compound of claim 1, which is (2S)-2-[(2S)-2-acetamido-3-(1-methyl-1H-indol-3-yl)propanamido]-5,5-dimethylhexanoic 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. The pharmaceutical composition of claim 11 for use in the treatment or prevention of a neurodegenerative disorder, an inflammatory disorder, cancer, pain, diabetes mellitus, diabetic retinopathy, glaucoma, uveitis, cardiovascular disease, an inherited eye condition, or hearing loss.

14. the neurodegenerative disorder 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; 14. The pharmaceutical composition for use according to claim 13, wherein the hearing loss is selected from noise-induced hearing loss, toxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss.

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