JP2016026142A - Neurotrophin mimetics and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide neurotrophin mimetic compounds that specifically bind to p75 neurotrophin receptors (p75) and useful for the prophylaxis and/or treatment of neurodegenerative disease and the like.SOLUTION: The present invention provides compounds represented by morpholine compounds and purine compounds, and pharmaceutical compositions comprising the compounds.SELECTED DRAWING: None

Description

This application is a continuation of US patent application 11 / 396,936 filed Apr. 3, 2006, claiming priority of US patent application 60 / 671,785 filed Apr. 15, 2005. The book is entirely incorporated. This application also claims the priority of US patent application 61 / 158,306 filed on March 6, 2009 and US patent application 61 / 164,282 filed on March 27, 2009, which is hereby incorporated by reference in its entirety. Is captured.
This study was funded by the National Institutes of Health Grant No. N30687. Accordingly, the US Government has certain rights in this invention.
The present invention generally relates to compounds having binding specificity for p75 ^NTR molecules, and such in the treatment of diseases associated with degeneration or dysfunction of cells expressing p75, including, for example, neurodegenerative diseases. It relates to the use of compounds.

  Neurotrophins are polypeptides that play a role in the development, function, and / or survival of certain cells, including neurons, oligodendrocytes, Schwann cells, hair follicle cells, and other cells. Cell death or dysfunction of neurons and other cell types is directly related to many neurodegenerative diseases. Thus, it has been suggested that alterations in neurotrophin localization, neurotrophin expression levels, and / or expression levels of receptors that bind to neurotrophins lead to neurodegeneration. Degeneration occurs particularly in neurodegenerative Alzheimer's disease, Parkinson's disease and ALS. Oligodendrocyte degeneration can occur in central nervous system injury, multiple sclerosis and other pathological conditions.

  Nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 / 5 (NT-4 / 5), neurotrophin 6 (NT-6), and brain-derived neurotrophic factor ( Many neurotrophins including BDNF) have been identified. Neurotrophins are found in both precursor and mature forms known as pre- (pro) trophic factors. The mature form is a protein of about 120 amino acids in length and exists as a non-covalent homodimer of about 25 kDa that is stable in physiological conditions. Each neurotrophin monomer contains three β-hairpin loops that are exposed to solvent, which are referred to as loops 1, 2, and 4, which show a relatively high degree of amino acid conservation throughout the neurotrophin family. ing.

Mature neurotrophins preferentially bind to receptors Trk and p75 ^NTR (also called p75 neurotrophin receptor, low-affinity nerve growth factor receptor or LNGFR), but in the mature form N is removed by proteolysis Pro (precursor) neurotrophins, including terminal regions, interact primarily with the p75 ^NTR and interact with the sorting receptor sortilin through these N-terminal regions (1-3). p75 ^NTR interacts with Trk and alters Trk signaling, but independently of this, pro-survival signals, IRAK / TRAF6 / NF.kappa.B, PI3 / AKT, and pro-apoptotic signals It is linked to several signal transduction systems including NRAGE / JNK (Non-Patent Documents 4 to 6).

  When administered for therapeutic use, neurotrophins have instability due to low serum half-life (short life), possibly low biological oral availability, and limited penetration to the central nervous system. It shows suboptimal pharmacological properties such as sex (Non-Patent Documents 7 to 9). Furthermore, the highly multifaceted effects of neurotrophins made by dual receptor signaling networks increase the chances of adverse effects appearing.

Non-ligand p75 ^NTR is proapoptotic, and homodimerization induced by neurotrophin binding has been suggested to eliminate this effect (Non-Patent Document 10). Is consistent with studies showing that monomeric p75 ^NTR ligands have no effect on survival, including unitary Fab (Non-patent Document 11) and monomeric cyclic peptides (Non-patent Document 12), The bivalent form involved in each study promotes cell survival. However, these monomeric ligands, like the natural ligands, may not bind to the receptor. Active NGF is a homodimer containing two p75 ^NTR binding sites, but according to recent structural evidence, active NGF binds only to one p75 ^NTR molecule and the other p75 ^NTR It is suggested not to perform the coupling | bonding (nonpatent literature 13).

Fahnestock, M., et al. (2001) Mol Cell Neurosci 18, 210-220 Harrington, A. W. et al. (2004) Proc Natl Acad Sci USA 101, 6226-6230 Nykiaer. A. et al., (2004) Nature 427, 843-848 Mamidipudi, V., et al. (2002) J Biol Chem 277, 28010-28018 Roux, P. P., et al. (2001) J Biol Chem 276, 23097-23104 Salehi, A. H., et al. (2000) Neuron 27, 279-288 Podulso, J. F., Curran, G. L. (1996) Brain Res Mol Brain Res 36, 280-286 Saltzman, W. M., et al (1999) Pharm Res 16, 232-240; Partridge W. M. (2002) Adv Exp Med Bio 513, 397-430 Wang, J. J., et al (2000) J Neurosci Res 60, 587-593 Maliartchouk, S., et al (2000) J Biol Chem 275, 9946-9956 Longo, F. M.,. (1997) J Neurosci Res 48, 1-17 He, X. L., (2004) Science 304, 870-875

  Unfortunately, technical and ethical considerations have hampered the development of neurotrophin-based therapeutics. That is, it is technically difficult to produce a sufficient amount of pure neurotrophin using recombinant DNA technology, and further, neurotrophin can be produced using human fetal cells. Ethical derivation issues raised by the use of (generally obtained from miscarried fetuses) had to preclude the use of such methods. Thus, there is a need for the development of small molecule reagents with favorable drug-like characteristics based on neurotrophins that can target specific neurotrophin receptors for use in the treatment of disorders or diseases. However, it has not been dealt with.

又は

の一般的構造（これらの構造の医薬的に許容可能な塩、エステル、溶媒、及びこれらのプロドラッグ（前駆薬剤）を含む）により表され、式中、Ｒ^１、Ｒ^１′、Ｒ^２、Ｒ^２′、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１９、Ｒ^１９′、Ｒ^２０、Ｒ^２０′、Ｒ^２１、Ｒ^２１′、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３２′、Ｒ^３３、Ｒ^３４、Ｒ^３４′、Ｒ^３５、Ｒ^３５′、Ｒ^３６、Ｒ^３６′、Ｅ、Ｖ、Ｗ、Ｘ、Ｙ、Ｚｍ、ｎ、ｐ、ｑ、Ｒ、ｓ、ｔ、は以下のように定義される。 The present application generally discloses compounds that specifically bind to p75 ^NTR , and methods for the formulation and use of such compounds and pharmaceutical compositions comprising the compounds. More particularly, the compounds of the present application are:

Or

Represented by the general structure of R ¹ , R ^{1 ′} , R ² , including pharmaceutically acceptable salts of these structures, esters, solvents, and prodrugs (precursors) thereof, R ^{2 ′} , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ^{22, R 23, R 24,} R 30, R 31, R 32, R 32 ', R 33, R 34, R 34', R 35, R 35 ', R 36, R 36', E, V, W , X, Y, Zm, n, p, q, R, s, t are defined as follows.

(2S, 3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド

(2R, 3R)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド

(2S, 3R)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド

(2R, 3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド
を有する立体異性体を開示する。 In addition, the following structural formula:

(2S, 3S) -2-Amino-3-methyl-N- (2-morpholinoethyl) pentanamide

(2R, 3R) -2-Amino-3-methyl-N- (2-morpholinoethyl) pentanamide

(2S, 3R) -2-Amino-3-methyl-N- (2-morpholinoethyl) pentanamide

Stereoisomers with (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) pentanamide are disclosed.

The disclosure herein is generally a method of treating neurodegeneration or other disorders in a patient, the method comprising administering to the patient an effective amount of a compound having binding specificity for p76 ^NTR .
Further disclosed herein is a method for promoting the survival of a neuronal cell, oligodendrocyte or multiple cell types comprising contacting a cell with a compound having binding specificity for a p75 ^NTR molecule. The present specification further discloses methods of treating disorders associated with p75 expression.
As noted above, one object of the present invention is addressed in whole or in part in the present invention, while the other objects are already described in connection with the accompanying examples and diagrams best described below. It will become clear as the statement progresses.

Ribbon representation of the X-ray crystal structure of human NGF with designated β-turn loops 1, 2 and 4. The average side chain position for loop 1 is depicted. FIG. 6 represents a comparison of loop 1 peptide sequences (SEQ ID NOs: 1-3) from NGF and NT3 from the indicated animal species and identification of pharmacophores. The positively charged substituent is indicated by “+”. “HBD” and “HBA” represent hydrogen bond donor and hydrogen bond acceptor, respectively. The application of pharmacophore characteristics to a 3D loop model is shown. A pair of spheres with relative positions indicating acceptor and donor positions, representing hydrogen bonding properties. One sphere of the pair is centered on the putative acceptor / donor property in the model, while the other sphere shows the target location of the complementary property on all interactable molecules. The diameter of the sphere represents the spatial tolerance to chemical properties compatible with 3D conformer library scanning. As disclosed herein, the application of a novel pharmacophore in library screening, which later proved active, discloses a representative fit of the two identified compounds to the pharmacophore. It is a loop model. Culture medium only (CM) or BDNF or compound (i) (indicated as “LM11A-28” or “28” in the figure), compound (ii) (indicated as “LM11A-7” or “7” in the figure), compound (Iii) (represented as “LM11A-24” or “24” in the figure), compound (iv) (represented as “LM11A-31” or “31” in the figure) or compound (v) (represented as “LM11A-36 in the figure) It is a series of fluorescence micrographs of cultured E16-17 mouse hippocampal nerve cells treated with a medium containing “or“ 36 ”. Forty-eight hours after treatment, cultured cells were stained for expression of the neuron-specific, growth-related protein GAP43. The 2D structure of each compound is shown adjacent to each image. A dose response curve of BDNF, NGF, and compound (i-v) for a range of neuronal viability, showing similar activity and maximal response between NGF and compound (i-iv) up to 5 nM, compound (V) shows no response. BDNF has similar activity but exhibits a higher maximum response. Each compound (i-v) shows a decreasing response at 5 nM or more. Viability was measured as the total number of cells in each well that were morphologically intact and filled with blue formazan MTT conversion product (Longo, FM, Manthorpe, M., Xie, YM, and Varon, S. (1997) J Neurosci Res 48, 1-17). Counts were normalized to viability or baseline obtained with 25 ng / ml BDNF. n is 4-18 for all measurements. Symbols and bars indicate mean +/− s.e.m, and the curve fits a monoexponential increasing model for the data. The dotted curve in each graph represents the fitted NGF response. FIG. 5 is a series of NGF / p75 ^NTR- Fc binding curves in the presence of increasing concentrations of compound (iv) detected by NGF ELISA. Symbol is mean +/− sem. N > 10 for all measurements. The R ² value for compound (iv) is 0.93 and the curve represents a fit to the modified Gaddum / Schild equation. Also, P <0.0001 by ANOVA with post hoc Bonferroni / Dunn test for comparison between the binding curve for 0 nM compound and the binding curve for > 500 nM compound (iv). Compound absence, K _D to NGF is 0.8 to 0.9 nM, previous reports about 1 nM (Nykjaer, A. et al ., (2004) Nature 427, 843-848) and do not conflict. The label symbols “●”, “▽”, “■”, “◇”, “▲”, and “○” indicate the compound (iv) concentration, 0, 125, 500, 1500, 4500, and 10,000 nanomolar concentrations ( nM). FIG. 4 is a series of NGF / p75 ^NTR- Fc binding curves in the presence of increasing concentrations of compound (iii) detected by NGF ELISA. Symbol is mean +/− sem. N > 10 for all measurements. The R ² value for compound (iii) is 0.96 and the curve represents a fit to the modified Gaddum / Schil equation. Also, P <0.0001 by ANOVA with post hoc Bonferroni / Dunn test for comparison between the binding curve in 0 nM compound and the binding curve in > 125 nM compound (iii). Compound absence, K _D to NGF is 0.8 to 0.9 nM, previous reports about 1 nM (Nykjaer, A. et al ., (2004) Nature 427, 843-848) and do not conflict. The label symbols “●”, “▽”, “■”, “◇”, “▲”, and “○” indicate the compound (iii) concentration, 0, 125, 500, 1500, 4500 and 10,000 nanomolar concentrations ( nM). A series of NGF / TrkA-Fc binding curves in the presence of increasing concentrations of compound (v) showing no compound effect up to 10,000 nM. Symbol is mean +/− sem. N > 10 for all measurements. Label symbols “●”, “" ”,“ ■ ”represent compound (v) concentrations of 0, 4,500, and 10,000 nM, respectively. A series of NGF / TrkA-Fc binding curves in the presence of increasing concentrations of compound (iv) showing no compound effect up to 10,000 nM. Symbol is mean +/− sem. N > 4 for all measurements. Label symbols “●”, “" ”,“ ■ ”represent the compound (iv) concentrations 0, 4,500, and 10,000 nM, respectively. A series of NGF / TrkA-Fc binding curves in the presence of increasing concentrations of compound (iii) showing no compound effect up to 10,000 nM. Symbol is mean +/− sem. N > 4 for all measurements. Label symbols “●”, “" ”, and“ ■ ”represent compound (iii) concentrations of 0, 4,500, and 10,000 nM, respectively. FIG. 4 is a digital image of a Western blot showing the replacement of anti-p75 ^NTR Ab9651 from anti-p75 ^NTR expressing 3T3 cells with compound (iv) but not with compound (v). The upper panel represents the IgG heavy chain and the lower panel represents β-actin. This graph represents quantification. Bars represent mean +/− sem normalized to bound antibody (lane 4). N = 4 for each condition. A single asterisk (*) represents P <0.0005 by Student-test compared to binding in the absence of compound. Antibody and compound treatment is shown above each lane. Ab9651 did not bind to p75 ^NRT negative cells (lanes 1 and 2). Ab9651 bound to p75 ^NRT positive cells (lane 4) and was significantly replaced by compound (iv) (lane 5), but compound (v) had no effect (lane 6). Bar graph showing that Ab9651 has no effect on baseline viability (CM), partially inhibits BDNF, and completely inhibits the promotion of hippocampal neuronal viability by compound (iii) and compound (iv) It is. Black bars represent non-immune serum treatment. Gray bars indicate Ab9652 treatment. Bars represent mean +/- sem. N > 26 for each condition. Double asterisk (**) indicates P <0.00001 (for Ab9651 and non-immune comparisons). NS indicates that there is no significant difference by Student t-test. The survival rate in the presence of BDNF + Ab9651 is significantly larger than the survival rate in the presence of CM + Ab9651 (P <0,00001), but CM and compound (iii), compound (iv), and compound (v) in the presence of this antibody There is no significant difference between them. FIG. 5 is a bar graph showing that p75 ^NTR deficiency partially inhibits the BDNF effect on hippocampal neuronal cell survival promotion and completely inhibits the effects of NGF, compound (iii), and compound (iv). Neurotrophin was added at 1.8 nM and the compound was added at 5 nM. Black bars represent p75 ^{NTR + / +} cells. Gray bars represent p75 ^NTR-/- cells. Bars represent mean +/− sem. N > 5 for each condition. A single star (*) represents P <0.05 and a double star (**) represents P <0.005. NS represents no significant difference by Student-test (for knockout and wild comparison). In p75 ^NTR-/- cultures, BDNF treatment results in greater survival than NGF (P <0.05) or compounds (iii-v) (P <0.01). There were no significant differences in baseline survival among these genotypes. ^{Figure 2} shows a digital image of a Western blot of hippocampal cultured neurons using anti-phosphorylated Trk ^Y490 antibody compared to total TrkB. At 10 or 30 minutes, BDNF activated TrkB, but NGF and compounds (iii-v) did not produce detectable activation. FIG. 5 is a digital image of a Western blot of TrkA-expressing 3T3 cells using anti-phosphorylated Trk ^Y490 antibody compared to total TRkA. It can be seen that NGF activates TrkA, but compound (iv) does not produce a detectable activation. The results of two additional independent assays for TrkB and TrkA activation were identical. Digital images of Western blots of hippocampal cultured cell extracts treated with medium (C), 50 ng / ml BDNF (B), 50 ng / ml NGF (N), or 20 nM compound (iii-v) A representative band corresponding to phosphorylation signal factor (white arrowhead) and all corresponding factors (black arrowhead) and quantification of phosphorylation factor / total factor ratio are shown, and the degree of activation is shown. Bars are average +/− s. e. m. Indicates. Black bars represent sampling after 10 minutes. Gray bar represents sampling after 30 minutes. n = 6 independent blots for each measurement. A single star (*) represents P <0.001 for comparison with CM by Student t-test. In the case of other comparisons, the P value by Student t-test is shown on each section. Digital image of Western blot showing NFκB-p65 activation analysis showing similar activation kinetics for all biological activation treatments. FIG. 4 is a digital image of a Western blot showing AKT activation analysis, where activation with an active compound shows a shorter lag time compared to NGF. It is a digital image of a Western blot showing ERK44 activation analysis, showing lower activation in 10 minutes for compounds compared to NGF. It is a digital image of a Western blot showing ERK42 activation analysis, and shows longer activation by BDNF treatment compared to NGF and compounds (iii to v). FIG. 2 is a bar graph showing the viability of cultured hippocampal neurons treated with a signal transduction pathway inhibitor and BDNF (25 ng / ml), NGF (25 ng / ml) or compound (iii-v) (5 nM), NFκB And shows significant inhibition by P13K pathway inhibitors, small effects of ERK inhibition on activation by BDNF and NGF, and no effect of ERK inhibition on activation by compounds (iii-v). SN50 is an NFκB translocation (translocation) inhibitor. LY represents LY294002, a P13K inhibitor. PD stands for PD98059, an ERK inhibitor. N = 18 for each bar, representing the mean + s.e.m. NS indicates that the data are not significantly different. Single asterisk (*) indicates P <0.05, double asterisk (**) indicates P <0.001 compared to control (no inhibitor) in each group. White, black, light gray and dark gray bars represent control, SN50, LY and PD, respectively. FIG. 5 is a Western blot digital image of signal transduction activation analysis of NFκB pathway activation. Bars represent mean +/- sem. N > 6 for each condition. P values are shown. Activation is detected between 0 and 0.5 nM for NFκB, reaching a plateau level at 5 nM. FIG. 5 is a digital image of a Western blot of signal transduction activation analysis of AKT pathway activation. Bars represent mean +/− sem. N > 6 for each condition. P values are shown. Activation is detected between AKT 0.5 and 1 nM, reaching a plateau level at 5 nM. FIG. 5 is a digital image of a Western blot showing AKT activation by growth factors and compounds in p75 ^{NTR − / −} cells. For each condition, n > 9. There is no significant difference between medium alone and NGF or compounds (iii-v). 6 is a bar graph disclosing that compounds (iii-v) do not promote mature oligodendrocyte death and do not inhibit pro (precursor) NGF-induced cell death. Mature oligodendrocytes were processed as indicated, and cell death was assayed by measuring the percentage of MBP positive cells that were also TUNEL positive. In the absence of pro NGF, the compound did not promote cell death. In the presence of 2.8 ng / ml (0.05 nM) pro-NGF, compound (iii) and compound (iv) inhibited cell death, but not compound (v). Bars represent mean + s.em. The effect of 1 nM compound (v) in the presence of pro NGF was a single test, but otherwise n > 2. P <0.05 by Student t-test for comparison with pro-NGF treatment without compound. Black, light gray, and dark gray bars represent compound (iii), compound (iv), and compound (v), respectively. It is a line graph which shows the substitution of pro NGF from p75 ^NTR by the compound (iii) and the compound (iv). Incubated with 100 ng / ml pro-NGF and the indicated concentrations of compounds and detected by ELISA. For each condition, n = 4. The symbol represents the mean +/- sem. The signal from all compound treated samples was significantly lower than pro NGF alone and P <0.01 by student t-test. The symbols “Δ” and “●” represent the compound (v) and the compound (iii), respectively. It shows that compound (iii) inhibits Aβ-induced neurodegeneration. FIG. 6a is a bar graph showing the proportion of surviving hippocampal neurons after addition of Aβ _1-42 (10 μM or 30 μM). Addition of Aβ _1-42 resulted in approximately 40% neuronal loss after 3 days of exposure. The addition of NGF (100 pg / ml) did not protect against Aβ _1-42 . FIG. 6b is a bar graph showing the survival rate of hippocampal neurons after addition of Aβ _1-42 (10 μM) together with the test compound.

Neurotrophin localization, neurotrophin expression levels, expression levels of receptors that bind to neurotrophins, and / or in patients with disorders related to degeneration or dysfunction of p75-expressing cells, such as neurodegenerative disorders, and / or Or receptor signaling and functional outcome changes occur. In addition to these disorders, changes occur in signaling pathways or other mechanisms that can be linked to and regulated by p75 receptor mechanisms. Other disorders relate to cells that do not express the p75 receptor, however, cells that express p75 have the ability to compensate for the functional impairment or loss of cells that do not express p75. Thus, to prevent cytopathy or dysfunction, patients suffering from such disorders are provided with the corresponding neurotrophic factor or its mimetics that alter p75 ^NTR function or pro-NGF / NGF binding. Thus, such neurodegeneration can be alleviated or prevented. As disclosed herein, methods of treating neurodegeneration and other disorders and / or methods of promoting cell survival by administering a compound having binding specificity for a p75 ^NTR molecule are provided. .

The methods and compounds of the present application relate to compounds that have binding specificity for the p75 ^NTR molecule. Compounds with binding specificity for p75 ^NTR are suitable for modulation that increases the viability of neurons and other cells, and / or for inhibition of degeneration, for example, inhibition or recovery of neuronal spinous process loss Particularly in cells that exhibit a trophic response to neurotrophins, or cells that express the p75 ^NTR constitutively or in response to a disorder or disease, this compound promotes survival signaling, and Inhibits degenerative or dysfunctional signaling. In cells sensitive to neurotrophin-induced cell death, this compound does not induce apoptosis but inhibits neurotrophin-mediated cell death. Such mechanisms are involved across the nervous system and include neurotrophin regulation of p75 receptor-expressing hair follicle cell survival and hair loss.

  Additional aspects and advantages of the present application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned from practice of the invention. Both the foregoing general description and the following detailed description are exemplary and illustrative only and are not restrictive of the claimed invention.

Abbreviation
2D: 2D; 3D: 3D; Aβ: Amyloid-β; Ab: Antibody; AD: Alzheimer's disease; BCA: Bicinchoninic acid; BDNF: Brain-derived neurotrophic factor; bid: Twice a day; D: Dalton; DMEM: Dulbecco modified Eagle medium; ECL: electrogenic chemiluminescence; EDTA: ethylenediaminetetraacetic acid; ELISA: enzyme-linked immunosorbent assay; ERK: extracellular signal-regulated protein kinase; FBS: calf fetal serum; g: gram; h: time; HBA: hydrogen bond acceptor; HBD: hydrogen bond donor; HEPES: 4-hydroxyethyl-1-piperazine ethanesulfonic acid; HRP: horseradish peroxidase; IgG: immunoglobulin G; IP: intraperitoneal; IV: intravenous; K ^32: 32 th lysine residue; kcal: kcal; kg: kilogram; MBP: myelin basic protein; mg: milligram; min: minutes; ml: Milliliters; mM: millimolar concentration; mol: mol; MTT: 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide; MW: molecular weight; NaCl: sodium chloride; ng: nanogram; nM: nanomolar concentration; NS: significant No difference; NMR: nuclear magnetic resonance; NGF: nerve growth factor; nM: nanomolar concentration; p: probability; p75 ^NTR : p75 neurotrophin receptor; PBS: phosphate buffered saline; pmol: picomolar; PMSF: fluoride PO: oral; pro-NGF: pro NGF (untreated precursor of NGF); PVDF: polyvinylidyl difluoride; SDS: sodium dodecyl sulfate; SE: standard error; sem: standard error of measurement; Tris : 2-amino-2- (hydroxymethyl) -1,3-propanediol; TUNEL: deoxyuridine triphosphate cleavage end labeling with terminal deoxynucleotidyl transferase; μg: microgram; μl: microliter; μM: micro Molar ;%: Percent; ° C.: degrees Celsius;>: - equal to or greater than the;>: Greater than <: equal to or less than the ~; <: ~ less

Definitions The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials identical or equivalent to those described herein can be used in the practice or testing of the present application, representative methods and materials are described herein.

  In accordance with long-standing patent law conventions, the terms “a” (one), “an” (one), and “the” (“this”), as used herein, including the claims, are “one or more”. "Represents. Thus, for example, “a carrier” includes a mixture of one or more, two or more, etc. carriers.

  Unless otherwise indicated, it is to be understood that the amounts of ingredients, reaction conditions, etc. used in the specification and claims are modified by the term “about” in all examples. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that can vary depending on the desired properties obtained by the present application. As generally used herein, the term “about” when referring to a measurable value, such as weight, time, dose, or other quantity, from a particular value, in one example, ± 20% or ± 10 %, ± 5% in other examples, ± 1% in other examples, and ± 0.1% in other examples, so that such variations would perform the disclosed method Is appropriate to do.

As used herein, the phrase “disorder associated with degeneration or dysfunction of cells expressing p75” includes, but is not limited to, disorders associated with upregulation (upregulation) of p75. Such disorders include conditions associated with degeneration of p75 ^NTR expressing cells, such as neurodegenerative disorders and hair loss. Within the neuronal cell line, the p75 receptor is expressed by a variety of cell types including neurons, oligodendrocytes, astrocytes and microglia. Compounds that target the p75 receptor expressed by neurons are Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis Including, but not limited to, neurosis, myopathy, and various types of retinal degeneration. It can be used to prevent neuronal loss of function, degeneration and / or cell death in many nervous system disorders. In each of these disorders, neurons and other cells that express p75 are affected.

  To inhibit oligodendrocyte loss of function, degeneration and / or cell death in many nervous system disorders, including but not limited to multiple sclerosis, spinal cord disorders and perinatal anoxia Compounds that target the p75 receptor expressed by oligodendrocytes can be used. Compounds targeting the p75 receptor expressed by microglial cells are used to inhibit the detrimental activation of microglial cells, thereby reducing the inflammatory component of neurodegenerative disorders and other disorders be able to.

  Outside the nervous system, many cell populations express the p75 receptor. These cells include hair follicle cells, stem cells, vascular endothelial cells, vascular smooth muscle cells, and cardiomyocytes. In addition, the p75 receptor is expressed by certain tumor cells that are involved in breast cancer or prostate cancer. Given these expression patterns, compounds targeting the p75 receptor can be used for the following applications: prevention of hair follicle cell loss and thereby prevention of hair loss; prevention of cirrhosis and liver regeneration Regulation of angiogenesis and promotion of neovascularization at the onset of diabetic wounds or other ischemia; inhibition of cardiomyocyte loss after ischemia initiation or myocardial infarction or promotion of new cardiomyocyte proliferation Prevention; and inhibition of tumor cell growth. Further, p75 is expressed in stem cells and is known to regulate stem cell proliferation; therefore, p75 ligands are used to promote stem cell proliferation as part of a method to promote tissue and organ regeneration. Can do. Also, as part of a diagnostic or cell harvesting method, a p75 receptor ligand can be used to tag or identify cells that express p75 or cells that are upregulating p75.

  As used herein, the term “neurodegenerative disorder” includes all disorders characterized by neuronal cell damage or loss of function, and includes Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, Including, but not limited to epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, encephalopathy, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, and peripheral neuropathy.

  Compounds disclosed herein function as ligands for the p75 neurotrophin receptor and thereby inhibit cell degeneration or cell death and / or upregulate cell function or cell proliferation To induce. The intracellular signaling mechanism regulated by the p75 receptor is a fundamental mechanism present in virtually all cell types; thus, for the purpose of preventing cell or tissue degeneration and promoting cell survival It is expected that all cells and tissues expressing this receptor will be repairable by treatment with these compounds, and / or to up-regulate function or proliferation.

The term “alkyl group”, alone or in combination, represents a linear or branched alkyl group optionally having a substituent with 1 to about 20 carbon atoms. The term also includes straight or branched chain alkyl groups having 1 to about 6 carbon atoms, and optionally having 1 to about 4 carbon atoms, optionally substituted. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, Including heptyl, octyl, and the like. “Branch” represents an alkyl group in which a lower alkyl group such as a methyl group, an ethyl group, or a propyl group is added to a linear alkyl chain. A “lower alkyl group” is an alkyl group having 1 to 8 carbon atoms (ie, a C _1-8 alkyl group), such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Represent. “Higher alkyl group” refers to an alkyl group having from about 10 to about 20 carbon atoms, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, an “alkyl group” particularly represents a C _1-8 straight chain alkyl group. In another embodiment, “alkyl group” especially represents a C _1-8 branched chain alkyl group. Alkyl groups can be optionally substituted.

  The term “heteroalkyl group” refers to an alkyl group as described above, wherein one or more skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof. The term heteroalkyl group also includes alkyl groups in which 1 to about 6 skeletal atoms are oxygen, nitrogen, sulfur, or combinations thereof, and alkyl groups in which 1 to 4 skeletal atoms are oxygen, nitrogen, sulfur, or combinations thereof. And 1 to 2 backbone atoms include an alkyl group that is oxygen, nitrogen, sulfur, or a combination thereof. Heteroalkyl groups are optionally substituted.

The term “alkenyl group”, alone or in combination, has one or more carbon-carbon double bonds, and has from 2 to about 18 carbon atoms, optionally having a linear or branched chain. Represents a branched chain hydrocarbon group. The term also includes straight or branched chain hydrocarbon groups having one or more carbon-carbon double bonds, and optionally having 2 to about 6 carbon atoms, and 2 to These hydrocarbon groups having about 4 carbon atoms are included. Examples of alkenyl groups are ethenyl, propenyl, butenyl, 1,4-butadienyl, and the like. Suitable alkenyl groups include allyl groups. The term “allyl” or “allyl” refers to —CH ₂ HC═CH ₂ groups and derivatives thereof made by substitution. Thus, the term “alkenyl group and / or substituted alkenyl group includes allyl groups, such as, but not limited to, allyl groups, methylallyl groups, dimethylallyl groups, etc. The term“ allylic position ”or“ allyl moiety ” Represents a saturated carbon atom of an allyl group, and thus a substituent such as a hydroxyl group bonded to an allyl site, or other substituent, can be represented as “allyl group.” “1-alkenyl group” Represents an alkenyl group in which the double bond is between the first and second carbon atoms.

  The term “alkynyl group”, alone or in combination, has one or more carbon-carbon triple bonds, and may optionally have a substituent having 2 to about 12 carbon atoms, straight or branched chain carbonization. Represents a hydrogen group. The term also includes straight or branched chain hydrocarbon groups having one or more carbon-carbon triple bonds and optionally having 2 to about 6 carbon atoms, and 2 to These hydrocarbon groups having about 4 carbon atoms are included. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. A “1-alkynyl group” represents an alkynyl group in which the triple bond is between the first and second carbon atoms.

  "Cyclic alkyl" and "cycloalkyl" are about 3 to about 10 carbon atoms, or about 3 to about, such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Represents a 6-carbon atom non-aromatic mono- or polycyclic system. This cycloalkyl group optionally represents partially unsaturated. Cycloalkyl groups are also optionally substituted as defined herein. Representative monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Furthermore, the cycloalkyl group is optionally substituted with a linking group such as an alkylene group as defined above, eg, a methylene group, an ethylene group, a propylene group, and the like. In such a case, the cycloalkyl group can be represented as, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, and the like. Furthermore, polycyclic cycloalkyl groups include adamantyl, octahydronaphthyl, decalin, camphor (camphor), camphane, and noradamantyl.

  The terms “heterocyclic alkyl group” and “heterocycloalkyl group” represent a 3 to 6 atom or 3 to 10 atom cyclic group containing at least one heteroatom. In one embodiment, these substituents contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. A heterocyclic group can be attached to the ring via a nitrogen atom or via a carbon atom. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl groups. Such substituents can be substituted.

  The term "aryl group" has 5 to 14 ring atoms and a ring having at least one π-electron system conjugated and can be optionally substituted, carbocyclic aryl group, heterocyclic aryl group, and biaryl group Represents an aromatic group containing As used herein, the term “aryl group” refers to a monocyclic aromatic ring or polycyclic aromatic ring, which is fused to each other or covalently bonded, or a methylene group or ethylene group moiety (restricted thereto). (But not) to general substituents such as The common linking group may also be a carbonyl group as in benzophenone, or oxygen as in diphenyl ether, or nitrogen as in diphenylamine. The aromatic ring can in particular consist of a phenyl group, a naphthyl group, a biphenyl group, a diphenyl ether group, a diphenylamine group, and a benzophenone group, all of which can be optionally substituted. In a particular embodiment, the term “aryl group” consists of about 5 to about 10 carbon atoms, such as, for example, 5, 6, 7, 8, 9 or 10 carbon atoms, and 5- and 6-membered ring carbonizations. By cyclic aromatic, including hydrogen and heterocyclic aromatic rings. Examples of aryl groups include cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine , Triazine groups, pyrimidine groups, quinoline groups, isoquinoline groups, indole groups, carbazole groups, and the like, all of which are optionally substituted, but are not limited thereto.

  The aryl group can be optionally substituted with one or more aryl group substituents, which can be the same or different, wherein the “aryl group substituent” includes an alkyl group, a substituted alkyl group, an aryl group, Substituted aryl group, aralkyl group, hydroxyl group, alkoxyl group, aryloxyl group, aralkyloxyl group, carboxyl group, acyl group, halo group, nitro group, alkoxycarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, acyloxyl Group, acylamino group, aroylamino group, carbamoyl group, alkylcarbamoyl group, dialkylcarbamoyl group, arylthio group, alkylthio group, alkylene group, and NR′R ″ group (wherein R ′ and R ″ are independently hydrogen Atom, alkyl group, substituted alkyl group, aryl group, Can be an aryl group and aralkyl group) it is.

  Thus, as used herein, the term “substituted aryl group” includes aryl groups as defined herein, where one or more atoms or a functional group of the aryl group is another atom. Or substituted by a functional group, and these are, for example, alkyl group, substituted alkyl group, halogen group, aryl group, substituted aryl group, alkoxyl group, hydroxyl group, nitro group, amino group, alkylamino group, dialkylamino group, sulfate group And a mercapto group.

  Specific examples of aryl groups are cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine Groups, triazine groups, pyrimidine groups, quinoline groups, isoquinoline groups, indole groups, carbazole groups, and the like, but are not limited thereto.

で一般的に表される構造は、本明細書で用いる様に、置換Ｒ基、から成る６炭素環構造を表し、ここでＲ基は、存在又は、不存在であることができて、存在する時、１以上のＲ基は、環構造の１以上の可能な炭素原子上で置換を受けることができる。Ｒ基の存在又は不存在及びＲ基の数は、整数ｎの値により定められる。もし１以上の場合、各Ｒ基は、環構造の可能な炭素上に置換され、他のＲ基上で置換されない。例えば、構造：

（式中、ｎは０から２の整数）は、以下：

等々を含む化合物群から成るが、これらに限定されない。 The following structure:

The structure generally represented by, as used herein, represents a 6-carbocyclic ring structure consisting of a substituted R group, where the R group can be present or absent and present When doing so, one or more R groups can undergo substitution on one or more possible carbon atoms of the ring structure. The presence or absence of the R group and the number of R groups are determined by the value of the integer n. If more than one, each R group is substituted on a possible carbon of the ring structure and is not substituted on any other R group. For example, the structure:

(Where n is an integer from 0 to 2) is:

And the like, but not limited to.

（式中、ｎは１）は、以下：

を含む化合物群から成るが、式中１個のＲ置換基に、他の指定された置換基により占領されてない、ベンゾフラン親構造上のどの炭素原子にも結合することができて、この場合、炭素６はＸにより置換され、及び炭素２はＹにより置換される。 Construction

(Where n is 1) is:

In which one R substituent can be bonded to any carbon atom on the benzofuran parent structure that is not occupied by other specified substituents, in this case , Carbon 6 is substituted by X, and carbon 2 is substituted by Y.

  A dotted line representing a bond in a cyclic structure indicates that this bond can be present or absent in a ring. Representing a bond in the cyclic structure by a dotted line indicates that the cyclic structure is selected from the group consisting of a saturated cyclic structure, a partially saturated cyclic structure, and an unsaturated cyclic structure.

“Carbocyclic aryl group” refers to a substituent wherein the ring atom on the aromatic ring is a carbon atom. The carbocyclic aryl group includes a condensed compound such as a monocyclic carbocyclic aryl group and a polycyclic or optionally substituted naphthyl group.
A “heterocyclic aryl group” or “heteroaryl group” represents a substituent having 1 to 4 heteroatoms as ring atoms of an aromatic ring, and the remaining ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, etc., all optional Is replaced by

The phrase “carbocycle” refers to a saturated or unsaturated monocyclic or bicyclic ring in which all ring atoms are carbon. The term thus includes cycloalkyl groups and carbocyclic aryl rings.
The phrase “heterocycle” is a saturated or unsaturated monocyclic or bicyclic ring, has 1 to 4 heteroatoms as ring atoms of the aromatic ring, and the remainder of the ring atoms are carbon atoms. The term thus includes heterocyclic alkyl ring groups and heterocyclic aryl ring groups.

  The term “optionally substituted” or “substituted” means a lower alkyl group, a lower aryl group, a lower aralkyl group, a lower alicyclic group, a heterocyclic alkyl group, a hydroxyl group, a lower alkoxy group, Lower aryloxy group, perhaloalkoxy group, aralkoxy group, heteroaryl group, heteroaryloxy group, heteroarylalkyl group, heteroaralkoxy group, azido group, amino group, guanidino group, amidino group, halo group, lower alkylthio Group, oxo group, acylalkyl group, carboxy ester, carboxyl group, -carboxamide group, nitro group, acyloxy group, aminoalkyl group, alkylaminoaryl group, alkylaryl group, alkylaminoalkyl group, alkoxyaryl group, arylamino group Aralkylamino group, phosphono group, Phenyl group, -carboxamidoalkylaryl group, -carboxamidoaryl group, hydroxyalkyl group, haloalkyl group, alkylaminoalkylcarboxy group, aminocarboxamidoalkyl group, cyano group, lower alkoxyalkyl group, lower perhaloalkyl group, and arylalkyl Includes substituents substituted with 1 to 4 substituents independently selected from oxyalkyl groups.

  In some embodiments, the compounds described by the present invention have a linking group. As used herein, the term “linking group” consists of chemical moieties that bind to two or more other chemical moieties to form a stable structure. Exemplary linking groups include, but are not limited to, furanyl groups, phenylene groups, thienyl groups, or pyrrolyl groups that link two or more aryl groups.

  When a specified atom of a ring or chain is defined as "absent", the specified atom is replaced by a direct bond or incorporated into a double bond with an attached atom. When a linking group or spacer group is defined as absent, this linking group or spacer group is replaced by a direct bond.

An “alkylene group” is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms Represents a straight or branched divalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, such as The alkylene group is linear, branched or cyclic. The alkylene group can also be optionally unsaturated and / or substituted with one or more “alkyl group substituents”. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl groups”) can optionally be incorporated along the alkylene group, where A nitrogen substituent represents an alkyl group as defined above. Examples of the alkylene group include a methylene group (—CH ₂ —); an ethylene group (—CH ₂ —CH ₂ —); a propylene group (— (CH ₂ ) ₃ —); a cyclohexylene group (—C ₆ H ₁₀ —). -CH = CH-CH = CH-; -CH = CH-CH ₂ -;-(CH ₂ ) _q -N (R)-(CH ₂ ) _r- , where each q and r are independent For example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 , An integer from 0 to about 20, and R is a hydrogen atom or a lower alkyl group; a methylenedioxyl group (—CH ₂ —O—); and an ethylenedioxyl group (—O— (CH ₂ ) ₂ —O -) Represents. An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbon atoms.

The term “alkenylene group” represents a cyclic carbon chain having a carbon-carbon double bond (ie, having an open chain structure) and is represented by the chemical formula C _n H _2n-2 , which can be substituted one or more. Representative alkenylene groups include, but are not limited to, ethenylene, propenylene, 1- or 2-butenylene, 1- or 2-pentenylene, and the like.
As used herein, an “acyl group” refers to an organic acid group, where the —OH of the carboxyl group is replaced by another substituent (ie, as represented by RCO— R is an alkyl group or an aryl group as defined herein). Thus, the term “acyl group” specifically includes arylacyl groups, such as acetylfuran and phenacyl groups. Specific examples of acyl groups include acetyl groups and benzoyl groups.

“Alkoxyl” or “alkoxyalkyl” refers to an alkyl-O— group wherein alkyl is as previously described. As used herein, the term “alkoxyl group” is straight chain, branched, or cyclic, saturated or (eg, methoxyl group, ethoxyl group, propoxyl group, isopropoxyl group, butoxyl group, t-butoxyl And C _1-20 containing unsaturated oxo hydrocarbon chains (including groups and pentoxyl groups).
“Aryloxyl group” refers to an aryl-O— group in which the aryl group includes a substituted aryl group as previously described. As used herein, the term “aryloxyl group” represents a phenyloxyl group, or a hexyloxyl group and an alkyl group, a substituted alkyl group, a halo group, or an alkoxyl-substituted phenyloxyl group, or a hexyloxyl group.
"Aralkyl group" represents an aryl-alkyl- group, wherein the aryl group and alkyl group are as described above and include substituted aryl groups and substituted alkyl groups. Examples of the aralkyl group include a benzyl group, a phenylethyl group, and a naphthylmethyl group.
“Aralkyloxyl” refers to an aralkyl-O— group wherein the aralkyl is as previously described. An example of an aralkyloxyl group is a benzyloxyl group.

“Dialkylamino group” represents a —NRR ′ group, wherein R and R ′ each independently represents an alkyl group and / or a substituted alkyl group, as described above. Examples of the alkylamino group are an ethylmethylamino group, a dimethylamino group, and a diethylamino group.
An “alkoxycarbonyl group” is an alkyl-O—CO— group. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a butyloxycarbonyl group, and a t-butyloxycarbonyl group.
“Aryloxycarbonyl” refers to an aryl-O—CO— group. Examples of aryloxycarbonyl groups include phenoxy-carbonyl groups and naphthoxy-carbonyl groups.
“Aralkoxycarbonyl” refers to an aralkyl-O—CO— group. An example of an aralkoxycarbonyl group is a benzyloxycarbonyl group.
A “carbamoyl group” represents a H ₂ N—CO— group.

“Alkylcarbamoyl” refers to the group R′RN—CO—, wherein one of R and R ′ is a hydrogen atom, and the other of R and R ′ is an alkyl group and / Or represents a substituted alkyl group.
“Dialkylcarbamoyl” represents R′RN—CO—, wherein R and R ′ each independently represents an alkyl group and / or a substituted alkyl group.
“Acyloxyl” refers to an acyl-O— group wherein acyl is as previously described.
“Acylamino” refers to an acyl-NH— group wherein acyl is as previously described.
“Aroylamino” refers to an aroyl-NH— group wherein aroyl is as previously described.

The term “amino group” refers to the —NH ₂ group.
The term “carbonyl group” refers to a — (C═O) — group.
The term “carboxyl group” represents a —COOH group.
The term “cyano” refers to the group —CN.
As used herein, the term “halo group”, “halide” or “halogen group” refers to fluorinated, chlorinated, brominated and iodinated groups.
The term “hydroxyl group” refers to an —OH group.
The term “hydroxyalkyl group” refers to an alkyl group substituted with one —OH group.
The term “mercapto group” refers to the —SH group.
The term “oxo group” refers to the ═O group.
The term “nitro group” refers to a —NO ₂ group.
The term “thio group” refers to a compound already described herein, wherein a carbon or oxygen atom is replaced by a sulfur atom.
The term “sulfate group” refers to the —SO ₄ group.

  The term “cycloalkenyl group” includes 3 or more carbon atoms per ring (such as 3, 4, 5, 6, 7, or 8 carbon atoms per ring) (eg 1 ring, 2 rings, 3 rings, etc.). Represents a partially unsaturated cyclic hydrocarbon group containing one or more rings (such as a ring or four rings). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. Cycloalkenyl groups can be optionally substituted at all possible addition positions with one or more substituents (eg, as 1, 2, 3, or 4 substituents). Examples of substituents include alkyl groups, substituted alkyl groups, halo groups, arylamino groups, acyl groups, hydroxyl groups, aryloxyl groups, alkoxyl groups, alkylthio groups, arylthio groups, aralkyloxyl groups, aralkylthio groups, carboxyl groups. , An alkoxycarbonyl group, an oxo group, and a cycloalkyl group, but are not limited thereto.

  The term “substituted cycloalkenyl group” represents a cycloalkenyl group substituted with one or more substituents, preferably 1, 2, 3 or 4 substituents, in all possible addition positions. Examples of substituents include alkyl groups, substituted alkyl groups, halo groups, arylamino groups, acyl groups, hydroxyl groups, aryloxyl groups, alkoxyl groups, alkylthio groups, arylthio groups, aralkyloxyl groups, aralkylthio groups, carboxyl groups. , Alkoxycarbonyl group, oxo group and cycloalkyl group, but are not limited thereto.

When the term “independently selected” is used, the relevant substituents (eg, R groups such as substituents R ¹ and R ² , or substituent X and substituent Y) are the same or different. For example, both R ¹ and R ² can be substituted alkyl groups, or R ¹ can be a hydrogen atom, R ² can be a substituted alkyl group, and the like.

  The designated R, R ′, X, Y, Y ′, A, A ′, B, L, or Z group is generally recognized by the technique corresponding to the substituent unless otherwise specified herein. It is a structure that has been. For purposes of illustration, certain representative R, X, and Y groups described above are defined below. These definitions are intended to be supplemental and explanatory and do not exclude definitions that are obvious to those of skill in the art listed herein.

  As used herein, the term “therapy” encompasses all treatment of an animal or human, particularly a human disease and / or condition, and (i) is susceptible to a disease, disorder, and / or condition. Diseases, disorders from humans or humans who are at risk of being exposed to factors that can cause the disease, disorder and / or pathology and / or symptoms and have never been diagnosed as such And / or prevent disease state and / or symptom; (ii) inhibit disease, disorder and / or condition and / or symptom, ie stop disease progression; (iii) disease, disorder and Relieving the pathology and / or symptoms, i.e. recovering from the disease, disorder and / or pathology; (iv) stem cells that do not treat the initial disease but can reduce the symptoms and improve function Like the growth of Includes increased compensation mechanism.

The term “mimetic” refers to (a) other known compounds and (b) {known compounds of biological origin (such as known compounds such as polypeptides or fragments thereof)} of other known compounds. A particular fragment represents a compound that has similar functional and / or structural properties.
“Binding specificity” refers to the activity by which a protein or other type of molecule can recognize and interact with complementary sites on other proteins or other types of molecules.

  As used herein, the term “pharmacophore” refers to a specific model that can exert a selected biochemical effect, such as, for example, inhibition of an enzyme, binding to a receptor, chelation of an ion, and the like. Represents a representative molecular part. The selected pharmacophore can have one or more biochemical effects, for example, an inhibitor of one enzyme and an agonist of a second enzyme. The therapeutic agent can include one or more pharmacophores, which can have the same or different biochemical activities.

  As used herein, the term “derivative” refers to a compound that has been chemically modified to distinguish it from the parent compound. Such chemical modification can include, for example, replacement of a hydrogen atom with an alkyl group, an acyl group, or an amino group. Derivative compounds can be modified, for example, by glycosylation, pegylation, or all similar manipulations to retain at least one biological or immunological function of the parent compound.

The term “hydrophilic” is commonly used in this field as having an affinity for water, water absorption and / or solubility.
The term “lipophilic” is commonly used in the art as having affinity for lipid, binding to lipid, solubility in lipid.
As used herein, the term “amphiphilic” describes a structure having separate hydrophobic and hydrophilic regions. Thus, one part of the structure interacts advantageously with aqueous solutions and other polar solvents, while the other part of the structure interacts advantageously with nonpolar solvents.
As used herein, the term “solubility” describes the maximum amount of solution that dissolves in a given amount of solvent at a particular temperature.
As used herein, the term “bioavailability” refers to the overall availability (ie, blood / plasma concentration) of a given amount of a compound administered to a patient. The term further encompasses the rate and rate of absorption of the compound that reaches the site of action.

  As used herein, a “solvate” is a complex formed by solvation (a combination of a solvent molecule and an active agent molecule or ion of the present invention), or a solute with one or more solvent molecules. It means an aggregate composed of ions or solute molecules (active factor of the present invention). Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate and others. It will be appreciated by those skilled in the art that pharmaceutically acceptable salts of the compounds of the invention can exist as solvated forms. Solvates are generally formed by the natural absorption of moisture by hydrates that are part of the preparation of the compounds of the invention or by the anhydrous compounds of the invention. Solvates, including hydrates, can be found as stoichiometric ratios, eg, as 2, 3, 4 salt molecules per solvent or hydrated molecule. Solvents used for crystallization, such as alcohols, especially methanol and ethanol; aldehydes; especially ketones such as acetone; esters such as ethyl acetate; can be embedded in the crystal lattice.

As used herein, the term “prodrug” refers to an agent in one or more steps that, when administered to a biological system, involves a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, or both. It represents all compounds that generate substances (bioactive compounds). Standard prodrugs, for example combined with drug substance to be cleaved in in vivo, HO-, HS-, HOOC- , R 2 N- , such as is created using a substituent with functionality. Prodrugs for such substituents are known to those skilled in the art and are often used to enhance oral bioavailability or other characteristics beneficial to formulation, delivery, or drug activity. . Standard prodrugs include carboxylic acid esters (wherein the substituent is an alkyl group, aryl group, aralkyl group, acyloxyalkyl group, alkoxycarbonyloxyalkyl group), and (wherein the substituent is a hydroxyl group, an ester of a thiol, And amines (added to acyl groups, alkoxycarbonyl groups, aminocarbonyl groups, phosphates or sulfates).

When the compounds according to the invention have at least one asymmetric center, they can therefore exist as optical isomers. When these mixtures have more than one asymmetric center, they can also exist as diastereoisomers. All such stereoisomers and all proportions of these mixtures are included within the scope of the present invention. Where the compound has geometric isomers, all such isomers and all proportions of these mixtures are included within the scope of the invention. When so indicated in the claims herein, if desired the single optical isomer of the disclosed optically active heterocyclic compound, for health or efficacy reasons, is preferably at least It is present in the optical isomer in excess of about 80%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%, or at least about 99.5%.
Tautomers of the compounds of the present invention are included in this application. Thus, for example, a carbonyl group includes its hydroxyl tautomer.

In one embodiment of the compounds of the present application, the present application discloses compounds having binding specificity for the p75 ^NTR molecule.
In some embodiments, the compound having binding specificity for the p75 ^NTR molecule is a neurotrophin β-turn loop mimetic.
In some embodiments, the compound consists of a pharmacophore that is substantially identical to the pharmacophore displayed in FIG. 1c.
In some embodiments, the compound is a small molecule or peptide.

及び

から成る群から選択される化合物を開示する。 In one aspect, the present invention provides the following:

as well as

Disclosed are compounds selected from the group consisting of:

（式中；ｎは、０〜８の整数であり、；Ｌ_１及びＬ_２は、アルキレン基、置換アルキレン基、シクロアルキル基、置換シクロアルキル基、シクロアルケン基、置換シクロアルケン基、アリール基、置換アリール基、アルケニレン基、及び置換アルケニル基から成る群から選択される連結基であり；Ｒ_１、Ｒ_２及びＲ_３は、各々、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、ハロ基、シアノ基、ニトロ基、メルカプト基、ヒドロキシル基、アルコキシル基、アリール基、アリールオキシル基、置換アリール基、及びアラルキルオキシル基から成る群から独立して選択され；Ａ_１、Ａ_２、Ａ_３、Ａ_４及びＡ_５は各々、Ｎ及びＣＨからなる群から独立して選択され；Ｂ_１、Ｂ_２、Ｂ_３、Ｂ_４及びＢ_５は各々、Ｏ、Ｓ、及びＮＲ_４からなる群より独立して選択されるが、ここでＲ_４は、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、アリール基、及び置換アリール基から成る群から選択され；及び
Ｄ_１及びＤ_２は、以下：

（式中：各Ｒ_５、Ｒ_６、Ｒ_８、Ｒ_９及びＲ_１０は、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、アリール基、置換アリール基、アラルキル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、アルコキシシクロアルキル基、アミノアルキル基、アシルオキシル基、アルキルアミノアルキル基、及びアルコキシカルボニル基から成る群から独立して選択され；各Ｒ_７は、Ｈ、ヒドロキシル基、アルキル基、置換アルキル基、アリール基、置換アリール基、アシルオキシル基、及びアルコキシル基からなる群から独立して選択され；又はＲ_７及びＲ_５、又はＲ_７及びＲ_９は共に、Ｃ_２からＣ_１０アルキル基、Ｃ_２からＣ_１０ヒドロキシアルキル基、又はＣ_２からＣ_１０アルケン基を表す。）からなる群から選択される。）化合物から成る群から選択される化合物、又はこれらの医薬的に許容される塩を開示する。 In another embodiment, the present application provides Formula A or Formula B:

Wherein n is an integer of 0 to 8; L ₁ and L ₂ are an alkylene group, a substituted alkylene group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkene group, a substituted cycloalkene group, an aryl group , A substituted aryl group, an alkenylene group, and a substituted alkenyl group; R ₁ , R ₂ and R ₃ are each H, an alkyl group, a substituted alkyl group, a cycloalkyl group, a halo, Independently selected from the group consisting of a group, a cyano group, a nitro group, a mercapto group, a hydroxyl group, an alkoxyl group, an aryl group, an aryloxyl group, a substituted aryl group, and an aralkyloxyl group; A ₁ , A ₂ , A ₃ , A ₄ and A ₅ are each independently selected from the group consisting of N and CH; B ₁ , B ₂ , B ₃ , B ₄ and B ₅ are each O, S, and Independently selected from the group consisting of NR ₄ , wherein R ₄ is selected from the group consisting of H, alkyl groups, substituted alkyl groups, cycloalkyl groups, aryl groups, and substituted aryl groups; and D ₁ And D ₂ are:

(Wherein R ₅ , R ₆ , R ₈ , R ₉ and R ₁₀ are H, alkyl group, substituted alkyl group, cycloalkyl group, aryl group, substituted aryl group, aralkyl group, hydroxyalkyl group, hydroxycyclo Independently selected from the group consisting of alkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; each R ₇ is H, hydroxyl, alkyl, substituted alkyl Independently selected from the group consisting of a group, an aryl group, a substituted aryl group, an acyloxyl group, and an alkoxyl group; or R ₇ and R ₅ , or R ₇ and R ₉ are both C ₂ to C ₁₀ alkyl groups, _{C 10} hydroxyalkyl group from C _2, or selected is from the group consisting of _{C 2} from representing a _{C 10} alkene group.) That. ) Disclosed are compounds selected from the group consisting of compounds, or pharmaceutically acceptable salts thereof.

In some embodiments, L ₁ and L ₂ are each independently (CH ₂ ) m-, where m is an integer from 1 to 8.

（式中：ｍは１〜８の整数であり；Ｒ_１及びＲ_２は各々、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、アリール基、アリールオキシル基、置換アリール基、及びアラルキルオキシル基からなる群から独立して選択され；及びＲ_５及びＲ_６は各々、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、アリール基、置換アリール基、アラルキル基、ヒドロキシル基、アルコキシル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、アルコキシシクロアルキル基、アミノアルキル基、アシルオキシル基、アルキルアミノアルキル基、及びアルコキシカルボニル基からなる群から独立して選択される；）
を有する。 In some embodiments, the compound represented by Formula (A) has the following structure:

Wherein m is an integer from 1 to 8; R ₁ and R ₂ are each H, an alkyl group, a substituted alkyl group, a cycloalkyl group, an aryl group, an aryloxyl group, a substituted aryl group, and an aralkyloxyl group. And R ₅ and R ₆ are each selected from H, alkyl group, substituted alkyl group, cycloalkyl group, aryl group, substituted aryl group, aralkyl group, hydroxyl group, alkoxyl group, hydroxyalkyl Independently selected from the group consisting of a group, a hydroxycycloalkyl group, an alkoxycycloalkyl group, an aminoalkyl group, an acyloxyl group, an alkylaminoalkyl group, and an alkoxycarbonyl group;)
Have

を有する。 In some embodiments, the compound represented by Formula (A) has the following structure:

Have

（式中：ｍは１〜８の整数を表し、；Ｒ_３は、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、ハロ基、ヒドロキシル基、アルコキシル基、アリール基、アリールオキシル基、置換アリール基、及びアラルキルオキシル基からなる群から選択され；及びＲ_５及びＲ_６は各々、Ｈ、アルキル基、置換アルキル基、シクロアルキル基、アリール基、置換アリール基、アラルキル基、ヒドロキシル基、アルコキシル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、アルコキシシクロアルキル基、アミノアルキル基、アシルオキシル基、アルキルアミノアルキル基、及びアルコキシカルボニル基からなる群から独立して選択される。）を有する。 In some embodiments, the compound represented by Formula (B) has the following structure:

(Wherein m represents an integer of 1 to 8; R ₃ represents H, an alkyl group, a substituted alkyl group, a cycloalkyl group, a halo group, a hydroxyl group, an alkoxyl group, an aryl group, an aryloxyl group, and a substituted aryl. And R ₅ and R ₆ are each selected from H, alkyl group, substituted alkyl group, cycloalkyl group, aryl group, substituted aryl group, aralkyl group, hydroxyl group, alkoxyl group; And independently selected from the group consisting of a hydroxyalkyl group, a hydroxycycloalkyl group, an alkoxycycloalkyl group, an aminoalkyl group, an acyloxyl group, an alkylaminoalkyl group, and an alkoxycarbonyl group.

を有する。 In some embodiments, the compound represented by formula (B) has the following structure:

Have

ではなく、化学式（Ｂ）で表される化合物は以下：

ではない。 In some embodiments, the compound represented by formula (A) is:

Instead, the compound represented by the chemical formula (B) is:

is not.

  In some embodiments, the neurotrophin is nerve growth factor (NGF). In some embodiments, the β-turn loop is loop 1 of NGF.

を有する。 In some embodiments, the compound has the chemical formula:

Have

In some embodiments, the compound has binding specificity for the neurotrophin binding site of the p75 ^NTR molecule.
In some embodiments, the compound comprises a derivative of the parent compound that has binding specificity for the p75 ^NTR molecule, wherein the derivative also has binding specificity for the p75 ^NTR molecule.
In some embodiments, compared to the parent compound, the derivative has at least one property selected from the group consisting of hydrophilicity, lipophilicity, amphiphilicity, solubility, bioavailability, and resistance to liver degradation. Indicates up-regulation.

で表される化合物又は医薬的に許容可能なこれらの塩、エステル、プロドラッグ若しくは溶媒和物を開示し、ここで：Ｒ^１、Ｒ^１'、Ｒ^２、Ｒ^２'、Ｒ^３、及びＲ^４は、それぞれ独立して、水素原子、又は任意に置換基を有していてもよいアルキル基を表し、又はＲ^２及びＲ^２'は共に=O、=S又は=CH₂を形成してもよい。Ｒ^５は、ヘテロシクロアルキル基を表し、Ｘは、CH₂、NH、Ｏ、又はＳを表し、ｎは０、１、２、３、４、又は５を表し、及びｍは１又は２を表す。他の態様において、化学式Ｉで表される化合物において、Ｒ^１、Ｒ^１'、Ｒ^２、Ｒ^２'、Ｒ^３、及びＲ^４は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基を表し、又はＲ^２及びＲ^２'は共に=O又は=Sを形成してもよい。Ｒ^５は、ヘテロシクロアルキル基を表し、ＸはＯ又はＳを表し、ｎは０、１、２、３又は４を表し、及びｍは１又は２を表す。開示した態様の何れかの実施態様において、ＸはＯを表し、及びｍは１を表す。他の態様において、Ｒ^２及びＲ^２'は共に=Oを形成し；及びＲ^３及びＲ^４は、それぞれ独立して、任意に置換基を有していてもよいＣ_１〜Ｃ_６アルキル基を表す。他の実施態様において、Ｒ^５は、モルホリニル基、チオモルホリニル基、テトラヒドロ−２Ｈ−ピラン基、１メチルピペラジニル基、ピペリジニル基、又はピロリジニル基を表し、及びＲ^１及びＲ^１'は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。他の実施態様において、ＸはＯを表し、ｍは１を表し、Ｒ^２及びＲ^２'は共に=Oを形成し；Ｒ^３及びＲ^４は、それぞれ独立して、任意に置換基を有していてもよいＣ_１〜Ｃ_６アルキル基を表し、Ｒ^５はモルホリニル基、チオモルホリニル基、テトラヒドロ-2H-ピラン基、１メチルピペラジニル基、ピペリジニル基又はピロリジニル基を表し、及びＲ^１及びＲ^１'は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、ｍは２を表し、Ｘは０を表し、Ｒ^２及びＲ^２'は、それぞれ水素原子を表し、Ｒ^３は、任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、Ｒ^５は、窒素結合のモルホリニル基、１−メチルピペラジニル基、ピペリジニル基又はピロリジニル基を表し、及びＲ^１及びＲ^１'は、それぞれ独立して水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。 In one embodiment, the present application has Formula I:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein: R ¹ , R ^{1 ′} , R ² , R ^{2 ′} , R ³ , and R ⁴ each independently represents a hydrogen atom or an optionally substituted alkyl group, or R ² and R ^{2 ′} together form ═O, ═S or ═CH _2. Also good. R ⁵ represents a heterocycloalkyl group, X represents CH ₂ , NH, O, or S, n represents 0, 1, 2, 3, 4, or 5, and m represents 1 or 2. Represent. In another embodiment, in the compound represented by Formula I, R ¹ , R ^{1 ′} , R ² , R ^{2 ′} , R ³ , and R ⁴ are each independently a hydrogen atom, optionally having a substituent. Represents an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, or R ² and R ^{2 ′} are both ═O or = S may be formed. R ⁵ represents a heterocycloalkyl group, X represents O or S, n represents 0, 1, 2, 3 or 4, and m represents 1 or 2. In any embodiment of the disclosed aspects, X represents O and m represents 1. In another embodiment, R ² and R ^{2 ′} together form ═O; and R ³ and R ⁴ are each independently an optionally substituted C ₁ -C ₆ alkyl group. Represents. In another embodiment, R ⁵ represents a morpholinyl group, a thiomorpholinyl group, a tetrahydro-2H-pyran group, a 1 methylpiperazinyl group, a piperidinyl group, or a pyrrolidinyl group, and R ¹ and R ^{1 ′} are each independently And a C ₁ -C ₄ alkyl group optionally having a substituent. In another embodiment, X represents O, m represents 1, R ² and R ^{2 ′} together form ═O; R ³ and R ⁴ each independently have an optionally substituted group An optionally substituted C ₁ -C ₆ alkyl group, R ⁵ represents a morpholinyl group, a thiomorpholinyl group, a tetrahydro-2H-pyran group, a 1 methylpiperazinyl group, a piperidinyl group or a pyrrolidinyl group, and R ¹ and R ^{1 ′} each independently represents a hydrogen atom or an optionally substituted C ₁ -C ₄ alkyl group. In still another embodiment, m represents 2, X represents 0, R ² and R ^{2 ′} each represent a hydrogen atom, and R ³ optionally has a substituent C _1. represents -C ₄ alkyl group, R ⁵ is nitrogen binding morpholinyl group, 1-methyl piperazinyl group, a piperidinyl group or an pyrrolidinyl group, and R ¹ and R ^{1 'are} each independently a hydrogen atom or optionally having a substituent represent an C ₁ -C ₄ alkyl group.

の構造を持ち、ここで：Ｒ^１、Ｒ^１'、Ｒ^３及びＲ^４は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表し、及びｎは、０、１、２、３、４又は５を表す。他の態様は、化学式ＩＡの構造を有する化合物を表し、ここでＲ^１、Ｒ^１'、Ｒ^３及びＲ^４は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基を表し、及びｎは、１、２、３又は４を表す。全ての開示した態様の１実施態様において、ｎは２を表し、Ｒ^１及びＲ^１'は、それぞれ水素原子を表し、Ｒ^３はメチル基を表し及びＲ^４は、sec-ブチル基を表す。他の実施態様において、Ｒ^５は、異種原子を介して結合したヘテロシクロアルキル基を表し、ｍは２を表し、及びＸは〇を表す。他の実施態様において、Ｒ^２及びＲ^２'は、それぞれ水素原子を表し、及びＲ^３は、任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、Ｒ^５は、窒素結合モルホリニル基、１−メチルピペラジニル基、ピペリジニル基又はピロリジニル基を表し、Ｒ^１及びＲ^１'は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。 In other embodiments, the compound has the formula IA:

Wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group, and n is Represents 0, 1, 2, 3, 4 or 5. Another embodiment represents a compound having the structure of formula IA, wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently have a hydrogen atom, optionally a substituent. An alkyl group, an alkenyl group optionally having substituent (s) or an alkynyl group optionally having substituent (s) may be represented, and n represents 1, 2, 3 or 4. In one embodiment of all disclosed aspects, n represents 2, R ¹ and R ^{1 ′} each represent a hydrogen atom, R ³ represents a methyl group, and R ⁴ represents a sec-butyl group. In another embodiment, R ⁵ represents a heterocycloalkyl group attached through a heteroatom, m represents 2 and X represents ◯. In other embodiments, R ² and R ^{2 ′} each represent a hydrogen atom, and R ³ represents an optionally substituted C ₁ -C ₄ alkyl group. In yet another embodiment, R ⁵ represents a nitrogen-bonded morpholinyl group, a 1-methylpiperazinyl group, a piperidinyl group or a pyrrolidinyl group, and R ¹ and R ^{1 ′} are each independently a hydrogen atom or optionally It may have a substituent represents an C ₁ -C ₄ alkyl group.

の構造を有する。一態様は、化学式ＩＢの構造を有する化合物であり、ここで、Ｒ^１、Ｒ^１'、Ｒ^３及びＲ^４は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基を表し、及びｎは、１、２、３又は４を表す。全ての開示した態様の一実施態様において、ｎは２を表し、Ｒ^１及びＲ１^'は、それぞれ水素原子を表し、Ｒ^３はメチル基を表し、及びＲ^４はsec-ブチル基を表す。他の実施態様において、Ｒ^５は、異種原子を介して結合するヘテロシクロアルキル基を表し、ｍは２を表し、及びＸは０を表す。他の実施態様において、Ｒ^２及びＲ^２'は各々、水素原子を表し、及びＲ^３は、任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、Ｒ^５は、窒素結合モルホリニル基、１−メチルピペラジニル基、ピペリジニル基又はピロリジニル基であり；及びＲ^１及びＲ^１'は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。 In yet other variations, the compound has the formula IB:

It has the structure of. One embodiment is a compound having the structure of Formula IB, wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently have a hydrogen atom, optionally a substituent. An alkyl group, an alkenyl group optionally having substituent (s) or an alkynyl group optionally having substituent (s) may be represented, and n represents 1, 2, 3 or 4. In one embodiment of all the disclosed aspects, n represents 2, R ¹ and R1 ^′ each represent a hydrogen atom, R ³ represents a methyl group, and R ⁴ represents a sec-butyl group. In another embodiment, R ⁵ represents a heterocycloalkyl group attached through a heteroatom, m represents 2 and X represents 0. In other embodiments, R ² and R ^{2 ′} each represent a hydrogen atom, and R ³ represents an optionally substituted C ₁ -C ₄ alkyl group. In yet another embodiment, R ⁵ is a nitrogen-bound morpholinyl group, 1-methylpiperazinyl group, piperidinyl group or pyrrolidinyl group; and R ¹ and R ^{1 ′} are each independently a hydrogen atom or any may have a substituent represent an C ₁ -C ₄ alkyl group.

で表される化合物、又はこれらの医薬的に許容された塩、エステル、プロドラッグ若しくは溶媒和物を開示し、ここでｐは、０、１、２、３、４、５又は６を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、=CH₂、=NH、=O又は=Sを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、水素原子、-NR^aR^b、-OH、-C(=O)OR^a、-C(=O)NHR^a、-NHC(=O)R^a、-NHS(=O)₂R^a又は任意に置換基を有していてもよいアルキル基を表し、Ｒ^ａ及びＲ^ｂは、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表し、及びＺはヘテロシクロアルキル基又はヘテロアリール基を表し、ここで各ヘテロシクロアルキル基又はヘテロアリール基には、異種原子を介して結合し、及びこれらは任意に置換される。他の態様は、化学式ＩＩで表される化合物であり、ここでｐは、１、２、３、４又は５を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、=O又は=Sを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、水素原子、−NR^aR^b、−OH、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基、又は任意に置換基を有していてもよいアルキニル基を表し、Ｒ^ａ及びＲ^ｂは、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表し、Ｚは、ヘテロシクロアルキル基又はヘテロアリール基を表し、ここで各ヘテロシクロアルキル基又はヘテロアリール基には、異種原子を介して結合し及びこれらは任意に置換される。全ての開示した態様の１つの実施態様において、ｐは１、２、又は３を表し、Ｙ、Ｖ及びＷは、それぞれＯを表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、及びＺは任意に置換基を有していてもよい窒素結合ヘテロシクロアルキル基を表す。他の実施態様において、ｐは１を表し、Ｒ^１０及びＲ^１１は、それぞれ水素原子を表し、及びＲ^１２及びＲ^１３は、それぞれ独立して、Ｃ_１〜Ｃ_４アルキル基を表す。 In another embodiment, the present application has Formula II:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V, and W each independently represent ═CH ₂ , ═NH, ═O, or ═S, and R ¹⁰ and R ¹¹ each independently have a hydrogen atom or an optional substituent. Each of R ¹² and R ¹³ independently represents a hydrogen atom, —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, and each of R ^a and R ^b independently represents a hydrogen atom or Represents an optionally substituted alkyl group, and Z represents a heterocycloalkyl group or a heteroaryl group, wherein each heterocycloalkyl group or heteroaryl group includes Bonded via a heteroatom, and which are optionally substituted. Another embodiment is a compound represented by Formula II, wherein p represents 1, 2, 3, 4 or 5, and Y, V and W are each independently ═O or ═S. R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted group. Represents an alkynyl group which may have, R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, an optionally substituted alkyl group, optionally Represents an alkenyl group optionally having a substituent, or an alkynyl group optionally having a substituent, and R ^a and R ^b each independently represent a hydrogen atom or an optional substituent. Represents an alkyl group which may have, Z represents a heterocycloalkyl group or a heteroary It represents a group, wherein each heterocycloalkyl group or a heteroaryl group, bonded via a heteroatom and which are optionally substituted. In one embodiment of all disclosed aspects, p represents 1, 2, or 3, Y, V and W each represent O, and R ¹² and R ¹³ each independently represent a hydrogen atom or An optionally substituted C ₁ -C ₄ alkyl group is represented, and Z represents an optionally substituted nitrogen-bonded heterocycloalkyl group. In another embodiment, p represents 1, R ¹⁰ and R ¹¹ each represent a hydrogen atom, and R ¹² and R ¹³ each independently represent a C ₁ -C ₄ alkyl group.

の構造で表される化合物、又はこの化合物の医薬的に許容された塩、エステル、プロドラッグ若しくは溶媒和物であり、ここでｐは、０、１、２、３、４、５又は６を表し、ｑは、１、２、３又は４を表し、ｔは、０、１、２、又は３を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、Ｏ又はＳを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子、又は任意に置換基を有していてもよいアルキル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して水素原子、-NR^aR^b、-OH、-C(=O)OR^a、-C(=O)NHR^a、-NHC(=O)R^a、-NHS(=O)₂R^a又は任意に置換基を有していてもよいアルキル基を表し、Ｒ^６は、それぞれ独立して、-NR^aR^b、-OH、-C(=O)OR^a、-C(=O)NHR^a、-NHC(=O)R^a、-NHS(=O)₂R^a又は任意に置換基を有していてもよいアルキル基を表し、及びＲ^ａ及びＲ^ｂは、それぞれ独立して、水素原子、又は任意に置換基を有していてもよいアルキル基を表す。一実施態様において、qは、１、２、３又は４を表し、tは、０、１、２、又は３を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、Ｏ又はＳを表し、及びＲ^６は、それぞれ独立して、-NR^aR^b、-OH、-C(=O)OR^a、-C(=O)NHR^a、-NHC(=O)R^a、-NHS(=O)₂R^a又は任意に置換基を有していてもよいアルキル基を表す。さらに他の態様において、この化合物は、化学式ＩＩＡの構造を有し、ここでＰは、１、２、３、４又は５を表し、ｑは、２又は３を表し、ｔは、０、１、２又は３を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、Ｏ又はＳを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基、又は任意に置換基を有していてもよいアルキニル基を表し、Ｒ^６は、それぞれ独立して、-NR^aR^b、-OH、又は任意に置換基を有していてもよいアルキル基を表し、Ｒ^ａ及びＲ^ｂは、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表す。全ての開示した態様の他の実施態様において、Ｙ、Ｖ及びＷは、それぞれＯを表し、ｑは１を表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子又はＣ_１〜Ｃ_４アルキル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、Ｃ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、Ｒ^１０及びＲ^１１は、それぞれ独立して水素原子を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、-Meを表し、及びＲ^６、Ｒ^６'、Ｒ^７、Ｒ^７'、Ｒ^８、Ｒ^８'、Ｒ^９及びＲ^９'は、それぞれ独立して、水素原子、-NR^aR^b、-OH又は任意に置換基を有していてもよいアルキル基を表す。全ての開示した実施態様の更なるバリエーション（変種）において、Ｒ^１０及びＲ^１１は、それぞれ独立してHを表し、Ｒ^１２及びＲ^１３は、それぞれ独立してMeを表し、ｑは２を表し、及びＲ^６、Ｒ^６'、Ｒ^７、Ｒ^７'、Ｒ^８、Ｒ^８'、Ｒ^９及びＲ^９'は、それぞれ独立して水素原子、-NR^aR^b、-OH、又は任意に置換基を有していてもよいアルキル基を表す。全ての開示された実施態様の更なる他のバリエーションにおいて、Ｒ^６、Ｒ^６'、Ｒ^７、Ｒ^７'、Ｒ^８、Ｒ^８'及びＲ^９は、それぞれ水素原子を表し、及びＲ^９'は、-N(CH₃)₂を表す。 In another embodiment, the compound has formula IIA:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate of this compound, wherein p is 0, 1, 2, 3, 4, 5 or 6. Q represents 1, 2, 3 or 4; t represents 0, 1, 2 or 3; Y, V and W each independently represent O or S; and R ¹⁰ and R ¹¹ independently represents a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , — OH, -C (= O) OR ^a , -C (= O) NHR ^a , -NHC (= O) R ^a , -NHS (= O) ₂ R ^a or optionally have a substituent R ⁶ represents an alkyl group, and each R ⁶ independently represents —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , -NHS (= O) represents ₂ R ^a or optionally may have a substituent group an alkyl group, and R ^a and R Each independently represent a hydrogen atom, or optionally may have a substituent alkyl group. In one embodiment, q represents 1, 2, 3 or 4, t represents 0, 1, 2 or 3, Y, V and W each independently represent O or S; And R ⁶ are each independently —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (= O) ₂ R ^a or an optionally substituted alkyl group. In yet another embodiment, the compound has the structure of Formula IIA, where P represents 1, 2, 3, 4 or 5, q represents 2 or 3, and t is 0, 1 2 or 3; Y, V and W each independently represent O or S; and R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, optionally having a substituent. Represents a good alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group, each R ⁶ independently represents —NR ^a R ^b , —OH, or an optionally substituted alkyl group, and R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted alkyl group. . In other embodiments of all disclosed aspects, Y, V and W each represent O, q represents 1, R ¹⁰ and R ¹¹ are each independently a hydrogen atom or C ₁ -C _4. Represents an alkyl group, and R ¹² and R ¹³ each independently represents a C ₁ -C ₄ alkyl group. In yet another embodiment, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, R ¹² and R ¹³ each independently represent —Me, and R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are each independently a hydrogen atom, —NR ^a R ^b , —OH or an optionally substituted alkyl group Represents. In further variations (variants) of all disclosed embodiments, R ¹⁰ and R ¹¹ each independently represent H, R ¹² and R ¹³ each independently represent Me, and q represents 2. , And R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are each independently a hydrogen atom, —NR ^a R ^b , —OH, or optionally The alkyl group which may have a substituent is represented. In still other variations of all disclosed embodiments, R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ⁸ , R ^{8 ′} and R ⁹ each represent a hydrogen atom, and R ^{9 ′.} Represents —N (CH ₃ ) ₂ .

の構造で表される化合物、又はこの化合物の医薬的に許可された塩、エステル、プロドラッグ若しくは溶媒和物であり、ここで、ｐは、０、１、２、３、４、５又は６を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、Ｏ又はＳを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子又は、任意に置換基を有していてもよいアルキル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、水素原子、-NR^aR^b、-OH、-C(=O)OR^a、-C(=O)NHR^a、-NHC(=O)R^a、-NHS(=O)₂R^a又は任意に置換基を有していてもよいアルキル基を表し、及びＲ'及びＲ"は、これに結合する窒素原子と共に任意に置換基を有していてもよい複素環アリール基を形成する。更に他の態様において、この化合物は、化学式ＩＩＢの構造を有し、ここでＰは１、２、３、４又は５を表し、Ｙ、Ｖ及びＷは、それぞれ独立して、Ｏ又はＳを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基、又は任意に置換基を有していてもよいアルキニル基を表し、Ｒ'及びＲ"は、これらに結合した窒素原子と共に任意に置換基を有していてもよいピリジル基、任意に置換基を有していてもよいピロリル基、任意に置換基を有していてもよいピリミジル基又は任意に置換基を有していてもよいピラジニル基を形成する。全ての開示した態様の他の実施態様において、Ｙ、Ｖ及びＷは、それぞれＯを表し、Ｒ^１０及びＲ^１１は、それぞれ独立して、水素原子又はＣ_１〜Ｃ_４アルキル基を表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、Ｃ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、Ｒ^１０及びＲ^１１は、それぞれ独立して水素原子を表し、Ｒ^１２及びＲ^１３は、それぞれ独立してMeを表す。全ての開示した実施態様の更なるバリエーションにおいて、Ｒ^１０及びＲ^１１は、それぞれ独立して、-Hを表し、Ｒ^１２及びＲ^１３は、それぞれ独立して、-Meを表し、ｑは２を表し、及びＲ'及びＲ"は、これらに結合する窒素原子と共に任意に置換基を有していてもよいピロリル基を形成する。 In another embodiment, the compound has the formula IIB:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate of this compound, wherein p is 0, 1, 2, 3, 4, 5 or 6 Y, V and W each independently represent O or S, and R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted alkyl group. R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O ) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, and R ′ and R ″ are optionally substituted together with the nitrogen atom bonded thereto. In yet another embodiment, the compound has the structure of Formula IIB, where P represents 1, 2, 3, 4 or 5; , V and W are each independently O or S, R ¹⁰ and R ¹¹ are each independently hydrogen atom, optionally optionally substituted alkyl group, an optionally substituted group Represents an alkenyl group optionally having a substituent, or an alkynyl group optionally having a substituent, and R ′ and R ″ optionally have a substituent together with a nitrogen atom bonded thereto. A pyridyl group which may optionally have a pyrrolyl group which may optionally have a substituent, a pyrimidyl group which may optionally have a substituent or a pyrazinyl group which may optionally have a substituent. In other embodiments of all disclosed aspects, Y, V and W each represent O, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group, R ¹² and R ¹³ each independently represents a C ₁ -C ₄ alkyl group. In yet another embodiment, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, and R ¹² and R ¹³ each independently represent Me. In further variations of all disclosed embodiments, R ¹⁰ and R ¹¹ each independently represent —H, R ¹² and R ¹³ each independently represent —Me, and q represents 2. And R ′ and R ″ together with the nitrogen atom bound to them form an optionally substituted pyrrolyl group.

を有する。 In other further variations, the compound has the structural formula:

Have

で表される化合物、又はこの医薬的に許容された塩、エステル、プロドラッグ若しくは溶媒和物を開示するが、ここで、Ｘは、CH₂、NH、O又はSを表し、ｓは、０、１、２、３又は４を表し、Ｒ^１９、Ｒ^１９′、Ｒ^２０、Ｒ^２０′、Ｒ^２１、Ｒ^２１′、Ｒ^２２、Ｒ^２２′及びＲ^２４は、それぞれ独立して、不存在、水素原子、又は任意に置換基を有していてもよいアルキル基を表し、又はＲ^２０及びＲ^２０'は共に=O、=S又は=CH₂を形成してもよく、又はＲ^２０及びＲ^２１はこれらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成してもよく、又はＲ^２０及びＲ^２１はこれらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成してもよく、又はＲ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成してもよく、又はＲ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成してもよく、及びＲ^２３は、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいシクロアルキル基、又は任意に置換基を有していてもよいアリール基を表す。全ての開示した態様又はバリエーションの一実施態様において、Ｒ^２３は水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいシクロアルキル基又は任意的置換アリール基を表す。全ての開示した態様又はバリエーションの一実施態様において、化学式IIIで表される化合物は、2-アミノ-3-メチル-N-(2-モルホリノエチル)-ブタンアミドではない。更に他の態様は、化学式IIIで表される化合物を表し、ここでＸがＯ又はＳを表し、ｓが０、１、２又は３を表し、Ｒ^１９、Ｒ^１９′、Ｒ^２０、Ｒ^２０′、Ｒ^２１、Ｒ^２１′、Ｒ^２２、Ｒ^２２′及びＲ^２４は、それぞれ独立して、不存在、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基、又は任意に置換基を有していてもよいアルキニル基を表し、又はＲ^２０及びＲ^２０'は共に=O又は=Sを形成してもよく、Ｒ^２０及びＲ^２１は、結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成し；又はR²⁰及びＲ^２１は、これらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成してもよく、又はＲ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成してもよく、又はＲ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成してもよく、及びＲ^２３は、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基、任意に置換基を有していてもよいシクロアルキル基又は任意に置換基を有していてもよいアリール基を表す。開示した全ての態様の一実施態様において、ＸはＯを表し、ｓは０を表し、Ｒ^２２'は水素原子を表し、Ｒ^２２は、任意に置換基を有していてもよいＣ_１〜Ｃ_６アルキル基を表す。他の実施態様において、Ｒ^２０、Ｒ^２０'、Ｒ^２１及びＲ^２１'は、独立して、水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、又はＲ^２０及びＲ^２０'は、共に=Oを形成する。他の実施態様において、ＸはＯを表し、ｓは０を表し、Ｒ^２２及びＲ^２２'は、それぞれ水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_６アルキル基を表し、Ｒ^２０、Ｒ^２０'、Ｒ^２１及びＲ^２１'は、それぞれ独立して、水素原子、又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、又はＲ^２０及びＲ^２０'は、共に=Oを形成する。他の実施態様において、Ｒ²⁰及びＲ^２１は、これらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成する；又はＲ^２０及びＲ^２１は、これらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成する。 In another embodiment, the present application provides Formula III:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein X represents CH ₂ , NH, O or S, and s is 0 , 1, 2, 3 or 4 and R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² , R ^{22 ′} and R ²⁴ are each independently absent. , A hydrogen atom, or an optionally substituted alkyl group, or R ²⁰ and R ^{20 ′} may form ═O, ═S or ═CH ₂ , or R ²⁰ and R ²¹ may form an optionally substituted cycloalkyl group together with the atoms bonded to these, or R ²⁰ and R ²¹ may optionally have a substituent together with the atoms bonded thereto. May form an aryl group, or R ¹⁹ and R ²⁰ may be bonded to them. A cycloalkyl group which may optionally have a substituent may be formed together with the atoms to be combined, or R ¹⁹ and R ²⁰ may optionally have a substituent together with the atoms bonded thereto. An aryl group may be formed, and R ²³ may have an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted group. Represents an optionally substituted aryl group. In one embodiment of all disclosed aspects or variations, R ²³ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group or optionally Represents a substituted aryl group. In one embodiment of all disclosed aspects or variations, the compound of formula III is not 2-amino-3-methyl-N- (2-morpholinoethyl) -butanamide. Yet another embodiment represents a compound represented by Formula III, wherein X represents O or S, s represents 0, 1, 2 or 3, and R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² , R ^{22 ′} and R ²⁴ are each independently absent, a hydrogen atom, an optionally substituted alkyl group, and optionally a substituent. Represents an alkenyl group which may have, or optionally an alkynyl group which may have a substituent, or R ²⁰ and R ^{20 ′} may form ═O or ═S, and R ²⁰ and R ²¹ forms an optionally substituted cycloalkyl group with the atom to which it is bonded; or R ²⁰ and R ²¹ may optionally have a substituent with the atom to which they are bonded. It may form an aryl group, or R ¹⁹ and R ^20, to bind to these Optionally may form a cycloalkyl group which may have a substituent together with the atom, or R ¹⁹ and R ^20, an aryl group which may have optionally substituent together with the atoms bonded thereto And R ²³ may optionally have a substituent, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted group. It represents a good alkynyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group. In one embodiment of all disclosed aspects, X represents O, s represents 0, R ^{22 ′} represents a hydrogen atom, and R ²² optionally has a substituent from C ₁ to C ₁ . It represents a C ₆ alkyl group. In another embodiment, R ²⁰ , R ^{20 ′} , R ²¹ and R ^{21 ′} independently represent a hydrogen atom or an optionally substituted C ₁ -C ₄ alkyl group, or R ²⁰ and R ^{20 ′} together form ═O. In another embodiment, X represents O, s represents 0, R ²² and R ^{22 ′} each represent a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group. , R ²⁰ , R ^{20 ′} , R ²¹ and R ^{21 ′} each independently represent a hydrogen atom or an optionally substituted C ₁ -C ₄ alkyl group, or R ²⁰ and R ^{20 ′} together form ═O. In other embodiments, R ²⁰ and R ²¹ together with the atoms bonded to them form an optionally substituted cycloalkyl group; or R ²⁰ and R ²¹ are bonded to them. And an aryl group optionally having a substituent is formed.

を有する。他の実施態様において、ｓは２を表し、ＸはＯを表し、Ｒ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成し；又はＲ^１９及びＲ^２０は、これらに結合する原子と共に任意に置換基を有していてもよいアリール基を形成する。 In one variation, the compound has the structural formula:

Have In another embodiment, s represents 2, X represents O, and R ¹⁹ and R ²⁰ together with the atoms bonded to them form an optionally substituted cycloalkyl group; or R ¹⁹ and R ²⁰ together with the atoms bonded thereto form an aryl group that may optionally have a substituent.

を有する。 In one variation, the compound has the structural formula:

Have

から成る群から選択される構造式を有する。 In other variations, the compound has the following:

Having a structural formula selected from the group consisting of

から成る群から選択される構造式を有する。 In still other variations of all disclosed embodiments, the compound is:

Having a structural formula selected from the group consisting of

から成る群から選択される構造式を有する化合物が含まれる。
このような化合物は、本明細書の開示及び当業者が熟知している化学合成法に基づいて調剤することができる。 In addition:

A compound having a structural formula selected from the group consisting of:
Such compounds can be formulated based on the disclosure herein and chemical synthesis methods familiar to those skilled in the art.

で表される化合物又は医薬的に許容されたこれらの塩、エステル、プロドラッグ若しくは溶媒和物を開示し、ここでｐは、１、２、３、４、５又は６を表し、Ｙ、Ｖ及びＷは、それぞれ独立してＣＨ_２、ＮＨ、Ｏ又はＳを表し、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３２′Ｒ^３３、Ｒ^３４、Ｒ^３４′、Ｒ^３５、Ｒ^３５′、Ｒ^３６、及びＲ^３６′は、それぞれ独立して、不存在、水素原子、又は任意に置換基を有していてもよいアルキル基を表し、又はＲ^３４及びＲ^３６は、これらに結合する原子と共に、任意に置換基を有していてもよい炭化水素環を形成してもよく、Ｅは、-CHR^cR^d、-NR^cR^d、-OR^c又はSR^cを表し、及び Ｒ^ｃ及びＲ^ｄは、それぞれ独立して、水素原子又は任意に置換基を有していてもよいアルキル基を表し、又は、Ｒ^ｃ及びＲ^ｄはこれらに結合する窒素原子と共に任意に置換基を有していてもよい複素環基を形成し、又はＲ^ｃ及びＲ^ｄはこれらに結合する炭素原子と共に任意に置換基を有していてもよい炭素環基を形成する。全ての開示した態様又はバリエーションの一実施態様において、化学式ＩＶで表される化合物は、N-(3-(ジエチルアミノ)プロピルl)-2-(4,6-ジメチル-5,7-ジオキソ-4,5,6,7-テトラヒドロ-1H-ベンゾ[d]イミダゾール-1-yl)アセトアミドではない。１つのバリエーションにおいて、ｐは１，２又は３を表し、Ｙ，Ｖ及びＷは、それぞれＯ又はＳを表し、Ｒ^３０及びＲ^３１は、それぞれ独立して、任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、Ｒ^３２、Ｒ^３２′Ｒ^３３、Ｒ^３４、Ｒ^３４′、Ｒ^３５、Ｒ^３５′、Ｒ^３６、及びＲ^３６′は、それぞれ独立して水素原子又は、任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表し、及びＥは、-OR^c、-SR^c又は-NR^cR^d を表し、ここでＲ^ｃ及びＲ^ｄは、これらに結合する窒素原子と共に任意に置換基を有していてもよい複素環アルキル基を形成する。 In another embodiment, the present application provides Formula IV:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein p represents 1, 2, 3, 4, 5 or 6, and Y, V And W each independently represent CH ₂ , NH, O or S, and R ³⁰ , R ³¹ , R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ^36. , And R ^{36 ′} each independently represents an absent group, a hydrogen atom, or an optionally substituted alkyl group, or R ³⁴ and R ³⁶ together with the atoms bonded thereto, An optionally substituted hydrocarbon ring may be formed, E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c or SR ^c , and R ^c and R ^d each independently represents a hydrogen atom or an optionally substituted alkyl group, or R ^c and R ^d together with the nitrogen atom bonded to these form an optionally substituted heterocyclic group, or R ^c and R ^d optionally combine with the carbon atom bonded to these. A carbocyclic group which may be present is formed. In one embodiment of all disclosed aspects or variations, the compound of formula IV is N- (3- (diethylamino) propyl 1) -2- (4,6-dimethyl-5,7-dioxo-4 , 5,6,7-tetrahydro-1H-benzo [d] imidazol-1-yl) acetamide. In one variation, p represents 1, 2 or 3, Y, V and W each represent O or S, and R ³⁰ and R ³¹ are each independently optionally substituted. Represents a C ₁ -C ₄ alkyl group, and R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} each independently represent a hydrogen atom. Or an optionally substituted C ₁ -C ₄ alkyl group and E represents —OR ^c , —SR ^c or —NR ^c R ^d , wherein R ^c and R ^d Forms a heterocyclic alkyl group optionally having a substituent together with the nitrogen atom bonded thereto.

In one embodiment, the compound has the structure of formula IV, wherein p represents 1, 2, 3 or 4, and Y, V and W each independently represent O or S. , R ³⁰ , R ³¹ , R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} are each independently, absent, hydrogen atom, Represents an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group, or R ³⁴ and R ³⁶ may form a carbocyclic group optionally having substituent (s) together with the atoms bonded thereto, and E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c or — represents SR ^c, and R ^c and R ^d are independently hydrogen atom, an alkyl group optionally having a substituent Optionally represents an alkynyl group which may be have a good alkenyl group or an optionally substituted group optionally having a substituent, or R ^C and R ^d optionally substituent together with the nitrogen atom bonded thereto An optionally substituted heterocyclic group is formed, or R ^c and R ^d together with the carbon atom bonded to these form an optionally substituted carbocyclic group. In one embodiment of all disclosed aspects, p represents 1, 2 or 3, Y, V and W each represent O or S, E represents —OR ^c or —SR ^c , R ³² , R ^{32 ′} R ³³ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , and R ^{36 ′} each independently represent a hydrogen atom, and R ³⁰ and R ³¹ are each independently, optionally It may have a substituent represents an C ₁ -C ₄ alkyl group. In another embodiment, p represents 1, 2 or 3, Y, V and W each represent O or S, E represents NR ^c R ^d , and R ^c and R ^d represent these A heterocycloalkyl group optionally having substituent (s) is formed together with a nitrogen atom bonded to R; and R ³⁰ and R ³¹ are each independently optionally substituted C _1. represents -C ₄ alkyl ^{radical, R 32, R 32 ',} R 33, R 34, R 34', R 35, R 35 ', R 36 and ^{R 36'} are each independently a hydrogen atom or an optionally It may have a substituent represents an C ₁ -C ₄ alkyl group. Furthermore, in another embodiment, p represents 1, Y, V and W each represents O, R ³⁰ and R ³¹ each independently represent —CH ₃ , and R ³³ represents a hydrogen atom. And R ³² , R ^{32 ′} , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. In one variation of all disclosed embodiments, E represents —NR ^c R ^d , and R ^c and R ^d are each independently a hydrogen atom or an optionally substituted alkyl group. Represents. In other embodiments, R ³⁴ and R ³⁶ together with the atoms attached to them form an optionally substituted cycloalkyl group; and R ³⁴ and R ³⁶ are atoms attached to them. Together with optionally forming a carbocyclic aryl group which may have a substituent.

を有する。全ての開示した実施態様の他のバリエ―ションにおいて、Ｅは、-NR^cR^dを表し、及びＲ^ｃ及びＲ^ｄは、これらに結合する窒素原子と共に任意に置換基を有していてもよいヘテロシクロアルキル基を形成する。 In another embodiment, the compound has the structural formula:

Have In other variations of all disclosed embodiments, E represents —NR ^c R ^d , and R ^c and R ^d optionally have a substituent with a nitrogen atom attached thereto. Forms a good heterocycloalkyl group.

から成る群から選択される構造式を有する。 In one variation, the compound has the following:

Having a structural formula selected from the group consisting of

から成る群から選択される構造式を有する。 In yet another embodiment, the compound has the following:

Having a structural formula selected from the group consisting of

を含む。 Alternatively, such compounds are:

including.

も含まれる。 In addition:

Is also included.

で表される化合物又はこれらの化合物の医薬的に許容された塩、エステル、プロドラッグ若しくは溶媒和物を提供するが、ここでｐは１、２、３、４、５又は６を表し、Ｖは、CH₂、NH、O又はSを表し、Ｒ^３２、Ｒ^３２'、Ｒ^３３、Ｒ^３４、Ｒ^３４'、Ｒ^３５、Ｒ^３５'、Ｒ^３６及びＲ^３６'は、それぞれ独立して、不存在、水素原子又は任意に置換基を有していてもよいアルキル基を表し、又はＲ^３４及びＲ^３６は、これらに結合する原子と共に任意に置換基を有していてもよい炭素環基を形成してもよく、Ｅは、-CHR^cR^d、-NR^cR^d、-OR^c及び-SR^cを表し、及びＲ^ｃ及びＲ^ｄは、それぞれ独立して水素原子又は任意に置換基を有していてもよいアルキル基を表し、又はＲ^ｃ及びＲ^ｄは、これらに結合する窒素原子と共に任意に置換基を有していてもよい複素環基を形成し、又はＲ^c及びＲ^ｄは、これらに結合する炭素原子と共に任意に置換基を有していてもよい炭素環基を形成する。一態様において、この化合物は、化学式IVＡの構造を有し、ここでｐは、１、２、３又は４を表し、Ｖは、Ｏ又はＳを表し、Ｒ^３２、Ｒ^３２'、Ｒ^３３、Ｒ^３４、Ｒ^３４'、Ｒ^３５、Ｒ^３５'、Ｒ^３６及びＲ^３６'は、それぞれ独立して、不存在、水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基又は任意に置換基を有していてもよいアルキニル基を表し、又はＲ^３４及びＲ^３６はこれらに結合する原子と共に任意に置換基を有していてもよい炭素環基を形成してもよく、Ｅは、-CHR^cR^d、-NR^cR^d、-OR^c又は-SR^cを表し、及びＲ^ｃ及びＲ^ｄは、それぞれ独立して水素原子、任意に置換基を有していてもよいアルキル基、任意に置換基を有していてもよいアルケニル基、又は任意に置換基を有していてもよいアルキニル基を表し、又はＲ^ｃ及びＲ^ｄは、これらに結合する窒素原子と共に任意に置換基を有していてもよい複素環基を形成し、又はＲ^ｃ及びＲ^ｄは、これらに結合する炭素原子と共に任意に置換基を有していてもよい炭素環基を形成する。全ての開示した態様の一実施態様において、ｐは、１、２又は３を表し、ＶはＯ又はＳを表し、Ｅは、-OR^c又はSR^cを表し、Ｒ^３２、Ｒ^３２'、Ｒ^３３、Ｒ^３４'、Ｒ^３５、Ｒ^３５'及びＲ^３６'は、それぞれ独立して水素原子を表す。他の実施態様において、ｐは、１、２又は３を表し、ＶはＯ又はＳを表し、Ｅは、-NR^cR^dを表し、及びＲ^ｃ及びＲ^ｄは、これらに結合する窒素原子と共に任意に置換基を有していてもよいヘテロシクロアルキル基を形成し；及びＲ^３２、Ｒ^３２'、Ｒ^３３、Ｒ^３４、Ｒ^３４'、Ｒ^３５、Ｒ^３５'、Ｒ^３６、及びＲ^３６'は、それぞれ独立して水素原子又は任意に置換基を有していてもよいＣ_１〜Ｃ_４アルキル基を表す。更に他の実施態様において、ｐは１を表し、Ｖは、Ｏを表し、Ｒ^３３は、水素原子を表し、及びＲ^３２、Ｒ^３２'、Ｒ^３４、Ｒ^３４'、Ｒ^３５、Ｒ^３５'、Ｒ^３６、及びＲ^３６'は、それぞれ独立して水素原子又はＣ_１〜Ｃ_４アルキル基を表す。全ての開示した実施態様の一バリエーションにおいて、Ｅは、-NR^cR^dを表し、及びＲ^ｃ及びＲ^ｄは、それぞれ独立して水素原子又は任意に置換基を有していてもよいアルキル基を表す。他の実施態様において、Ｒ^３４及びＲ^３６は、これらに結合する原子と共に任意に置換基を有していてもよいシクロアルキル基を形成し；又はＲ^３４及びＲ^３６は、これらに結合する原子と共に任意に置換基を有していてもよい炭素環アリール基を形成する。 In another embodiment, the present application provides a chemical formula IVA:

Or a pharmaceutically acceptable salt, ester, prodrug or solvate of these compounds, wherein p represents 1, 2, 3, 4, 5 or 6; Represents CH ₂ , NH, O or S, and R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} are each independently Absence, a hydrogen atom or an optionally substituted alkyl group, or R ³⁴ and R ³⁶ are optionally substituted with atoms bonded to these carbocyclic groups E represents -CHR ^c R ^d , -NR ^c R ^d , -OR ^c and -SR ^c , and R ^c and R ^d are each independently a hydrogen atom or an optionally substituted It represents an alkyl group which may have a group, or R ^c and R ^d, optionally substituted group together with the nitrogen atom bonded thereto Also form a heterocyclic group optionally having, or R ^c and R ^d form a optionally may have a substituent group carbocyclic group together with the carbon atoms bonded thereto. In one embodiment, the compound has the structure of formula IVA, where p represents 1, 2, 3 or 4, V represents O or S, R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} are each independently absent, a hydrogen atom, an optionally substituted alkyl group, and optionally substituted. Represents an alkenyl group which may have a group or an alkynyl group which may optionally have a substituent, or R ³⁴ and R ³⁶ may optionally have a substituent together with an atom bonded thereto. May form a good carbocyclic group, E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c or —SR ^c , and R ^c and R ^d each independently represents a hydrogen atom; An optionally substituted alkyl group, an optionally substituted alkenyl group, or optionally It represents an alkynyl group which may have a substituent, or R ^c and R ^d, optionally having a substituent to form a well heterocyclic group together with the nitrogen atom bonded thereto, or R ^c And R ^d together with the carbon atom bonded to these forms an optionally substituted carbocyclic group. In one embodiment of all disclosed aspects, p represents 1, 2 or 3, V represents O or S, E represents —OR ^c or SR ^c , R ³² , R ^{32 ′} , R ³³ , R ^{34 ′} , R ³⁵ , R ^{35 ′} and R ^{36 ′} each independently represent a hydrogen atom. In another embodiment, p represents 1, 2 or 3, V represents O or S, E represents —NR ^c R ^d , and R ^c and R ^d represent a nitrogen atom bonded thereto. Together with an optionally substituted heterocycloalkyl group; and R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} each independently represents a hydrogen atom or an optionally substituted C ₁ -C ₄ alkyl group. In yet another embodiment, p represents 1, V represents O, R ³³ represents a hydrogen atom, and R ³² , R ^{32 ′} , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′.} , R ³⁶ , and R ^{36 ′} each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. In one variation of all disclosed embodiments, E represents —NR ^c R ^d , and R ^c and R ^d are each independently a hydrogen atom or an optionally substituted alkyl group. Represents. In other embodiments, R ³⁴ and R ³⁶ together with the atoms attached to them form an optionally substituted cycloalkyl group; or R ³⁴ and R ³⁶ are atoms attached to them. Together with optionally forming a carbocyclic aryl group which may have a substituent.

を有する。 In one embodiment, the compound has the structural formula:

Have

  Since the p75 receptor is upregulated in various physiological conditions, the compounds disclosed herein can also be coupled to molecular markers that can be detected by imaging or other methods. Such conjugates can be made by synthetic methods known to those skilled in the art and are applied to diagnostic methods designed to detect such pathological conditions.

  In other embodiments, the invention provides (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N A compound selected from the group consisting of-(2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; or a medicament thereof A pharmaceutically acceptable salt, solvate, ester or prodrug is provided. In one embodiment, the compound has a purity of about 80% or greater. In other embodiments, the compound has a purity of about 85% or greater. In other embodiments, the compound has a purity of about 90% or greater. In other embodiments, the compound has a purity of about 95% or greater. In other embodiments, the compound has a purity of about 96% or greater. In other embodiments, the compound has a purity of about 97% or greater. In other embodiments, the compound has a purity of about 98% or greater. In other embodiments, the compound has a purity of about 99% or greater. In other embodiments, the compound has a purity of about 99.5% or greater.

  In other embodiments, the invention provides (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3R) -2-amino-3-methyl-N -(2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3- Provided is a mixture of two or more compounds selected from the group consisting of methyl-N- (2-morpholinoethyl) -pentanamide; or a pharmaceutically acceptable salt, solvate or prodrug of these compounds. Provided that (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide and (2R, 3R) -2-amino-3-methyl-N- (2 (2S, 3S) -2-amino-3-methyl-N- () when it is a mixture consisting only of -morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The amount of 2-morpholinoethyl) -pentanamide or a pharmaceutically acceptable salt, solvate or prodrug thereof is less than about 5% by weight relative to the total amount of the mixture. In one embodiment, the mixture consists of only two of any of the above four compounds. In other embodiments, the mixture consists of any three of the above four compounds. In another embodiment, the mixture consists of the above four compounds. Under the above conditions, the individual compounds in the mixture can be in any proportions or weight percentages. In one embodiment, any two or more compounds in the mixture is about 0.5% or more by weight. In other embodiments, the amount of any of the two or more compounds in the mixture is about 5% by weight or more. In other embodiments, each of the two or more compounds in the mixture is about the same amount.

(2S,3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)-ペンタンアミド

(2R,3R)-2-アミノ-3-メチル-N-(2-モルホリノエチル)-ペンタンアミド

(2S,3R)-2-アミノ-3-メチル-N-(2-モルホリノエチル)-ペンタンアミド

(2R,3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)-ペンタンアミド Mechanism A provides the chemical structure of the compound.
Mechanism A:

(2S, 3S) -2-Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide

(2R, 3R) -2-Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide

(2S, 3R) -2-Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide

(2R, 3S) -2-Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide

  In one embodiment, the present invention provides (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, and (2S, 3S) -2-amino-3-methyl- Provide a mixture of N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate or prodrug of these compounds, but (2S, 3S) -2 for the total amount of the mixture -Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide or a pharmaceutically acceptable salt, solvate or prodrug amount of this compound is less than about 5% by weight . Under the above conditions, the individual compounds in the mixture may be in any proportion and weight%. In certain embodiments, the mixture comprises about equal amounts of (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, and (2S, 3S) -2 It consists of -amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate or prodrug of these compounds.

  In one embodiment, the invention provides (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, and (2S, 3R) -2-amino-3-methyl- Provided are mixtures of N- (2-morpholinoethyl) -pentanamide, or pharmaceutically acceptable salts, solvates, esters or prodrugs of these compounds. The individual compounds in the mixture can be in any proportion or weight percent. In certain embodiments, the mixture comprises (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, and (2S, 3R) -2-amino-3 It consists of a mixture of -methyl-N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate, ester or prodrug of these compounds.

  In another embodiment, the present invention provides (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl- N- (2-morpholinoethyl) -pentanamide and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or pharmaceutically acceptable salts of these compounds And a solvate, ester or prodrug; and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

  In other embodiments, the invention provides (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3R) -2-amino-3-methyl-N -(2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide and (2S, 3R) -2-amino-3-methyl A mixture of two or more compounds selected from the group consisting of: -N- (2-morpholinoethyl) -pentanamide; or a pharmaceutically acceptable salt, solvate or prodrug of these compounds; Provides a pharmaceutical composition consisting of (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, and (2R, 3R) A mixture consisting of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate or prodrug of these compounds; then (2S, 3S ) -2- Under conditions that amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt, solvate or prodrug of this compound is not more than about 5% by weight .

The present application provides compounds having binding specificity for the p75 ^NRT molecule. These compounds, along with related pharmaceutical compounds and methods, are useful in the treatment and prevention of neurodegeneration and other disorders.

A set of compounds disclosed herein is indicated below:
Table I. Structure of compounds i to vii

One object of the present invention is to provide a method of promoting cell survival using neurotrophin mimetics.
In accordance with the present invention, exemplary neurotrophins include, but are not limited to, NGF. More specifically, a neurotrophin β-turn loop having binding specificity for the p75 ^NTR molecule includes, but is not limited to, loop 1 of NGF.
As disclosed herein, representative structures of the compounds or mimetics having binding specificity for p75 ^NTR molecule can bind to neurotrophin binding site of the p75 ^NTR molecule.
The compounds disclosed herein can also include derivatives of the parent compound that have binding specificity for p75 ^NTR , where the derivative also has binding specificity for p75 ^NTR . The derivative exhibits an enhancement of at least one property selected from the group consisting of hydrophilicity, lipophilicity, amphiphilicity, solubility, bioavailability, and resistance to degradation in the liver as compared to the parent compound. be able to.
It should be understood that in some embodiments, the compounds disclosed herein can include a pharmacophore that is substantially identical to the pharmacophore described in FIG. 1c. Representative examples of such compounds include, but are not limited to, compounds encompassed by chemical formula (A) and chemical formula (B).

The individual compounds or mixtures described above can be used for the treatment of a wide range of conditions and diseases described herein.
In one embodiment, a pharmaceutically acceptable diluent or carrier, and a compound of formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt thereof, Pharmaceutical compositions comprising esters, prodrugs or solvates are provided.
In another embodiment, to a patient in need of such treatment, a compound of formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt or ester thereof A method of treating a disorder associated with p75 expression comprising administering a prodrug or solvate. In one embodiment, the disorder is directly related to cells expressing p75; in other embodiments, the cells do not express p75 and are affected by p75 expression.
In another embodiment, a cell containing the p75 receptor, a compound represented by the formula I, IA, IB, II, IIA, IIB, III, IV or IVA, or a pharmaceutically acceptable salt, ester, pro thereof Provided is a method for activating the p75 receptor comprising contacting with a drug or solvate.

  In another embodiment, a compound of formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt thereof to a patient in need of such treatment A method for treating disorders associated with degeneration or dysfunction of cells expressing p75, comprising administering an ester, prodrug or solvate. In one embodiment, the method of treatment consists of promoting cell survival; in other embodiments, the method of treatment consists of inhibiting degenerative p75 signaling; in yet another embodiment, the method of treatment is dysfunctional. consists of inhibition of p75 signaling. In one embodiment, the disorder is a neurodegenerative disorder. In other embodiments, the disorder is Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord disorder, stroke, hypoxia, ischemia, encephalopathy, diabetic neuron Selected from the group consisting of cerebral disease, peripheral nerve disease, nerve transplantation, multiple sclerosis, peripheral neuropathy and hair loss.

  As disclosed herein, a compound represented by the formula I, IA, IB, II, IIA, IIB, III, IV or IVA targeting a p75 receptor expressed by a nerve cell, or a pharmaceutically acceptable salt thereof. Acceptable salts, esters, solvates or prodrugs are used to prevent neuronal loss of function, degeneration and / or cell death in many nervous system disorders. Such disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord disorder, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neurosis, myopathy, and various There are types of retinal degeneration, but are not limited to these. In one embodiment, the compounds of the present application are used for the treatment of Alzheimer's disease. A compound of formula I, IA, IB, II, IIA, IIB, III, IV or IVA that targets the p75 receptor expressed by oligodendrocytes as disclosed herein Or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, including many neurological disorders including but not limited to multiple sclerosis, spinal cord injury, and perinatal anoxia Is used to prevent oligodendrocyte function loss, degeneration and / or cell death. In other embodiments, the compounds of the present application are used to treat multiple sclerosis.

  Outside the nervous system, many cells express the p75 receptor. These include hair follicle cells, stem cells, vascular endothelial cells, vascular smooth muscle cells, and cardiomyocytes. In addition, the p75 receptor is expressed by certain tumor cells, such as those involved in breast or prostate cancer. Given this expression pattern, as disclosed herein, a compound of formula I, IA, IB, II, IIA, IIB, III, IV or IVA targeting the p75 receptor or These pharmaceutically acceptable salts, esters, solvates or prodrugs prevent hair follicle cell loss and thereby prevent hair loss; prevent cirrhosis and promote liver regeneration; Promotion of promotion of neovascularization at the beginning of regulation and diabetic wounds or other ischemia; for example, prevention of cardiomyocyte loss after initiation of ischemia or myocardial infarction, or prevention of cardiomyopathy by promoting neocardiac proliferation Used for inhibition of tumor cell growth. Furthermore, p75 is known to be expressed and regulates stem cell proliferation in stem cells; thus, as part of a method for promoting tissue and organ regeneration, p75 ligands are used to promote stem cell proliferation. Is used.

から成る群から選択される。 In one variation of all disclosed aspects or embodiments, the compound administered to a patient in need of this compound is:

Selected from the group consisting of

から成る群から選択される。 In all disclosed aspects or other variations of embodiments, the compound administered to a patient in need of this compound is:

Selected from the group consisting of

  In another embodiment, a method for treating a disorder associated with p75 expression is provided, the method comprising (2R, 3R) -2-amino-3-methyl to a patient in need of such treatment. -N- (2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino- Stereoisomers of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, including 3-methyl-N- (2-morpholinoethyl) -pentanamide, or pharmaceutically of these compounds A method comprising the administration of an acceptable salt, ester, solvate or prodrug. In one embodiment, the disorder is directly associated with cells that express p75; in other embodiments, the cells do not express p75 but are affected by p75 expression. In other embodiments, a method of activating a p75 receptor is provided, which comprises cells comprising a p75 receptor and (2R, 3R) -2-amino-3-methyl-N- (2-morpholino Ethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- ( Stereoisomers of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, including 2-morpholinoethyl) -pentanamide, or pharmaceutically acceptable salts, esters, solvents of these compounds It is a method consisting of contact with a Japanese or prodrug.

  In other embodiments, a method of treating a disorder associated with degeneration or loss of function of cells expressing p75 is provided, wherein the method is directed to a patient in need of such treatment (2R, 3R) -2- Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) 2-Amino-3-methyl-N- (2-morpholinoethyl) -pentanamide stereoisomers or compounds thereof, including 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide A pharmaceutically acceptable salt, ester, solvate or prodrug. In one embodiment, the method of treatment consists of promoting cell survival; in other embodiments, the method of treatment consists of inhibiting degenerative p75 signaling; in yet another embodiment, the method of treatment is functional. It consists of inhibition of defective p75 signaling. . In one embodiment, the disorder is a neurodegenerative disorder. In other embodiments, the disorder is Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord disorder, stroke, hypoxia, ischemia, encephalopathy, diabetic neuron Selected from the group consisting of dystrophy, peripheral neuropathy, nerve transplantation, multiple sclerosis, peripheral neuropathy, and hair loss.

  (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide targeting the p75 receptor expressed by neurons as disclosed herein; 2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentane Stereoisomers of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, including amides, or pharmaceutically acceptable salts, esters, solvates or prodrugs of these compounds are: Used to prevent neuronal loss of function, degeneration, and / or cell death in many nervous system disorders. Such disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord disorder, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neurosis, myopathy, and various types Including, but not limited to, retinal degeneration. In one embodiment, the compounds of the present application are used in the treatment of Alzheimer's disease. (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide targets the p75 receptor expressed by oligodendrocytes as disclosed herein (2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) Stereoisomers of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, including -pentanamide, or pharmaceutically acceptable salts, esters, solvates or prodrugs of these compounds Prevents oligodendrocyte loss of function, degeneration, and / or cell death in many neurological disorders including, but not limited to, multiple sclerosis, spinal cord disorders and perinatal anoxia Used for. In other embodiments, the compounds of the present application are used for the treatment of multiple sclerosis.

  Outside the nervous system, many cell populations express the p75 receptor. These cell populations include hair follicle cells, stem cells, vascular endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Furthermore, the p75 receptor is expressed by certain tumor cells, such as those included in breast or prostate cancer. Given this expression pattern, as disclosed herein, (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide targeting the p75 receptor; 2R, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentane Stereoisomers of 2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, including amides, or pharmaceutically acceptable salts, esters, solvates or prodrugs of these compounds are: Prevention of hair follicle cell loss and thereby prevention of hair loss; prevention of cirrhosis and promotion of liver regeneration; regulation of angiogenesis and promotion of neovascularization at the onset of diabetic wounds or other ischemia; For example, prevention of cardiomyocyte loss after ischemia initiation or myocardial infarction, or prevention of cardiomyopathy by promoting new cardiomyocyte proliferation ; And used for the inhibition of tumor cell proliferation. Furthermore, p75 is known to be expressed in and regulates stem cell proliferation; thus, as part of a method for promoting tissue and organ regeneration, p75 is promoted to promote stem cell proliferation. A ligand is used.

  In all disclosed aspects or variations of embodiments, the method comprises (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) to a patient in need of such treatment. -Pentanamide; (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholino Two or more compounds selected from the group consisting of: (ethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; Administration of a pharmaceutical composition consisting of a mixture of pharmaceutically acceptable salts, solvates or prodrugs, provided that the mixture comprises (2S, 3S) -2-amino-3-methyl-N- (2 -Morpholinoethyl) -pentanamide; and (2R, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or pharmaceutically acceptable of these compounds When consisting of a salt, solvate or prodrug; (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or a pharmaceutically acceptable salt of this compound, The solvate or prodrug is under conditions that it is less than about 5% by weight, based on the total amount of the mixture. In all disclosed aspects or other variations of the embodiments, the method comprises (2R, 3R) -2-amino-3-methyl-N- (2-morpholino) to a patient in need of such treatment. Ethyl) -pentanamide and (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide, or pharmaceutically acceptable salts, solvates or pros of these compounds (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide; or a pharmaceutically acceptable compound of this compound, comprising the administration of a pharmaceutical composition comprising a mixture of drugs Administration where the salt, solvate or prodrug is not less than about 5% by weight of the total weight of the mixture. In still other variations of all disclosed aspects or embodiments, the method may be used to treat a patient in need of such treatment with (2R, 3S) -2-amino-3-methyl-N- (2- Morpholinoethyl) -pentanamide; and (2S, 3R) -2-amino-3-methyl-N- (2-morpholinoethyl) -pentanamide or a pharmaceutically acceptable salt, solvate of these compounds or Consisting of administration of a pharmaceutical composition consisting of a mixture of prodrugs.

For the purposes of the present invention, the compound may be converted to a pharmaceutically acceptable carrier using a variety of methods including oral, parenteral, inhalation spray, topically, or rectal. It can be administered in a formulation comprising adjuvant and vehicle. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intraarterial injection using a variety of pharmaceutical infusion techniques. Intraarterial and intravenous injection as used herein includes administration through a catheter.

  The compounds disclosed herein can be formulated according to routine means appropriate to the intended route of administration. Thus, the compounds disclosed herein can take the form of suspensions, solutions or emulsions in oily or water-soluble media and can be suspended, stabilized, and / or dispersed. Formulations such as agents can be included. The compounds disclosed herein can be formulated as a pharmaceutical for implantation or injection. Thus, for example, the compound can be combined with a suitable polymeric or hydrophobic material (eg, an acceptable emulsion in oil) or ion exchange resin, or as a slightly less soluble derivative (eg, a slightly less soluble salt). Can be prescribed. Alternatively, the active ingredient can be powdered prior to use for formation with a suitable medium, such as sterile pyrogen-free water. Suitable drug formulations for each of these methods of administration can be found in, for example, Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa. .

  For example, pharmaceutical formulations for parenteral administration can include sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalene, and the like as common excipients. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers are useful excipients for controlling the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. The pharmaceutical formulation for inhalation administration contains, for example, lactose as an excipient or is an aqueous solution containing, for example, polyoxyethylene-9-auryl ether, glycocholate, and deoxycholate Or can be an oily solution for administration in the form of nasal drops, or it can be a gel that is applied intranasally. The pharmaceutical formulation for parenteral administration may also be glycocholate for sublingual tablet administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

  The pharmaceutical composition of the present invention may be in the form of a sterile injectable pharmaceutical preparation, such as a sterile injectable solution or oily suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may be a sterile injectable solution or solvent using a non-toxic parenterally acceptable diluent or solvent as formulated as a 1,3-butanediol solution or lyophilized powder. It may be a suspension. Among the acceptable media and solvents that can be used are water, Ringer's solution and isotonic saline. In addition, sterile, fixed oils can be routinely used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used as well for the preparation of injectables. Pharmaceutical formulations for intravenous administration can consist of aqueous solutions using sterile isotonic buffer. If necessary, the pharmaceutical formulation can also include a solubilizing agent and a local anesthetic to relieve pain at the site of the injection. In general, the formulation ingredients are separated in unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate, in a sealed container such as an ampoule or sachet that displays the amount of the active ingredient. Or mixed. Where the compound is administered by infusion, it can be formulated as a pharmaceutical formulation with an infusion bottle containing sterile pharmaceutical grade water, physiological saline, or glucose / water. Where the compound is administered by injection, sterile water or saline ampoule for injection is provided and the formulated ingredients are mixed prior to administration.

  In addition, water-soluble and water-insoluble sterile injection solutions that can contain antioxidants, buffers, bacilli, bactericidal antibiotics, and solutes (to make the drug formulation isotonic with the intended recipient's body fluid) Suitable pharmaceutical formulations include water-soluble and water-insoluble sterile suspensions, which may include suspending agents and thickeners.

  The compound can be further formulated for topical administration. Suitable topical drug formulations include one or more compounds in the form of a liquid, lotion, cream or gel. Topical administration can be accomplished by direct application to the treatment area. For example, such application can be accomplished by rubbing a formulation (such as a lotion or gel) into the skin of the treatment area or by spray application of a liquid formulation to the treatment area.

In some pharmaceutical formulations, bioimplantable materials can be coated with compounds to improve cell-embedded interactions.
Compound formulations may contain minor amounts of wetting or emulsifying agents or pH buffering agents. The formulation containing the compound may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
This compound can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

  A pharmaceutical composition comprising an active ingredient may be in any form suitable for the intended method of administration. For oral use, for example, tablets, troches, sweetened tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be formulated. . Compositions intended for oral use can be formulated according to known techniques for the manufacture of pharmaceutical compositions, and such compositions can be formulated for palatable preparations such as sweeteners, fragrances, One or more substances may be included, including colorants and preservatives. Oral formulations can include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate and the like. Tablets containing the active ingredient in admixture with excipients suitable for non-toxic pharmaceutically acceptable tablet formulations are acceptable. These excipients include, for example, calcium carbonate or sodium, lactose, calcium phosphate or sodium; granulating and disintegrating agents such as corn starch, or arginic acid; binders such as starch, gelatin or acacia; and stearic acid It may be a lubricant such as magnesium, stearic acid, or talc. The tablets can be uncoated or they can be coated by known techniques of microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

  Formulations for oral use are also as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, and the active ingredient is water or (peanut oil, liquid paraffin, or olive oil Can also be presented as soft gelatin capsules mixed with an oil medium.

  Aqueous suspensions according to the invention comprise the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include dispersing and wetting agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and naturally occurring phosphatides (eg lecithin), Condensation products of alkylene oxides with fatty acids (eg polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (eg heptadecaethyleneoxycetanol), condensation of ethylene oxide with partial esters derived from fatty acids Products, and suspending agents such as anhydrous hexitol (eg, polyoxyethylene sorbitan monooleate). Aqueous suspensions also include preservatives such as one or more ethyl or n-propyl p-hydroxy-benzoates, one or more colorants, one or more fragrances, and one or more sugars or saccharin. Sweetening agents can be included.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, and fragrances can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
This pharmaceutical composition comprising a compound of the present application comprises a substance that modulates the release of the compound, whereby the compound can be released or sustained released at a specified time.

Carriers Pharmaceutically acceptable carriers are known to those of skill in the art and include, but are not limited to, about 0.01 to about 0.1 M, and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions.
Examples of water-insoluble solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
Examples of suitable water-soluble carriers for use in this application include, but are not limited to, emulsions or suspensions including water, ethanol, alcohol / water solutions, glycerol, saline or buffered media. . Oral carriers can be elixirs, syrups, capsules, tablets and the like.

  Liquid carriers suitable for use herein can be used in formulating solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils and fats. Liquid carriers include other solubilizers, emulsifiers, buffers, preservatives, sweeteners, fragrances, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure regulators. Appropriate pharmaceutical additives can be included.

  Liquid carriers suitable for use in the present application include water (partially including the above additives, eg cellulose derivatives, preferably carboxymethylcellulose sodium solution), alcohols (monohydric and polyhydric alcohols). Including, but not limited to, glycol)), and derivatives thereof, and oils (eg, fractionated coconut oil and peanut oil). For parenteral administration, the carrier comprises an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers may be useful in sterile liquids composed of compounds for parenteral administration. The liquid carriers for pressurized compounds disclosed herein are halogenated hydrocarbons or other pharmaceutically acceptable propellants.

  Suitable solid carriers for use in the present application include, but are not limited to, inert materials such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. The solid carrier can further comprise one or more substances that act as fragrances, lubricants, solubilizers, suspending agents, fillers, lubricants, compression aids, binders or tablet disintegrants; It can also be an encapsulating material. In powders, the carrier can be a finely divided solid mixed with the finely divided active compound. In tablets, the active compound is mixed with the carrier having the necessary compression properties in the proper proportions and compressed into the intended shape and size. The powders and tablets preferably contain up to 99% active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, a low melting wax, and an ion exchange resin. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made using suitable machinery, optionally binders (eg, porobidon, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium starch glycolate, crosslinks) Free flow active ingredients, such as powders, granules, etc., can be made by compression, mixed with povidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be made by molding, using a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored and the active ingredient in the tablets can be slowed or adjusted, for example using various proportions of hydroxypropylmethylcellulose, to provide the desired release profile The release can be formulated to be possible. Tablets can optionally be provided with an intestinal coating so that they can be released in the intestinal portion other than the stomach.

Parenteral carriers for use in this application include, but are not limited to, sodium chloride solution, Ringer's glucose, glucose and salt, lactated Ringer's and non-volatile oils. Intravenous carriers include electrolyte supplements such as fluid and nutrient supplements, Ringer's glucose and the like. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, inert gases, and the like.
Carriers suitable for use in the present application can be mixed with disintegrants, diluents, granulating agents, lubricants, binders, etc., as required, using conventional techniques known in the art. The carrier can also be sterilized using methods that do not react vigorously with the compound, as is generally known in the art.

Salts It is to be understood that the disclosed compounds can further consist of pharmaceutically acceptable salts.
Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonia and alkylated ammonia salts. .
Acid addition salts include inorganic acid salts and organic acid salts. Representative examples of suitable inorganic acid salts include hydrochloric acid, bromic acid, iodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, Malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, Aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, There are acetates, benzoates, hydroxy naphthoates, glycerophosphates, ketoglutaric acids and the like.

Base addition salts include ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris- ( Hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, efamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, Examples include, but are not limited to, basic amino acids such as lysine and arginine, dicyclohexylamine and the like.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.

Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
Standard dispensing methods for pharmaceutically acceptable salts and formulations thereof are known in the art and are described in “Remington: The Science and Practice of Pharmacy”, edited by A. Gennaro, 20th edition, Lippincott, Williams & Wilkins. , Philadelphia, PA, in various references.

Methods of Use As previously disclosed, the present application provides for the treatment of disorders associated with p75 expression. In general, this application provides treatment for disorders involving degradation or dysfunction of cells expressing p75.
In one aspect, activating a p75 receptor comprising contacting a cell comprising the p75 receptor with one or more compounds of the present application or a pharmaceutically acceptable salt, ester, solvate or prodrug of the compound. Provide a way to do it. In addition, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neurosis, myopathy, and various types of retinal degeneration Disclosed are methods of treating neurological disorders, including but not limited to, based on the compounds of the present application, which can target p75 receptors expressed in neurons or other cells.

In addition, p75 receptors that express nervous system disorders in oligodendrocytes, microglia or astrocytes, including but not limited to multiple sclerosis, spinal cord disorders and perinatal anoxia Disclosed are methods of treatment based on the present compounds that can be targeted.
In addition, the following methods: prevention of hair follicle cell loss, thereby prevention of hair loss; prevention of cirrhosis and promotion of liver regeneration; regulation of angiogenesis and initiation of diabetic wounds or other ischemia initiation Nerves such as methods for promoting neovascularization; methods for preventing cardiomyopathy (for example, methods for inhibiting cardiomyocyte loss after ischemia initiation or myocardial infarction or methods for promoting new cardiomyocyte proliferation); and methods for inhibiting tumor cell growth; Disclosed are methods of treating diseases other than the system. In addition, p75 is known to be expressed in stem cells and regulate stem cell proliferation; therefore, the p75 ligand disclosed herein promotes stem cell proliferation as part of a method that promotes tissue and organ regeneration. Can be used.

The present application also provides a method of treating neurodegeneration and other disorders or conditions in a patient. In general, the methods of the present application involve administration to a patient of a compound having binding specificity for the p75 ^NTR molecule to treat neurodegeneration and other disorders or conditions. An effective amount of this compound can be administered to induce survival signals and / or inhibit pro-NGF-induced cell death, as determined to be associated with neurodegeneration and other disorders.

The condition to be treated can be any condition, at least in part, through neurotrophin binding to p75 ^NTR . Such conditions include Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord disorder, stroke, hypoxia, ischemia, encephalopathy, diabetic neuropathy, peripheral There are, but are not limited to, neurological disease, nerve transplantation, multiple sclerosis, peripheral neuropathy and hair loss.

  In general, the condition to be treated can be any condition, at least in part, through abnormal neurotransmission of the p75 receptor. In one embodiment, abnormal signaling is through the presence or absence of neurotrophin binding; in other embodiments, abnormal signaling is not through the presence or absence of neurotrophin binding. In one variation, abnormal signaling occurs without neurotrophin binding.

As disclosed herein, compounds having binding specificity for p75 ^NTR may be converted to neurodegenerative and / or neurodegenerative conditions (eg, chemotherapy-induced neurodegeneration) and (eg, chemotherapy). Can be used for the treatment of cell degeneration, including prevention of other pathological conditions (such as inducing hair follicle cell survival after hair follicle cell degeneration).

The present application further provides a novel method for promoting cell survival. Representative cells include, but are not limited to, septal cells, hippocampal cells, cortical cells, sensory cells, sympathetic neurons, motor neurons, hair follicle cells, progenitor cells and stem cells. In general, such cells include neurons, oligodendrocytes and hair follicle cells. In particular, the method consists of treating cells with a compound that has binding specificity for the p75 ^NTR molecule, whereby the compound induces survival signaling and inhibits pro-NGF-induced cell death.
The present application also provides a novel method for optimizing cellular function, comprising the use of the compounds disclosed herein. In one embodiment, decreased cell survival is not the primary endogenous disease mechanism; in other embodiments, decreased cell survival is the primary endogenous disease mechanism.

Administration application, in order to alleviate the condition through p75 ^NTR binding in a patient, discloses a method of administering a compound having a binding specificity for p75 ^NTR. This method can comprise administering to a patient an effective amount of a compound, such as any of the compounds disclosed herein, that has binding specificity for p75 ^NTR .
As used herein, administration can be accomplished or performed using any of a variety of methods known to those skilled in the art. This compound is included in a conventional dosage formulation comprising a non-toxic, physiologically acceptable carrier or vehicle, e.g., subcutaneously, intravenously, parenterally, intraperitoneally, intradermally. Intramuscularly, locally, in the intestine (eg orally), rectal, nasally, buccally, sublingually, vaginally, by inhalation spray or implanted with a medical pump Administered by reservoir.

In addition, the compounds disclosed herein can be administered to local areas in need of treatment. This includes, for example, topical infusions during surgery, topical application, transdermal patches, injections, catheters, suppositories, or implants including membranes, such as sialastic membranes or fibers (implantation is optionally porous, Can be non-porous or can be a gelatinous material).
The form in which the compound is administered (eg, syrup, elixir, capsule, tablet, solution, foam, emulsion, gel, sol) will depend in part on the route of administration. For example, nasal drops, mists, inhalants, nebulizers, eye drops, or suppositories can be used for mucosal administration (eg, oral mucosa, rectum, small intestinal mucosa, bronchial mucosa). The compound can also be coated with a bioimplantable material to promote neurite outgrowth, neuronal cell survival, or cell interaction with the implant surface. The compounds and agents disclosed herein can be combined with analgesics, anti-inflammatory agents, anesthetics, and other biologically active agents that can modulate one or more symptoms or causes of p75 ^NTR- mediated pathology. Can be administered.

Further, multiple dosages can be administered to a patient for an appropriate period. Such dosage regimens can be determined according to routine methods after listing this disclosure.
The compounds of the present application can be used as the sole active agent in pharmaceuticals or other active ingredients such as, for example, neurotrophins, or promote neuronal cell survival or axonal development in neurodegenerative diseases Can be used in combination with other factors, or drugs (eg, administered at about the same time or in the same formulation), but these factors or drugs include amyloid β inhibitors, acetylcholinesterase inhibition Including, but not limited to, N-methyl-D-aspartate subtypes of agents, butyrylcholinesterase inhibitors, and glutamate receptor antagonists.

Dosage A compound of the invention is generally administered at a dose of about 0.01 mg / kg / dose to about 100 mg / kg / dose. Alternatively, the dose may be from about 0.1 mg / kg / dose to about 10 mg / kg / dose, or from about 1 mg / kg / dose to 10 mg / kg / dose. In some dosages, the compounds disclosed herein are administered at about 5 mg / kg / dose. Sustained release formulations can be used, or for convenience, the dosage can be administered in multiple divided doses. When using other methods (e.g., intravenous administration), the compound is administered to the affected tissue at a rate of about 0.05 to about 10 mg / kg / hour, or about 0.1 to about 1 mg / kg / hour. Administer. When these compounds are administered intravenously as discussed herein, these rates can be easily maintained. Generally, topical dosage formulations are administered at a dose of about 0.5 mg / kg / dose to about 10 mg / kg / dose. Alternatively, the topical dosage formulation is administered at a dose of about 1 mg / kg / dose to about 7.5 mg / kg / dose, or about 1 mg / kg / dose to about 5 mg / kg / dose.
About 0.1 to about 100 mg / kg / dose is appropriate for a single dose. For continuous administration, a range of about 0.05 to about 10 mg / kg / dose is appropriate. Topical administration is appropriate for conditions such as hair loss or wound revascularization.

Since this method can provide a good correlation for certain metabolic and secretory functions, the drug can also be given in milligram quantities per square meter of body surface area, rather than per body weight. Furthermore, body surface area can be used as a common denominator for drug doses of adults and children, and different animal species (Freireich et al., (1966) Cancer Chemother Rep. 50, 219-244). The point is to multiply the dose by the appropriate km factor to represent the mg / kg dose as the equivalent mg / sqm dose in all animal species. In adults, 100 mg / kg is equal to 100 mg / kg x 37 kg / sqm = 3700 mg / m 2.

  As long as the compounds disclosed herein can take the form of these mimetics or fragments, it is understood that the effective amount of efficacy, and thus the dosage, can vary. However, one of ordinary skill in the art can readily estimate the efficacy of the class of compounds depicted by this application.

  In the context of progressively progressive nervous system disorders, the compounds of the present application are generally administered on an ongoing basis. In certain circumstances, administration of the compounds disclosed herein can be initiated prior to progression of disease symptoms as part of a method of delaying or preventing the disease. In other situations, the compounds disclosed herein are administered after the onset of disease symptoms as part of a method of slowing or reversing the disease process and / or improving cellular function and reducing symptoms. To do. Compounds have been developed that will be transported across the vascular brain barrier, by oral administration, or by other peripheral routes. Compounds that do not cross the vascular brain barrier are applied to target outside the central nervous system. Compounds are applied in acute or chronic situations by other oral or direct targeted administration (such as topical application) to targets and tissues outside the nervous system.

  It is understood by those skilled in the art that the dosage range depends on the compound and its potency. The dosage range is wide enough to produce the desired effect, but tractable side effects, such that neurodegeneration or other disorders and related symptoms are alleviated and / or cell survival is achieved It is understood that it is not so wide. However, as is well understood by those skilled in the art, for a particular patient, a particular dose level is dependent on the activity of the particular compound used; the age, weight, general health, sex and diet of the individual being treated; It depends on a variety of factors including time and route of administration; elimination rate; other drugs previously administered; and the severity of the particular disease being treated. For all comorbidities, the dosage can be adjusted by the individual physician. When the compounds disclosed herein are used in accordance with the present application, unacceptable toxic effects are not expected.

  An effective amount of a compound disclosed herein consists of an amount sufficient to produce a measurable biological response. The actual dosage level of active ingredient in the therapeutic compounds of the present application may vary to administer the amount of active compound effective to obtain the intended therapeutic response for a particular patient and / or application. Preferably, a minimum dose is administered and the dose is increased to a minimum effective amount without dose limiting toxicity. The determination and preparation of therapeutically effective doses and evaluation of when and how such adjustments are made are known to those of ordinary skill in the art.

  Further, for the methods of the present application, preferred patients are vertebrate patients. Preferred vertebrate patients are warm-blooded animals; preferred warm-blooded vertebrates are mammals. Patients treated by the methods of the present disclosure are preferably humans, but it should be understood that the principles of the present application are valid for all vertebrate species and vertebrates are also included in the term “patient”. It is. In this context, it should be understood that vertebrates are all vertebrates for which treatment of neurodegenerative disorders is desired. As used herein, the term “patient” includes human and animal patients. Accordingly, therapeutic use by a veterinarian is provided according to the present application.

  Therefore, the present application refers to the treatment of mammals such as humans, and mammals important for being endangered, such as Siberian tigers; economics such as animals kept on farms for consumption by humans. Provided for the treatment of mammals of interest; and / or mammals maintained in pets or zoos of social importance to humans. Examples of such animals include carnivores such as cats and dogs; domesticated pigs including piglets, pigs, and wild boars; cattle, steers, sheep, giraffes, deer, goats, bisons, camels and There are ruminants and / or ungulates such as horses, but are not limited to these. Endangered birds and / or birds preserved in zoos and domesticated poultry, ie domestic birds such as turkeys, chickens, ducks, geese, guinea fowls, etc. are also economically important to humans As such, treatments for birds containing these are also provided. Accordingly, livestock treatments are also provided, including but not limited to domesticated pigs, ruminants, ungulates, horses (including racehorses), domestic birds, and the like.

General synthetic methods Standard procedures and chemical changes and related methods are known to those skilled in the art, and such methods and procedures are described, for example, in Fiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York, NY , 2002; Organic Reactions ,. 1-83, John Wiley and Sons, New York, NY, 2006; March J. and Smith M., Advanced Organic Chemistry, 6th edition., John Wiley and Sons, New York, NY and Larock RC, Comprehensive Organic Transformations, Wiley-VCH Publishers, New York, 1999. All text and references cited herein are incorporated in their entirety.

  The reaction using a compound having a functional group can be carried out in a compound having a protected functional group. “Protected” compound or derivative means a derivative of a compound in which one or more reactive positions or sites, or functional groups, are hindered by a protecting group. Protected derivatives are useful for the synthesis of the compounds of the invention or themselves; the protected derivatives may be biologically active agents. Examples of comprehensive text with appropriate protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

A method for synthesizing many compounds such as compounds 1 to 21 can be exemplified by the following mechanism.

In general, the protecting group for amino acids is the Boc group. The coupling agent may be HATU, HBTU, EDC / HOBt, or DCC / DMAP. The reagent for deprotection may be 4 M HCl in MeOH, 4 M HCl in water, or TFA in DCM.
Generally, an amine or aniline is coupled with an N-protected amino acid, and the coupled intermediate is deprotected to yield the final compound or other intermediate. The second intermediate can be further modified, or directly once again, can yield the final compound via this coupling-deprotection cycle.

Example 1: Synthesis of Compound 1

Boc-IIe-OHのDCM溶液に対して、DIEA、HOBt、EDC、及びアミンをこの順序に加えた。この反応混合物を３時間、室温（RT）で攪拌した。
反応終了後（LC-MS）、１０％クエン酸を加えて反応を停止した。DCM層を分離して、飽和NaHCO₃、ブラインで洗浄し、無水Na₂SO₄で乾燥させ、濾過し、濃縮した。中間体A1eを灰白色固体（303 mg）として得た。 Synthesis of intermediate A1a:

To the Boc-IIe-OH DCM solution, DIEA, HOBt, EDC, and amine were added in this order. The reaction mixture was stirred for 3 hours at room temperature (RT).
After completion of the reaction (LC-MS), 10% citric acid was added to stop the reaction. The DCM layer was separated and washed with saturated NaHCO ₃ , brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Intermediate A1e was obtained as an off-white solid (303 mg).

A1a残渣に冷TFA/DCMを加えた。反応混合物を室温で２時間攪拌した。反応終了後（LC-MS）、混合物を濃縮し、最終化合物（272 mg）を得た。化合物１を¹H NMR、LC-MS及び HPLCで特徴付けた。. ¹H NMR (MeOD), δ: 4.07-4.21 (m, 2H), 3.77 (d, J=5.84 Hz, 1H), 3.65-3.70 (m, 4H), 3.56-3.58 (m, 2H), 3.45-3.51 (m, 2H), 1.88-1.98 (m, 1H), 1.56-1.66 (m, 1H), 1.21-1.31 (m, 1H), 1.05 (d, J=6.78 Hz, 3H), 0.99 (t, J=7.40 Hz, 3H). LC-MS, (M+1), 258. HPLC (>95%, 保持時間, 1.99 min) Synthesis of Compound 1:

To the A1a residue was added cold TFA / DCM. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (LC-MS), the mixture was concentrated to obtain the final compound (272 mg). Compound 1 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (MeOD), δ: 4.07-4.21 (m, 2H), 3.77 (d, J = 5.84 Hz, 1H), 3.65-3.70 (m, 4H), 3.56-3.58 (m, 2H), 3.45 -3.51 (m, 2H), 1.88-1.98 (m, 1H), 1.56-1.66 (m, 1H), 1.21-1.31 (m, 1H), 1.05 (d, J = 6.78 Hz, 3H), 0.99 (t , J = 7.40 Hz, 3H). LC-MS, (M + 1), 258. HPLC (> 95%, retention time, 1.99 min)

Example 2: Synthesis of compound 2

Boc-Ala-OHのDMF溶液に、HBTU、DIEA及びモルホリンをこの順番に加えた。反応混合物を室温で２時間攪拌した。反応終了後（LC-MS）、反応混合物を調製様HPLCにより精製して中間体A2a（333 mg）を得た。 Synthesis of intermediate A2a:

HBTU, DIEA and morpholine were added in this order to the DMF solution of Boc-Ala-OH. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (LC-MS), the reaction mixture was purified by preparative-like HPLC to yield intermediate A2a (333 mg).

A2aの残渣に冷TFA/DCMを加えた。反応混合物を室温で２時間攪拌した。反応終了後（LC-MS）、混合物を濃縮し、中間体A2b（180 mg）を得た。 Synthesis of intermediate A2b:

To the A2a residue was added cold TFA / DCM. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (LC-MS), the mixture was concentrated to obtain Intermediate A2b (180 mg).

A2bの残渣にDCM、Boc-Ala-OH、HOBt、EDC、及び DIEAをこの順に加えた。反応混合物を室温で２時間攪拌した。反応終了後（LC-MS）、0.5 HClを加えて反応を停止した。DCM層を分離して、飽和NaHCO₃、ブライン、で洗浄し、無水NaSO₄で乾燥させ、濾過した。液体を濃縮して、中間体A2c（64 mg）を得た。 Synthesis of intermediate A2c:

DCM, Boc-Ala-OH, HOBt, EDC, and DIEA were added to the A2b residue in this order. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (LC-MS), 0.5 HCl was added to stop the reaction. The DCM layer was separated and washed with saturated NaHCO ₃ , brine, dried over anhydrous NaSO ₄ and filtered. The liquid was concentrated to yield intermediate A2c (64 mg).

A2cの残渣に冷TFA/DCMを加えた。反応混合物を室温で３時間攪拌した。反応終了後（LC-MS）、混合物を濃縮して、最終化合物（51 mg）を得た。化合物２を¹H NMR、LC-MS 及び HPLCにより特徴付けた。¹H NMR (D₂O), δ: 3.62-3.92 (m, 10H), 1.99-2.05 (m, 1H), 1.54-1.60 (m, 1H), 1.41 (d, J=7.12 Hz, 2H), 1.26-1.33 (m, 1H), 1.06 (d, J=6.92 Hz, 3H), 0.99 (t, J=7.38 Hz, 3H). LC-MS, (M+1), 272. HPLC (>95%, 保持時間, 1.94 分) Synthesis of compound 2:

To the residue of A2c was added cold TFA / DCM. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (LC-MS), the mixture was concentrated to give the final compound (51 mg). Compound 2 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 3.62-3.92 (m, 10H), 1.99-2.05 (m, 1H), 1.54-1.60 (m, 1H), 1.41 (d, J = 7.12 Hz, 2H), 1.26-1.33 (m, 1H), 1.06 (d, J = 6.92 Hz, 3H), 0.99 (t, J = 7.38 Hz, 3H). LC-MS, (M + 1), 272. HPLC (> 95% , Retention time, 1.94 minutes)

Example 3: Synthesis of compound 3

Boc-Lle-OHのDMF溶液に、HATU、４−モルホリノアニリン及びDIEAをこの順番に加えた。反応混合物を室温で１時間攪拌した。
反応終了後（LC-MS）、飽和NaHCO₃を加えて反応を停止させ、産物を抽出するためにEtOAcを用いた。有機層を分離して、水、ブラインで洗浄し、無水Na₂SO₄で乾燥させ、濾過し、及び濃縮した。中間体A3aを灰白色固体（166 mg）として得た。 Synthesis of intermediate A3a:

To the DMF solution of Boc-Lle-OH, HATU, 4-morpholinoaniline and DIEA were added in this order. The reaction mixture was stirred at room temperature for 1 hour.
After completion of the reaction (LC-MS), saturated NaHCO ₃ was added to stop the reaction, and EtOAc was used to extract the product. The organic layer was separated, washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Intermediate A3a was obtained as an off-white solid (166 mg).

冷HClのMeOH溶液をA3a残渣に加えた。反応混合物を室温で３時間攪拌した。
反応終了後（LC-MS）、混合物を濃縮して、最終化合物３（120 mg）を得た。化合物3
を¹H NMR, LC-MS 及び HPLCにより特徴付けた。¹H NMR (MeOD), δ: 7.88 (d, J=9.16 Hz, 2H), 7.69 (d, J=9.12 Hz, 2H), 4.09-4.11 (m, 4H), 3.92 (d, J=5.80 Hz, 1H), 3.66-3.69 (m, 4H), 2.03-2.10 (m, 1H), 1.62-1.69 (m, 1H), 1.24-1.32 (m, 1H), 1.11 (d, J=6.92 Hz, 3H), 1.01 (t, J=7.40 Hz, 3H). LC-MS, (M+1), 292. HPLC (>95%, 保持時間, 4.86 分) Synthesis of compound 3:

Cold HCl in MeOH was added to the A3a residue. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was concentrated to give final compound 3 (120 mg). Compound 3
Was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (MeOD), δ: 7.88 (d, J = 9.16 Hz, 2H), 7.69 (d, J = 9.12 Hz, 2H), 4.09-4.11 (m, 4H), 3.92 (d, J = 5.80 Hz , 1H), 3.66-3.69 (m, 4H), 2.03-2.10 (m, 1H), 1.62-1.69 (m, 1H), 1.24-1.32 (m, 1H), 1.11 (d, J = 6.92 Hz, 3H ), 1.01 (t, J = 7.40 Hz, 3H). LC-MS, (M + 1), 292. HPLC (> 95%, retention time, 4.86 min)

Example 4: Synthesis of compound 4

Boc-Ile-OHのDCM溶液に、HOBt、EDC、DIEA、及び２−モルホリノアニリンをこの順番に加えた。この反応混合物を室温で、７．５時間攪拌した。
反応混合物を調製様HPLCによる精製を行い、中間体A4a（94 mg）を得た。 Synthesis of intermediate A4a:

To the Boc-Ile-OH DCM solution, HOBt, EDC, DIEA, and 2-morpholinoaniline were added in this order. The reaction mixture was stirred at room temperature for 7.5 hours.
The reaction mixture was purified by preparative HPLC to give intermediate A4a (94 mg).

A4aの残渣に冷HClのMeOH溶液を加えた。反応混合物を室温で３時間攪拌した。
反応終了後（LC-MS）、混合物を濃縮し、最終化合物４（73 mg）を得た。化合物４を¹H NMR, LC-MS 及び HPLCにより特徴付けた。¹H NMR (D2O), δ: 7.67 (dd, J=7.96 and 1.48 Hz, 1H), 7.49 (dd, J=8.10 and 1.34 Hz, 1H), 7.42 (dt, J=7.75 and 1.53 Hz, 1H), 7.34 (dt, J=7.67 and 1.43 Hz, 1H), 4.22 (d, J=5.00 Hz, 1H), 3.95-3.97 (m, 4H), 3.13-3.15 (m, 4H), 2.11-2.17 (m, 1H), 1.57-1.64 (m, 1H), 1.30-1.39 (m, 1H), 1.12 (d, J=6.96 Hz, 3H), 1.00 (t, J=7.40 Hz, 3H). LC-MS, (M+1), 292. HPLC (>95%, 保持時間, 5.31 分) Synthesis of compound 4:

To the A4a residue was added cold HCl in MeOH. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was concentrated to obtain the final compound 4 (73 mg). Compound 4 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D2O), δ: 7.67 (dd, J = 7.96 and 1.48 Hz, 1H), 7.49 (dd, J = 8.10 and 1.34 Hz, 1H), 7.42 (dt, J = 7.75 and 1.53 Hz, 1H) , 7.34 (dt, J = 7.67 and 1.43 Hz, 1H), 4.22 (d, J = 5.00 Hz, 1H), 3.95-3.97 (m, 4H), 3.13-3.15 (m, 4H), 2.11-2.17 (m , 1H), 1.57-1.64 (m, 1H), 1.30-1.39 (m, 1H), 1.12 (d, J = 6.96 Hz, 3H), 1.00 (t, J = 7.40 Hz, 3H). LC-MS, (M + 1), 292. HPLC (> 95%, retention time, 5.31 min)

Example 5: Synthesis of compound 5

Boc-Ile-OHのDCM溶液に、HOBt、EDC、DIEA,及び２−モルホリン−４−イル−プロピルアミンをこの順に加えた。反応混合物を室温で３時間攪拌した。
反応混合物を調製様HPLCにより精製し、中間体A5a（219 mg）を得た。 Synthesis of intermediate A5a:

To a DCM solution of Boc-Ile-OH, HOBt, EDC, DIEA, and 2-morpholin-4-yl-propylamine were added in this order. The reaction mixture was stirred at room temperature for 3 hours.
The reaction mixture was purified by preparative HPLC to give intermediate A5a (219 mg).

冷HClのMeOH溶液をA4a残渣に加えた。反応混合物を室温で、３時間攪拌した。
反応終了後（LC-MS）、混合物を調製様HPLCにより精製し、HClの MeOH溶液との処理によりHCl塩に変換し、最終化合物５（120 mg）を得た。化合物５を¹H NMR、LC-MS及びHPLCにより特徴付けした。¹H NMR (D2O), δ: 3.30-4.24 (m, 12H), 1.92-2.05 (m, 1H), 1.43-1.56 (m, 1H), 1.36-1.42 (m, 3H), 1.16-1.30 (m, 1H), 1.01 (d, J=6.92 Hz, 3H), 0.94 (d, J=7.34 Hz, 3H). LC-MS, (M+1), 258. HPLC (>95%, 保持時間, 1.41 分) Synthesis of compound 5:

Cold HCl in MeOH was added to the A4a residue. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was purified by preparative HPLC and converted to the HCl salt by treatment with HCl in MeOH to give the final compound 5 (120 mg). Compound 5 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D2O), δ: 3.30-4.24 (m, 12H), 1.92-2.05 (m, 1H), 1.43-1.56 (m, 1H), 1.36-1.42 (m, 3H), 1.16-1.30 (m , 1H), 1.01 (d, J = 6.92 Hz, 3H), 0.94 (d, J = 7.34 Hz, 3H). LC-MS, (M + 1), 258. HPLC (> 95%, retention time, 1.41 Min)

Example 6: Synthesis of compound 6

Boc-Ala-OHのDMF溶液に、HBTU、DIEA 及びモルホリンをこの順に加えた。この反応混合物を室温で２時間攪拌した。
反応終了後（LC-MS）、反応混合物を調製様HPLCにより精製し、中間体A6a（333 mg）を得た。 Synthesis of intermediate A6a:

HBTU, DIEA and morpholine were added in this order to the DMF solution of Boc-Ala-OH. The reaction mixture was stirred at room temperature for 2 hours.
After completion of the reaction (LC-MS), the reaction mixture was purified by preparative HPLC to give intermediate A6a (333 mg).

A6aをTHFに溶かした。この溶液に、BH₃-THFをゆっくり加えた。発泡が観察され、反応混合物を室温で一晩攪拌した。
反応終了後（LC-MS）、この混合物に注意深く水を加え反応を停止し、濃縮した。この混合物をさらに調製様HPLCにより精製し、中間体A6b（192 mg）を得た。 Synthesis of intermediate A6b:

A6a was dissolved in THF. To this solution was slowly added BH ₃ -THF. Foam was observed and the reaction mixture was stirred overnight at room temperature.
After completion of the reaction (LC-MS), water was carefully added to the mixture to stop the reaction, and the mixture was concentrated. This mixture was further purified by preparative HPLC to yield intermediate A6b (192 mg).

A6bの残渣に冷HClのMeOH溶液を加えた。この反応混合物を室温で３時間攪拌した。
反応終了後（LC-MS）、混合物を濃縮して、中間体A6c（158 mg）を得た。 Synthesis of intermediate A6c:

To the residue of A6b was added cold HCl in MeOH. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was concentrated to give intermediate A6c (158 mg).

Boc-Ile-OH及びA6cのDCM溶液に、HOBt、EDC、及びDIEAをこの順に加えた。この反応混合物を室温で１時間攪拌した。
この反応混合物を調製様HPLCにより精製して、中間体A6d（86 mg）を得た。 Synthesis of intermediate A6d:

HOBt, EDC, and DIEA were added in this order to the DCM solution of Boc-Ile-OH and A6c. The reaction mixture was stirred at room temperature for 1 hour.
The reaction mixture was purified by preparative HPLC to give intermediate A6d (86 mg).

A6d残渣に冷TFA/DCMを加えた。この反応混合物を室温で３時間攪拌した。
反応終了後（LC-MS）、この混合物を濃縮し、最終化合物６（89 mg）を得た。化合物６を¹H NMR, LC-MS and HPLCで特徴付けた。 ¹H NMR (D2O), δ: 4.21-4.32 (m, 1H), 3.88-4.11 (m, 2H), 3.65-3.87 (m, 3H), 3.34-3.53 (m, 2H), 3.07-3.34 (m, 4H), 1.83-1.95 (m, 1H), 1.30-1.41 (m, 1H), 1.21 (d, J=6.80 Hz, 3H), 1.04-1.17 (m, 1H), 0.91 (d, J=6.96 Hz, 3H), 0.82 (t, J=7.38 Hz, 3H). LC-MS, (M+1), 258. HPLC (>95%, 保持時間, 1.59分) Synthesis of compound 6:

To the A6d residue was added cold TFA / DCM. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was concentrated to give the final compound 6 (89 mg). Compound 6 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D2O), δ: 4.21-4.32 (m, 1H), 3.88-4.11 (m, 2H), 3.65-3.87 (m, 3H), 3.34-3.53 (m, 2H), 3.07-3.34 (m , 4H), 1.83-1.95 (m, 1H), 1.30-1.41 (m, 1H), 1.21 (d, J = 6.80 Hz, 3H), 1.04-1.17 (m, 1H), 0.91 (d, J = 6.96 Hz, 3H), 0.82 (t, J = 7.38 Hz, 3H). LC-MS, (M + 1), 258. HPLC (> 95%, retention time, 1.59 min)

Example 7: Synthesis of Compound 7

アミン及び臭化物を混合し、攪拌しつつ５時間、７０℃に加熱した。
LC-MSは、産物が非、モノ−、及びビス−アルキル化アミンの混合であることを示した。さらに精製することなくこの混合物を次のステップに用いた（5.5 ml）。 Synthesis of intermediate A7a:

The amine and bromide were mixed and heated to 70 ° C. with stirring for 5 hours.
LC-MS showed that the product was a mixture of non, mono-, and bis-alkylated amines. This mixture was used in the next step without further purification (5.5 ml).

Boc-Ile-OHのアセトニトリル溶液に、HBTUを加え、その後DIEAを加えた。混合物を室温で１０分間攪拌後、A7aを加えた。この反応混合物をさらに２時間攪拌した。
この反応終了後（LC-MS）、溶液の一部を調製様HPLCにかけて分離し、M⁺=460 (A7b, 2g)のピーク分画を集めた。 Synthesis of intermediate A7b:

HBTU was added to an acetonitrile solution of Boc-Ile-OH, and then DIEA was added. After the mixture was stirred at room temperature for 10 minutes, A7a was added. The reaction mixture was stirred for an additional 2 hours.
After this reaction was completed (LC-MS), a portion of the solution was separated by preparative HPLC, and a peak fraction with M ⁺ = 460 (A7b, 2g) was collected.

Synthesis of compound 7:
A7b was dissolved in cold HCl in MeOH. The reaction mixture was stirred at RT for 3 hours. After completion of the reaction (LC-MS), the mixture was concentrated to give an HCl salt intermediate (209 mg).
The above HCl salt intermediate was dissolved in a mixed solvent of acetonitrile and water and neutralized with saturated sodium bicarbonate to pH˜7. The reaction mixture was stirred at RT for 2.5 hours. Then excess NaBH ₄ was added and the mixture was stirred overnight. However, on the morning of the second day, many products were not observed by LC-MS, so the reaction mixture was heated to 45 ° C. for 7.5 hours.
After completion of the reaction (LC-MS), the mixture was filtered and purified by preparative HPLC to obtain the desired final product. This final product was converted to the HCl salt by treatment with HCl in MeOH (43 mg). Compound 7 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 2.90-4.20 (m, 17H), 1.84-2.35 (m, 1H), 1.07-1.53 (m, 2H), 0.80-1.02 (m, 6H). LC-MS , (M + 1), 270. HPLC (> 95%, retention time, 1.27 min).

Example 8: Synthesis of Compound 8

アセトニトリル中の酸及びHATU溶液に、攪拌しつつDIEAを加えた。２０分後、アミンを加え、この反応を１時間攪拌して、続けた。
LC-MSは、反応の終了を示した。反応溶液を調製様HPLCによる分離を行った（A8a、65 mg）。 Synthesis of intermediate A8a:

To the acid and HATU solution in acetonitrile, DIEA was added with stirring. After 20 minutes, amine was added and the reaction was stirred for 1 hour and continued.
LC-MS indicated the end of the reaction. The reaction solution was separated by preparative HPLC (A8a, 65 mg).

メタノール中のA8a溶液に、HCl水溶液を加え、２時間室温で攪拌した。
LC-MSは、反応の終了を示した。溶媒を真空で除き、化合物８（60 mg）を得た。化合物８を、¹H NMR, LC-MS,及びHPLCにより特徴付けた。¹H NMR (MeOD), δ: 3.82-4.11 (m, 5H), 3.78 (d, J=4.52 Hz, 1H), 3.68 (d, J=11.2 Hz, 1H), 3.45-3.59 (m, 2H), 3.11-3.41 (m, 5H), 2.78 (s, 3H), 1.93-2.05 (m, 1H), 1.56-1.68 (m, 1H), 1.15-1.32 (m, 1H) ), 0.96-1.09 (m, 6H). LC-MS, (M+1), 258. HPLC (>95%, 保持時間, 1.0 分) Synthesis of Compound 8:

To the A8a solution in methanol was added aqueous HCl solution and stirred for 2 hours at room temperature.
LC-MS indicated the end of the reaction. The solvent was removed in vacuo to give compound 8 (60 mg). Compound 8 was characterized by ¹ H NMR, LC-MS, and HPLC. ¹ H NMR (MeOD), δ: 3.82-4.11 (m, 5H), 3.78 (d, J = 4.52 Hz, 1H), 3.68 (d, J = 11.2 Hz, 1H), 3.45-3.59 (m, 2H) , 3.11-3.41 (m, 5H), 2.78 (s, 3H), 1.93-2.05 (m, 1H), 1.56-1.68 (m, 1H), 1.15-1.32 (m, 1H)), 0.96-1.09 (m LC-MS, (M + 1), 258. HPLC (> 95%, retention time, 1.0 min)

Example 9: Synthesis of compound 9

化合物８及びCDIのアセトニトリル溶液に、攪拌しながらEt₃Nを加えた。攪拌は３日間継続した。
LC-MSは反応の終了を示した。メタノールを加えて反応を停止した。揮発性溶媒を取り除いた後、残渣をメタノールに溶かし、調製様HPLCによる分離を行った。溶媒の除去後、25 mlの1.25 N HClのメタノール溶液と共に３回同時蒸発させて、産物であるギ酸塩をHCl塩に変換した（76 mg）。化合物９を¹H NMR, LC-MS, 及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 3.68-4.14 (m, 7H), 3.00-3.63 (m, 6H), 2.68 (d, J=8.40 Hz, 3H), 1.91-2.03 (m, 1H), 0.98-1.51 (m, 2H), 0.90 (d, J=7.00 Hz, 1H), 0.79-0.88 (m, 3H), 0.71 (d, J=6.92 Hz, 1H). LC-MS, (M+1), 284. HPLC (>95%, 保持時間, 4.32 分)。

Et ₃ N was added to an acetonitrile solution of compound 8 and CDI with stirring. Stirring was continued for 3 days.
LC-MS indicated the end of the reaction. Methanol was added to stop the reaction. After removing the volatile solvent, the residue was dissolved in methanol and separated by preparative HPLC. After removal of the solvent, the product formate was converted to the HCl salt (76 mg) by co-evaporation three times with 25 ml of 1.25 N HCl in methanol. Compound 9 was characterized by ¹ H NMR, LC-MS, and HPLC. ¹ H NMR (D ₂ O), δ: 3.68-4.14 (m, 7H), 3.00-3.63 (m, 6H), 2.68 (d, J = 8.40 Hz, 3H), 1.91-2.03 (m, 1H), 0.98-1.51 (m, 2H), 0.90 (d, J = 7.00 Hz, 1H), 0.79-0.88 (m, 3H), 0.71 (d, J = 6.92 Hz, 1H). LC-MS, (M + 1 ), 284. HPLC (> 95%, retention time, 4.32 min).

Example 10: Synthesis of compound 10

アセトニトリルにBoc-Gly-OH及びEDCの混合物を懸濁した。DIEAを加え、さらに２−モルホリノ−４−イル−エチルアミンを加えた。この反応混合物を２時間攪拌した。
LC-MSは、反応の終了を示した。反応混合物を調製様HPLCにより分離して、A10a純品を得た（177 mg）。 Synthesis of intermediate A10a:

A mixture of Boc-Gly-OH and EDC was suspended in acetonitrile. DIEA was added, followed by 2-morpholino-4-yl-ethylamine. The reaction mixture was stirred for 2 hours.
LC-MS indicated the end of the reaction. The reaction mixture was separated by preparative HPLC to give pure A10a (177 mg).

A10aのメタノール溶液に、HCl水溶液を加え、室温で２時間攪拌した。
LC-MSは、反応の終了を示した。溶媒を真空中で除き、化合物１０（160 mg）を得た。化合物１０を¹H NMR, LC-MS, 及びHPLCにより特徴付けた。¹H NMR (MeOD), δ: 3.93-4.08 (m, 4H), 3.77 (s, 2H), 3.56-3.72 (m, 4H), 3.32-3.36 (m, 3H), 3.09-3.24 (m, 2H). LC-MS, (M+1), 188. HPLC (>95%, 保持時間, 1.0 分)。 Synthesis of compound 10:

An aqueous HCl solution was added to a methanol solution of A10a, and the mixture was stirred at room temperature for 2 hours.
LC-MS indicated the end of the reaction. The solvent was removed in vacuo to give compound 10 (160 mg). Compound 10 was characterized by ¹ H NMR, LC-MS, and HPLC. ¹ H NMR (MeOD), δ: 3.93-4.08 (m, 4H), 3.77 (s, 2H), 3.56-3.72 (m, 4H), 3.32-3.36 (m, 3H), 3.09-3.24 (m, 2H LC-MS, (M + 1), 188. HPLC (> 95%, retention time, 1.0 min).

Example 11: Synthesis of Compound 11

アセトニトリルに、Boc-Ala-OH, BtOH-H₂O及びDIEAの混合物を懸濁した。その後攪拌しつつ、EDCを加え、溶液は、透明化した。2-モルホリン−４−イル−エチルアミンを加え、室温で２時間攪拌した。
LC-MSは、反応終了を示した。この反応混合物を調製様HPLCで分離して、A11a（66 mg）純品を得た。 Synthesis of intermediate A11a:

A mixture of Boc-Ala-OH, BtOH-H ₂ O and DIEA was suspended in acetonitrile. Thereafter, EDC was added with stirring, and the solution became clear. 2-Morpholin-4-yl-ethylamine was added and stirred at room temperature for 2 hours.
LC-MS indicated the end of the reaction. The reaction mixture was separated by preparative HPLC to give pure A11a (66 mg).

A11aのメタノール溶液に、HCl水溶液を加え、室温で２時間攪拌した。
LC-MSは、反応の終了を示した。溶媒を真空中で除き、化合物１１（60 mg）を得た。化合物１１を¹H NMR, LC-MS, 及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 4.10-4.27 (m, 3H), 3.87-4.01 (m, 2H), 3.77-3.88 (m, 1H), 3.60-3.76 (m, 3H) 3.40-3.55 (m, 2H), 3.26-3.39 (m, 2H), 1.60 (d, J=7.16 Hz, 3H). LC-MS, (M+1), 202. HPLC (>95%,保持時間, 1.0 分)。 Synthesis of Compound 11:

An aqueous HCl solution was added to a methanol solution of A11a, and the mixture was stirred at room temperature for 2 hours.
LC-MS indicated the end of the reaction. The solvent was removed in vacuo to give compound 11 (60 mg). Compound 11 was characterized by ¹ H NMR, LC-MS, and HPLC. ¹ H NMR (D ₂ O), δ: 4.10-4.27 (m, 3H), 3.87-4.01 (m, 2H), 3.77-3.88 (m, 1H), 3.60-3.76 (m, 3H) 3.40-3.55 ( m, 2H), 3.26-3.39 (m, 2H), 1.60 (d, J = 7.16 Hz, 3H). LC-MS, (M + 1), 202. HPLC (> 95%, retention time, 1.0 min) .

Example 12: Synthesis of compound 12

2-Boc-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタミドを、CF₃CO₂H/CH₂Cl₂に溶かし、室温で２時間攪拌した。LC-MSにより、出発物質の完全な脱保護が行われたことを示した後、溶媒を真空下で除いた。残渣をTHF/H₂Oに溶かし、溶液を塩基性に調整するために、Na₂CO₃を加えた。その後、塩化ベンゾイルを加えて、２時間攪拌した。
LC-MSは反応終了を示した。その後、THFを真空により除き、水溶液をAcOEtにより抽出した。次ぎにAcOEtをNa₂SO₄上で乾燥させ、取り除いた。残渣をメタノールに溶かし、調製様HPLCにかけ分離した。溶媒の除去後、産生したギ酸塩を、50 mLの1.25 HCl メタノール溶液で３回同時蒸発を行い、HCl塩に変換した（91 mg）。化合物１２を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (MeOD), δ: 7.86-7.91 (m, 2H), 7.56-7.61 (m, 1H), 7.47-7.53 (m, 2H), 4.20 (d, J=7.96 Hz, 1H), 4.00-4.10 (m, 2H), 3.82-3.92 (m, 2H), 3.71-3.80 (m, 1H), 3.59-3.69 (m, 2H), 3.15-3.56 (m, 5H), 1.96-2.08 (m, 1H), 1.63-1.75 (m, 1H), 1.26-1.39 (m, 1H), 0.94-1.06 (m, 6H). LC-MS, (M+1), 348. HPLC (>95%, 保持時間, 5.27 分)。

2-Boc-amino-3-methyl-N- (2-morpholinoethyl) pentamide was dissolved in CF ₃ CO ₂ H / CH ₂ Cl ₂ and stirred at room temperature for 2 hours. After LC-MS showed complete deprotection of the starting material, the solvent was removed in vacuo. The residue was dissolved in THF / H ₂ O and Na ₂ CO ₃ was added to adjust the solution to basic. Then, benzoyl chloride was added and stirred for 2 hours.
LC-MS indicated completion of reaction. Thereafter, THF was removed by vacuum and the aqueous solution was extracted with AcOEt. The AcOEt was then dried over Na ₂ SO ₄ and removed. The residue was dissolved in methanol and separated by preparative HPLC. After removal of the solvent, the produced formate was co-evaporated 3 times with 50 mL of 1.25 HCl in methanol and converted to the HCl salt (91 mg). Compound 12 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (MeOD), δ: 7.86-7.91 (m, 2H), 7.56-7.61 (m, 1H), 7.47-7.53 (m, 2H), 4.20 (d, J = 7.96 Hz, 1H), 4.00- 4.10 (m, 2H), 3.82-3.92 (m, 2H), 3.71-3.80 (m, 1H), 3.59-3.69 (m, 2H), 3.15-3.56 (m, 5H), 1.96-2.08 (m, 1H ), 1.63-1.75 (m, 1H), 1.26-1.39 (m, 1H), 0.94-1.06 (m, 6H). LC-MS, (M + 1), 348. HPLC (> 95%, retention time, 5.27 minutes).

Example 13: Synthesis of Compound 13

Boc-Phe-OH, HBTUのアセトニトリル溶液に対して、DIEAを加えた。５分間攪拌後、2-モルホリン-4-イル-エチルアミンを加え、この反応混合物をさらに２時間攪拌した。
LC-MSは反応終了を示した。この反応混合物を調製様HPLCで分離してA13a純品（210 mg）を得た。 Synthesis of intermediate A13a:

DIEA was added to an acetonitrile solution of Boc-Phe-OH and HBTU. After stirring for 5 minutes, 2-morpholin-4-yl-ethylamine was added and the reaction mixture was stirred for an additional 2 hours.
LC-MS indicated completion of reaction. The reaction mixture was separated by preparative HPLC to give pure A13a (210 mg).

A13aのエタノール溶液に、HCl水溶液を加え、室温で２時間攪拌した。
LC-MSは反応終了を示した。溶媒を真空中で除き、化合物１３（195 mg）を得た。化合物１３を、¹ NMR, LC-MS, 及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 7.32-7.41 (m, 2H), 7.43-7.57 (m, 3H), 4.30 (t, J=7.32 Hz, 1H), 3.94-4.10 (m, 4H), 3.61 (t, J=6.34 Hz, 2H), 3.08-3.44 (m, 9H). LC-MS, (M+1), 278. HPLC (>95%, 保持時間, 1.21 分) Synthesis of Compound 13:

An aqueous HCl solution was added to the ethanol solution of A13a, and the mixture was stirred at room temperature for 2 hours.
LC-MS indicated completion of reaction. The solvent was removed in vacuo to give compound 13 (195 mg). Compound 13 was characterized by ¹ NMR, LC-MS, and HPLC. ¹ H NMR (D ₂ O), δ: 7.32-7.41 (m, 2H), 7.43-7.57 (m, 3H), 4.30 (t, J = 7.32 Hz, 1H), 3.94-4.10 (m, 4H), 3.61 (t, J = 6.34 Hz, 2H), 3.08-3.44 (m, 9H). LC-MS, (M + 1), 278. HPLC (> 95%, retention time, 1.21 min)

Boc-Phe-OHをBoc-Leu-OHと置き換える以外は、化合物１４を化合物１３の合成法に従い合成した。化合物１４（175 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 4.07-4.20 (m, 2H), 4.03 (d, J=7.22 Hz, 1H), 3.71-3.93 (m, 3H), 3.50-3.70 (m, 3H), 3.18-3.44 (m, 4H), 1.74 (t, J=7.26 Hz, 2H), 1.61-1.72 (m, 1H), 0.89-1.03 (m, 6H). LC-MS, (M+1), 244. HPLC (>95%, 保持時間, 1.0 分) Examples 14-18
A number of compounds, including Compound 14, Compound 15, Compound 16, Compound 17, and Compound 18, were synthesized according to the synthesis method of Compound 13, substituting appropriate starting materials for Boc-Phe-OH.
Compound 14

Compound 14 was synthesized according to the synthesis method of Compound 13, except that Boc-Phe-OH was replaced with Boc-Leu-OH. Compound 14 (175 mg) was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 4.07-4.20 (m, 2H), 4.03 (d, J = 7.22 Hz, 1H), 3.71-3.93 (m, 3H), 3.50-3.70 (m, 3H), 3.18-3.44 (m, 4H), 1.74 (t, J = 7.26 Hz, 2H), 1.61-1.72 (m, 1H), 0.89-1.03 (m, 6H). LC-MS, (M + 1), 244 HPLC (> 95%, retention time, 1.0 min)

Boc-Phe-OHをBoc-D-t-butylglycine-OHと置き換える以外は、化合物１５を化合物１３の合成法に従い合成した。化合物１５（120 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 3.91-4.10 (m, 2H), 3.62-3.82 (m, 3H), 3.60 (s, 1H), 3.38-3.58 (m, 3H), 3.05-3.34 (m, 4H), 0.96 (s, 9H). LC-MS, (M+1), 244. HPLC (>95%, 保持時間, 1.0 分)。 Compound 15

Compound 15 was synthesized according to the synthesis method of Compound 13, except that Boc-Phe-OH was replaced with Boc-Dt-butylglycine-OH. Compound 15 (120 mg) was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 3.91-4.10 (m, 2H), 3.62-3.82 (m, 3H), 3.60 (s, 1H), 3.38-3.58 (m, 3H), 3.05-3.34 (m , 4H), 0.96 (s, 9H). LC-MS, (M + 1), 244. HPLC (> 95%, retention time, 1.0 min).

Boc-Phe-OHをBoc-Asp(OTBU)-OHと置き換える以外は、化合物１６を化合物１３の合成法に従い合成した。化合物１６（50 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 4.23 (t, J=6.24 Hz, 1H), 3.91-4.11 (m, 2H), 3.67-3.84 (m, 2H), 3.55-3.67 (m, 2H), 3.41-3.54 (m, 2H), 3.27 (t, J=6.32 Hz, 2H), 3.06-3.22 (m, 2H), 2.85-3.01 (m, 2H). LC-MS, (M+1), 246. HPLC (>95%, 保持時間, 1.0 分) Compound 16

Compound 16 was synthesized according to the synthesis method of Compound 13, except that Boc-Phe-OH was replaced with Boc-Asp (OTBU) -OH. Compound 16 (50 mg) was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 4.23 (t, J = 6.24 Hz, 1H), 3.91-4.11 (m, 2H), 3.67-3.84 (m, 2H), 3.55-3.67 (m, 2H), 3.41-3.54 (m, 2H), 3.27 (t, J = 6.32 Hz, 2H), 3.06-3.22 (m, 2H), 2.85-3.01 (m, 2H). LC-MS, (M + 1), 246 HPLC (> 95%, retention time, 1.0 min)

Boc-Phe-OHをBoc-Glu(OTBU)-OHと置き換える以外は、化合物１７を化合物１３の合成法に従い合成した。化合物１７（60 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 3.94-4.10 (m, 2H), 3.97 (t, J=6.56 Hz, 1H), 3.67-3.83 (m, 2H), 3.60-3.69 (m, 1H), 3.40-3.59 (m, 3H), 3.20 (t, J=6.78 Hz, 2H), 3.08-3.23 (m, 2H), 2.45 (t, J=7.18 Hz, 2H), 2.01-2.17 (m, 2H). LC-MS, (M+1), 260. HPLC (>95%, 保持時間 1.0 分) Compound 17

Compound 17 was synthesized according to the synthesis method of Compound 13, except that Boc-Phe-OH was replaced with Boc-Glu (OTBU) -OH. Compound 17 (60 mg) was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 3.94-4.10 (m, 2H), 3.97 (t, J = 6.56 Hz, 1H), 3.67-3.83 (m, 2H), 3.60-3.69 (m, 1H), 3.40-3.59 (m, 3H), 3.20 (t, J = 6.78 Hz, 2H), 3.08-3.23 (m, 2H), 2.45 (t, J = 7.18 Hz, 2H), 2.01-2.17 (m, 2H) LC-MS, (M + 1), 260. HPLC (> 95%, retention time 1.0 min)

Boc-Phe-OHをBoc-Pro-OHと置き換える以外は、化合物１８を化合物１３の合成法に従い合成した。化合物１８（80 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 4.27 (t, J=7.38 Hz, 1H), 3.91-4.10 (m, 2H), 3.60-3.81 (m, 3H), 3.37-3.57 (m, 3H), 3.19-3.37 (m, 4H), 3.04-3.19 (m, 2H), 2.25-2.40 (m, 1H), 1.85-2.02 (m, 3H). LC-MS, (M+1), 228. HPLC (>95%, 保持時間, 1.0 分)。 Compound 18

Compound 18 was synthesized according to the synthesis method of Compound 13, except that Boc-Phe-OH was replaced with Boc-Pro-OH. Compound 18 (80 mg) was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 4.27 (t, J = 7.38 Hz, 1H), 3.91-4.10 (m, 2H), 3.60-3.81 (m, 3H), 3.37-3.57 (m, 3H), 3.19-3.37 (m, 4H), 3.04-3.19 (m, 2H), 2.25-2.40 (m, 1H), 1.85-2.02 (m, 3H). LC-MS, (M + 1), 228.HPLC ( > 95%, retention time, 1.0 min).

Example 19: Synthesis of compound 19

(2S, 3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド及びアセトアルデヒドの混合物をメタノールに溶かし、NaCNBH₃を加えた。この反応混合物を一晩攪拌した。
LC-MSは反応終了を示した。K₂CO₃（270 mg）を加えて反応を停止した。２ｍＬ水を加えて、沈殿物を溶かし、その後溶液を調製様HPLCで分離した。その後、HCl／メタノール（1 N）溶液と同時蒸発を行い、ギ酸塩をHCl塩に変換した。化合物１９（50 mg）を¹H NMR及びLC-MSにより特徴付けた。¹H NMR (D₂O), δ: 4.05-4.23 (m, 2H), 3.48-3.94 (m, 7H), 3.38 (t, J=6.82 Hz, 2H), 3.17-3.34 (m, 2H), 3.08 (q, J=7.32 Hz, 2H), 1.94-2.07 (m, 1H), 1.44-1.60 (m, 1H), 1.30 (t, J=7.32 Hz, 1H), 1.14-1.26 (m, 3H), 0.89-1.06 (m, 6H). LC-MS, (M+1), 272

A mixture of (2S, 3S) -2-amino-3-methyl-N- (2-morpholinoethyl) pentanamide and acetaldehyde was dissolved in methanol and NaCNBH ₃ was added. The reaction mixture was stirred overnight.
LC-MS indicated completion of reaction. The reaction was stopped by adding K ₂ CO ₃ (270 mg). 2 mL water was added to dissolve the precipitate, and then the solution was separated by preparative HPLC. This was followed by coevaporation with an HCl / methanol (1 N) solution to convert the formate into the HCl salt. Compound 19 (50 mg) was characterized by ¹ H NMR and LC-MS. ¹ H NMR (D ₂ O), δ: 4.05-4.23 (m, 2H), 3.48-3.94 (m, 7H), 3.38 (t, J = 6.82 Hz, 2H), 3.17-3.34 (m, 2H), 3.08 (q, J = 7.32 Hz, 2H), 1.94-2.07 (m, 1H), 1.44-1.60 (m, 1H), 1.30 (t, J = 7.32 Hz, 1H), 1.14-1.26 (m, 3H) , 0.89-1.06 (m, 6H). LC-MS, (M + 1), 272

Example 20: Synthesis of compound 20

水中の(2S, 3S)-2-アミノ-3-メチル-N-(2-モルホリノエチル)ペンタンアミド、ホルムアルデヒド及びPd/Cを50 Psiで５時間水素化した。
LC-MSは反応終了を示した。Pd/Cを濾過して除き、透明な溶液を調製様HPLCにかけて分離した。HCl／メタノール（1 N）溶液と同時蒸発を行い、ギ酸塩をHCl塩（220 mg）に変換した。化合物２０（220 mg）を¹H NMR, LC-MS及びHPLCにより特徴付けた。
¹H NMR (D₂O), δ: 3.70-4.13 (m, 4H), 3.64-3.69 (m, 1H), 3.56-3.64 (m, 2H), 3.05-3.52 (m, 6H), 2.80 (s, 6H), 2.02-2.15 (m, 1H), 1.32-1.46 (m, 1H), 1.01-1.15 (m, 1H), 0.81-0.93 (m, 6H). LC-MS, (M+1), 272. HPLC (>95%, 保持時間, 1.14 分)。

(2S, 3S) -2-Amino-3-methyl-N- (2-morpholinoethyl) pentanamide, formaldehyde and Pd / C in water were hydrogenated at 50 Psi for 5 hours.
LC-MS indicated completion of reaction. Pd / C was filtered off and the clear solution was separated by preparative HPLC. Coevaporation with HCl / methanol (1 N) solution converted the formate salt to the HCl salt (220 mg). Compound 20 (220 mg) was characterized by ¹ H NMR, LC-MS and HPLC.
¹ H NMR (D ₂ O), δ: 3.70-4.13 (m, 4H), 3.64-3.69 (m, 1H), 3.56-3.64 (m, 2H), 3.05-3.52 (m, 6H), 2.80 (s , 6H), 2.02-2.15 (m, 1H), 1.32-1.46 (m, 1H), 1.01-1.15 (m, 1H), 0.81-0.93 (m, 6H). LC-MS, (M + 1), 272. HPLC (> 95%, retention time, 1.14 min).

Example 21: Synthesis of compound 21

酸のDMF溶液に、HATU, DIEA及びアミンをこの順に加えた。この反応混合物を室温で２時間攪拌した。
反応終了後（LC-MS及びTLC）、この中間体A21aを調製様HPLCにより精製した（228 mg）。 Synthesis of intermediate A11a:

HATU, DIEA and amine were added in this order to the DMF solution of acid. The reaction mixture was stirred at room temperature for 2 hours.
After completion of the reaction (LC-MS and TLC), this intermediate A21a was purified by preparative HPLC (228 mg).

冷HCl溶液を残渣A21aに加えた。この反応混合物を、室温で、一晩、攪拌した。
この反応終了後（LC-MS）、この混合物を濃縮した。これをさらに、調製様HPLCにより精製して、最終化合物２１を得た（206 mg）。化合物２１を¹H NMR, LC-MS 及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 7.34-7.49 (m, 5H), 5.04 (s, 1H), 3.86-3.98 (m, 2H), 3.58-3.72 (m, 2H), 3.54 (t, J=6.22 Hz, 2H), 3.14-3.39 (m, 4H), 2.92-3.07 (m, 2H). LC-MS, (M+1), 264. HPLC (>95%, 保持時間, 0.98 分)。 Synthesis of Compound 21:

Cold HCl solution was added to residue A21a. The reaction mixture was stirred overnight at room temperature.
After completion of the reaction (LC-MS), the mixture was concentrated. This was further purified by preparative HPLC to give final compound 21 (206 mg). Compound 21 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 7.34-7.49 (m, 5H), 5.04 (s, 1H), 3.86-3.98 (m, 2H), 3.58-3.72 (m, 2H), 3.54 (t, J = 6.22 Hz, 2H), 3.14-3.39 (m, 4H), 2.92-3.07 (m, 2H). LC-MS, (M + 1), 264. HPLC (> 95%, retention time, 0.98 min).

このような合成方法において、カップリング剤は、HATU又はHBTUであってもよい。Bocのような保護基を除くために用いる酸は、4M HCl のMeOH溶液又は4M HCl水溶液である。 The synthesis of lead analogs of many compounds of the present application is displayed in the following general mechanism 2:

In such a synthesis method, the coupling agent may be HATU or HBTU. The acid used to remove protecting groups such as Boc is 4M HCl in MeOH or 4M HCl in water.

この合成において、出発材料の酸は、エステルに変換される。その後、エステルは、アミンと反応し、アミド化合物が得られる。このアミド化合物は、最終化合物をもたらすために、還元的アミン化のような更なる変化を受けることができる。 The synthesis of further compounds of the present application can be represented by the following general mechanism 3.

In this synthesis, the starting acid is converted to an ester. The ester then reacts with an amine to give an amide compound. The amide compound can undergo further changes such as reductive amination to yield the final compound.

Example 22: Synthesis of compound 22

酸のDMF溶液に、HBTU, DIEA及びアミンをこの順に加えた。この反応混合物を室温で一晩攪拌した。
反応終了後（LC-MS及びTLC）、ブライン及び飽和重炭酸ナトリウム溶液を加え、反応を停止した。DCM中の１０％MeOHを用いて、水層を抽出した（ｘ３）。DCM層を分離、１つにまとめ、ブラインで洗浄し、無水Na₂SO₄で乾燥させ、濾過し、及び濃縮した。シリカゲルカラムクロマトグラフィーの後で灰白色固体（138 mg）として、化合物２２を得た。化合物２２を、¹H NMR, LC-MS及びHPLCにより特徴付けした。¹H NMR (D₂O), δ: 7.90 (s, 2H), 5.00 (s, 2H), 3.46 (s, 3H), 3.40 (t, J=6.40 Hz, 2H), 3.19-3.28 (m, 8H), 1.65-1.75 (m, 2H). LC-MS, (M+1), 310. HPLC (>95%, 保持時間, 5.76 分)

HBTU, DIEA and amine were added to the acid in DMF in this order. The reaction mixture was stirred at room temperature overnight.
After completion of the reaction (LC-MS and TLC), brine and saturated sodium bicarbonate solution were added to stop the reaction. The aqueous layer was extracted with 10% MeOH in DCM (x3). The DCM layers were separated, combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Compound 22 was obtained as an off-white solid (138 mg) after silica gel column chromatography. Compound 22 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 7.90 (s, 2H), 5.00 (s, 2H), 3.46 (s, 3H), 3.40 (t, J = 6.40 Hz, 2H), 3.19-3.28 (m, 8H), 1.65-1.75 (m, 2H). LC-MS, (M + 1), 310.HPLC (> 95%, retention time, 5.76 min)

Example 23: Synthesis of Compound 23

酸のDMF溶液に、HATU, DIEA及びアミンをこの順に加えた。反応混合物を１時間室温で攪拌した。
反応終了後（LC-MS及びTLC）、ブライン及び飽和炭酸水素ナトリウムを加えて、反応を停止した。５％MeOHのDCM溶液を用いて、水層を抽出した（ｘ３）。DCM層を分離し、全て合わせて、ブラインで洗浄し、無水Na₂SO₄で乾燥させ、濾過し、及び濃縮した。化合物をさらに、調製様HPLCにより精製した（150 mg）。 Synthesis of intermediate A23a:

HATU, DIEA and amine were added in this order to the DMF solution of acid. The reaction mixture was stirred for 1 hour at room temperature.
After completion of the reaction (LC-MS and TLC), brine and saturated sodium bicarbonate were added to stop the reaction. The aqueous layer was extracted with 5% MeOH in DCM (x3). The DCM layers were separated, all combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The compound was further purified by preparative HPLC (150 mg).

冷HCl溶液をC9aの残渣に加えた。この反応混合物を室温で３時間攪拌した。
反応終了後（LC-MS）、混合物を濃縮した。これをさらに調製様HPLC上で精製し、最終化合物２３を得た（73 mg）。化合物２３を¹H NMR, LC-MS及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 7.89 (s, 1H), 4.99 (s, 2H), 3.45 (s, 3H), 3.25 (t, J=6.58 Hz, 2H), 3.22 (s, 3H), 2.96 (t, J=7.66 Hz, 2H), 2.60 (s, 3H), 1.76-1.86 (m, 2H). LC-MS, (M+1), 309. HPLC (>95%, 保持時間, 1.20 分)。 Synthesis of compound 23:

Cold HCl solution was added to the residue of C9a. The reaction mixture was stirred at room temperature for 3 hours.
After completion of the reaction (LC-MS), the mixture was concentrated. This was further purified on preparative HPLC to give final compound 23 (73 mg). Compound 23 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 7.89 (s, 1H), 4.99 (s, 2H), 3.45 (s, 3H), 3.25 (t, J = 6.58 Hz, 2H), 3.22 (s, 3H) , 2.96 (t, J = 7.66 Hz, 2H), 2.60 (s, 3H), 1.76-1.86 (m, 2H). LC-MS, (M + 1), 309. HPLC (> 95%, retention time, 1.20 minutes).

酸のDMF溶液に、HATU, DIEA及びアニリンをこの順に加えた。この反応混合物を２時間室温で攪拌した。
反応終了後（LC-MS及びTLC）、この化合物を調製様HPLCにより精製した（250 mg）。化合物２４を¹H NMR, LC-MS 及び HPLCで特徴付けた。. ¹H NMR (CDCl3), δ: 9.25 (s, 1H), 7.77 (s, 1H), 7.15 (t, J=8.14 Hz, 1H), 7.05 (s, 1H), 6.74-6.80 (m, 1H), 6.46-6.53 (m, 1H), 4.95 (s, 2H), 3.61 (s, 3H), 3.46 (s, 3H), 2.93 (s, 6H), 1.59 (s, 3H). LC-MS, (M+1), 357. HPLC (>95%, 保持時間, 5.79 分)。 Example 24: Synthesis of compound 24

HATU, DIEA and aniline were added in this order to the DMF solution of acid. The reaction mixture was stirred for 2 hours at room temperature.
After completion of the reaction (LC-MS and TLC), the compound was purified by preparative HPLC (250 mg). Compound 24 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (CDCl3), δ: 9.25 (s, 1H), 7.77 (s, 1H), 7.15 (t, J = 8.14 Hz, 1H), 7.05 (s, 1H), 6.74-6.80 (m, 1H ), 6.46-6.53 (m, 1H), 4.95 (s, 2H), 3.61 (s, 3H), 3.46 (s, 3H), 2.93 (s, 6H), 1.59 (s, 3H). LC-MS, (M + 1), 357. HPLC (> 95%, retention time, 5.79 min).

Example 25: Synthesis of compound 25

エステル（300 mlの無水EtOH中の18 gのテオフィリン−７−酢酸及び触媒として1 mlの濃H₂SO₄を還流して得た）及び3-ピペリジン-1-イル-プロピルアミンの混合物を、無水エタノールに懸濁し、高圧圧力容器中に密閉した。反応混合物を１１０℃まで２時間攪拌しつつ加熱した。
LC-MSは、反応終了を示した。10 mLのメタノールを加えて、この溶液を調製様HPLCで分離した（200 mg）。化合物２５を¹H NMR, LC-MS 及び HPLCで特徴付けた。. ¹H NMR (D₂O), δ: 8.34 (s, 1H), 7.90 (s, 1H), 4.98 (s, 2H), 3.40-3.48 (m, 2H), 3.39 (s, 3H), 3.25 (t, J=6.48 Hz, 2H), 3.17 (s, 3H), 3.00-3.07 (m, 2H), 2.78-2.88 (m, 2H), 1.53-1.93 (m, 7H), 1.31-1.45 (m, 1H). LC-MS, (M+1), 363. HPLC (>95%, 保持時間, 1.91 分)。

A mixture of the ester (obtained by refluxing 18 g theophylline-7-acetic acid and 1 ml concentrated H ₂ SO ₄ as catalyst in 300 ml absolute EtOH) and 3-piperidin-1-yl-propylamine is obtained. It was suspended in absolute ethanol and sealed in a high pressure container. The reaction mixture was heated to 110 ° C. with stirring for 2 hours.
LC-MS indicated the end of the reaction. 10 mL of methanol was added and the solution was separated by preparative HPLC (200 mg). Compound 25 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 8.34 (s, 1H), 7.90 (s, 1H), 4.98 (s, 2H), 3.40-3.48 (m, 2H), 3.39 (s, 3H), 3.25 (t, J = 6.48 Hz, 2H), 3.17 (s, 3H), 3.00-3.07 (m, 2H), 2.78-2.88 (m, 2H), 1.53-1.93 (m, 7H), 1.31-1.45 (m LC-MS, (M + 1), 363. HPLC (> 95%, retention time, 1.91 min).

Example 26: Synthesis of compound 26

エステル及びジアミンをEtOHに懸濁した。この反応混合物を２時間還流した。
この混合物を濃縮し、調製様HPLCにより精製した。化合物をMeOH-Et₂Oと共に４回すりつぶし、極微量のジアミンを取り除いた（140 mg）。 Synthesis of intermediate A26a:

The ester and diamine were suspended in EtOH. The reaction mixture was refluxed for 2 hours.
The mixture was concentrated and purified by preparative HPLC. The compound was triturated 4 times with MeOH-Et ₂ O to remove traces of diamine (140 mg).

A26aをHCOH水溶液に溶かし、NaCNBH₃を加えた。この反応混合物をRTで２時間攪拌した。
混合物を濃縮した。これは、調製様HPLCを用いて精製し、化合物２６を得た（97 mg）。化合物２６を¹H NMR, LC-MS及び HPLCで特徴付けた。 ¹H NMR (D₂O), δ: 8.31 (s, 1H), 7.89 (s, 1H), 4.98 (s, 2H), 3.66-3.78 (m, 1H), 3.47 (s, 3H), 3.18-3.27 (m, 4H), 2.72-2.80 (m, 6H), 2.17-2.25 (m, 1H), 1.11-2.04 (m, 8H). LC-MS, (M+1), 363. HPLC (>95%, 保持時間, 1.95 分)。 Synthesis of Compound 26:

A26a was dissolved in HCOH aqueous solution and NaCNBH ₃ was added. The reaction mixture was stirred at RT for 2 hours.
The mixture was concentrated. This was purified using preparative-like HPLC to give compound 26 (97 mg). Compound 26 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 8.31 (s, 1H), 7.89 (s, 1H), 4.98 (s, 2H), 3.66-3.78 (m, 1H), 3.47 (s, 3H), 3.18- 3.27 (m, 4H), 2.72-2.80 (m, 6H), 2.17-2.25 (m, 1H), 1.11-2.04 (m, 8H). LC-MS, (M + 1), 363. HPLC (> 95 %, Retention time, 1.95 minutes).

化合物２７（180 mg）を、１，２−シクロヘキサンジアミンの代わりに適切な出発物質を用いて、化合物２６と同一方法で合成した。唯一の違いは、この反応を１３０℃、６時間行ったことであり、最終ギ酸塩を、50 mLの1.25N HClメタノール溶液と３回同時蒸発を行い、HCl塩に変換した。化合物２７を¹H NMR, LC-MS and HPLC.により特徴付けた。 ¹H NMR (D₂O), δ: 7.85 (s, 1H), 5.19-5.38 (m, 3H), 4.41-4.50 (m, 1H), 4.00-4.08 (m, 1H), 3.46-3.53 (m, 1H), 3.45 (s, 3H), 3.18-3.28 (m, 4H), 2.80 (s, 6H), 2.68-2.78 (m, 1H), 2.04-2.21 (m, 2H), 1.73-1.86 (m, 1H), 1.53-1.66 (m, 1H). LC-MS, (M+1), 349. HPLC (>95%, 保持時間, 1.71 分)。 Example 27: Synthesis of compound 27

Compound 27 (180 mg) was synthesized in the same manner as compound 26 using the appropriate starting material instead of 1,2-cyclohexanediamine. The only difference was that this reaction was carried out at 130 ° C. for 6 hours, and the final formate was converted to the HCl salt by co-evaporation with 50 mL of 1.25 N HCl in methanol three times. Compound 27 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 7.85 (s, 1H), 5.19-5.38 (m, 3H), 4.41-4.50 (m, 1H), 4.00-4.08 (m, 1H), 3.46-3.53 (m , 1H), 3.45 (s, 3H), 3.18-3.28 (m, 4H), 2.80 (s, 6H), 2.68-2.78 (m, 1H), 2.04-2.21 (m, 2H), 1.73-1.86 (m , 1H), 1.53-1.66 (m, 1H). LC-MS, (M + 1), 349. HPLC (> 95%, retention time, 1.71 min).

化合物２８（130 mg）を、１，２−シクロヘキサンジアミンの代わりに誘導体化したアミンを用いて、化合物２７と同一方法で合成し、最終ギ酸塩を、50 mLの1.25N HClメタノール溶液と３回同時蒸発を行い、HCl塩に変換した。化合物２８を¹H NMR, LC-MS及びHPLC.により特徴付けた。¹H NMR (D₂O), δ: 7.89 (s, 1H), 4.99 (s, 2H), 3.97-4.05 (m, 2H), 3.64-3.75 (m, 2H), 3.40-3.47 (m, 5H), 3.16-3.29 (m, 7H), 3.03-3.16 (m, 4H), 1.83-1.94 (m, 2H). LC-MS, (M+1), 365. HPLC (>95%, 保持時間, 1.0 分)。 Example 28: Synthesis of compound 28

Compound 28 (130 mg) was synthesized in the same manner as Compound 27 using the derivatized amine instead of 1,2-cyclohexanediamine, and the final formate was added 3 times with 50 mL of 1.25 N HCl in methanol. Co-evaporation was performed and converted to the HCl salt. Compound 28 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 7.89 (s, 1H), 4.99 (s, 2H), 3.97-4.05 (m, 2H), 3.64-3.75 (m, 2H), 3.40-3.47 (m, 5H ), 3.16-3.29 (m, 7H), 3.03-3.16 (m, 4H), 1.83-1.94 (m, 2H). LC-MS, (M + 1), 365. HPLC (> 95%, retention time, 1.0 minutes).

Example 29: Synthesis of compound 29

エステル及びジアミンをEtOHに懸濁した。反応混合物を２時間還流した。
反応終了後（LC-MS）、この混合物を濃縮した。これを調製様HPLC上で精製し、化合物２９を得た。最終化合物をMeOH-Et₂Oと共に４回すりつぶして、極微量のジアミンを取り除いた（155 mg）。化合物２９を、¹H NMR, LC-MS及びHPLCにより特徴付けた。 ¹H NMR (D₂O), δ: 8.33 (s, 1H), 7.87 (s, 1H), 4.99 (s, 2H), 3.44 (s, 3H), 3.24 (t, J=6.66 Hz, 2H), 3.20 (s, 3H), 2.91 (t, J=7.62 Hz, 2H), 1.74-1.82 (m, 2H). LC-MS, (M+1), 295. HPLC (>95%,保持時間 1.12 分)。

The ester and diamine were suspended in EtOH. The reaction mixture was refluxed for 2 hours.
After completion of the reaction (LC-MS), the mixture was concentrated. This was purified on preparative HPLC to give compound 29. The final compound was triturated 4 times with MeOH-Et ₂ O to remove traces of diamine (155 mg). Compound 29 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 8.33 (s, 1H), 7.87 (s, 1H), 4.99 (s, 2H), 3.44 (s, 3H), 3.24 (t, J = 6.66 Hz, 2H) , 3.20 (s, 3H), 2.91 (t, J = 7.62 Hz, 2H), 1.74-1.82 (m, 2H). LC-MS, (M + 1), 295. HPLC (> 95%, retention time 1.12 Min).

Example 30: Synthesis of compound 30

塩化クロロアセチルのTHF溶液に、０℃で3-(ジメチルアミノ)-1-プロピルアミンを加え、２０分間攪拌した。LC-MSは、アミドの生成を示した。この溶液に、THF中のイミダゾールナトリウム塩（10 mL THF中、イミダゾール及びNaHより合成）を加えた。この反応を攪拌しつつ２時間継続した。
反応終了後（LC-MS）、THFを除いた。残渣をメタノールに溶かし、調製様HPLCにより分離した。最終化合物は、この段階では純品ではない。その後、これを再びISCO C18逆相クロマトグラフィーで精製して、最終産物の純品を得た。HCl/メタノール（1N）溶液）との同時蒸発により、この産物をHCl塩に変換した（100 mg）。化合物３０を、¹H NMR, LC-MS 及びHPLCで特徴付けた。¹H NMR (D₂O), δ: 8.71 (s, 1H), 7.36-7.48 (m, 2H), 5.02 (s, 2H), 3.25 (t, J=6.80 Hz, 2H), 3.04-3.10 (m, 2H), 2.78 (s, 6H), 1.83-1.92 (m, 2H). LC-MS, (M+1), 211. HPLC (>95%, 保持時間, 1.01 分)。

3- (Dimethylamino) -1-propylamine was added to a THF solution of chloroacetyl chloride at 0 ° C. and stirred for 20 minutes. LC-MS showed amide formation. To this solution was added imidazole sodium salt in THF (synthesized from imidazole and NaH in 10 mL THF). The reaction was continued for 2 hours with stirring.
After completion of the reaction (LC-MS), THF was removed. The residue was dissolved in methanol and separated by preparative HPLC. The final compound is not pure at this stage. Thereafter, this was again purified by ISCO C18 reverse phase chromatography to obtain a pure product of the final product. The product was converted to the HCl salt (100 mg) by coevaporation with HCl / methanol (1N solution). Compound 30 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 8.71 (s, 1H), 7.36-7.48 (m, 2H), 5.02 (s, 2H), 3.25 (t, J = 6.80 Hz, 2H), 3.04-3.10 ( m, 2H), 2.78 (s, 6H), 1.83-1.92 (m, 2H). LC-MS, (M + 1), 211. HPLC (> 95%, retention time, 1.01 min).

中間体A31aの合成：
中間体A31a（250 mg）を化合物３０と同様に合成した。 Example 31: Synthesis of compound 31

Synthesis of intermediate A31a:
Intermediate A31a (250 mg) was synthesized in the same manner as Compound 30.

中間体A31aをメタノールに溶かし、HCl水溶液を加え、反応は、２時間攪拌して行った。
反応終了後（LC-MS）、この混合物を濃縮した。残渣を水に溶かし、調製様HPLC上で分離した。溶媒除去後、50 mL, 1.25 HClメタノール溶液と３回同時蒸発を行い、ギ酸塩をHCl塩に変換した（200 mg）。化合物３１は、¹H NMR, LC-MS 及びHPLCにより特徴付けた。¹H NMR (D₂O), δ: 8.70 (s, 1H), 7.33-7.46 (m, 2H), 5.01 (s, 2H), 3.25 (t, J=6.84 Hz, 2H) 2.95 (t, J=7.76 Hz, 2H), 2.60 (s, 3H), 1.77-1.87 (m, 2H). LC-MS, (M+1), 197. HPLC (>95%, 保持時間, 0.99 分)。 Synthesis of compound 31:

Intermediate A31a was dissolved in methanol, an aqueous HCl solution was added, and the reaction was stirred for 2 hours.
After completion of the reaction (LC-MS), the mixture was concentrated. The residue was dissolved in water and separated on a preparative HPLC. After removing the solvent, co-evaporation with 50 mL, 1.25 HCl methanol solution was performed three times to convert the formate into the HCl salt (200 mg). Compound 31 was characterized by ¹ H NMR, LC-MS and HPLC. ¹ H NMR (D ₂ O), δ: 8.70 (s, 1H), 7.33-7.46 (m, 2H), 5.01 (s, 2H), 3.25 (t, J = 6.84 Hz, 2H) 2.95 (t, J = 7.76 Hz, 2H), 2.60 (s, 3H), 1.77-1.87 (m, 2H). LC-MS, (M + 1), 197. HPLC (> 95%, retention time, 0.99 min).

Example 32: Synthesis of enantiomerically pure 2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide
2-Amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide can be synthesized by the method shown in Mechanism 4 below. First, 2-aminoethanol (compound 1E) is converted to this derivative with a leaving group (compound 2E). Examples of leaving groups are halides and alkoxy groups, or other activated hydroxyl groups. Second, compound 2E reacts with morpholine in a neutral or basic state to produce 2-morpholinoethanamine (compound 3E). The two-step reaction described above is carried out continuously as a one-step reaction involving compound 2E produced at that position. For example, compound 3E can be synthesized from compound 1E through a Mitsunobu reaction directly (wherein the hydroxyl group of compound 1E is directly activated by diethyl azodicarboxylate (DEAD)) prior to the addition of morpholine. The final product 2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide (compound 4E) was converted to 2-morpholinoethanamine and 2-amino-3-methylpentanoic acid by peptide coupling agent. It can be obtained by a coupling reaction with (Compound 5E). Examples of peptide coupling agents include 1,1′-carbonyldiimidazole (CDI), hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzo-7-azatriazole (HOAt) And so on.

  The enantiomeric 2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide (compound 5E) is the corresponding enantiomeric 2-amino-3-methylpentanoic acid (compound) in the above coupling step. 4E). For example, (2S, 3S) -2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide; (2R, 3R) -2-amino-3-methyl-N- (2-morpholino- Ethyl) -pentanamide; (2R, 3S) -2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide, and (2S, 3R) -2-amino-3-methyl-N- (2-morpholino-ethyl) -pentanamide is (2S, 3S) -2-amino-3-methylpentanoic acid, ie L-isoleucine; (2R, 3R) -2-amino-3-methylpentane, respectively. Acid, ie D-isoleucine; (2R, 3S) -2-amino-3-methylpentanoic acid, ie D-alloisoleucine; and (2S, 3R) -2-amino-3-methylpentanoic acid, ie It can be obtained using L-alloisoleucine.

Enantiomeric purity, also known as enantiomeric excess or EE, of enantiomer compound 5E can be measured by any method known to those skilled in the art. For example, enantiomer compound 5E can be hydrolyzed to compound 3E and the corresponding enantiomer compound 4E. The enantiomeric purity of enantiomer compound 5E can then be measured by comparing the enantiomer 4E obtained by hydrolysis with a standard enantiomer sample of compound 4E. This measurement can be performed using enantiomeric HPLC.
Details are described below, but by measuring the activity compared to BDNF, each isomer showed the potential for neurotrophin activity.

Example 33: Activity measurement compared to BDNF The compounds of the present application were tested for their ability to prevent hippocampal neuronal degeneration as described in Massa et al J Neurosci. (2006) 26 (20): 5288-300. In summary, hippocampal neurons were excised from 16-day-old fetal mice and seeded in 96-well tissue culture plates under conditions where the cultured neurons denatured in the absence of neurotrophin receptor ligand. Neuronal degeneration was assayed using morphological criteria 48 hours after cell seeding. Neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were used as positive controls. The maximum cell death prevention activity of BDNF was defined as 100% neurotrophin activity. The effect of NGF is 80% of BDNF. The neurotrophin activity of the test compound at each concentration used was quantified as a percentage of the maximum survival level in the presence of BDNF. In the presence of medium (CM) and in the absence of BDNF or compounds, the survival rate was approximately 40% of BDNF maximal effect, which was considered the baseline survival rate. For each compound, a dose response curve was generated leading to an EC ₅₀ and maximum survival. The compounds synthesized and characterized as disclosed herein showed an EC ₅₀ between about 1 nM and about 25 nM, and a maximum effect between about 20% and about 100% of BDNF.

Materials and Methods of Examples 34-40
Computer research
Computer studies were performed using Accelrys Catalyst (R) and Insight II systems obtained from Accelerys (San Diego, California, USA).

Antibody and protein polyclonal rabbit anti-NGF antibodies were obtained from Chemicon (Temecula, California, USA). Monoclonal anti-phosphorylated-ERK ^{T202 / Y204} , polyclonal anti-ERK42 / 44, monoclonal anti-phosphorylated-AKT ^S473 , polyclonal anti-AKT, polyclonal anti-phosphorylated-NFκB-p65 (Ser ⁵⁶³ ), and site-specific Polyclonal anti-Trk ^Y490 was ^obtained from Cell Signaling Technology, Inc. (Beverly, Massachusetts, USA). Monoclonal anti-NFκB-p65 was obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, California, USA). Monoclonal anti-actin was obtained from Sigma-Aldrich Corp. (St. Louis, Missouri, USA). Polyclonal TrkA and TrkB antibodies were obtained from Upstate USA, Inc. (Charlottesville, Virginia, USA). Anti-Pan-Trk 1087 and 1088 have been previously characterized (Zhou, Holtzman, DM, Weiner, RI, Mobley, WC (1994) Proc Natl Acad Sci USA 91, 3824), and these are referred to as Dr. William C. Mobley ( From Stanford University, California, USA). P75 ^NTR polyclonal rabbit antibody 9651 (Huber, LJ, Chao, raised against the neurotrophin binding region (43-161 residues, cysteine residue repeat regions II, III, and IV) of the extracellular domain of recombinant p75 ^NTR , MV (1995) Dev Bio 167, 227-238) and antibody 9650 were provided by Dr. Moses Chao (Skirball Inst., NYU, New York, USA). Recombinant human NGF was obtained from Invitrogen (Carlsbad, California, USA) and BDNF was obtained from Sigma-Aldrich (St. Louis, Missouri, USA). P75 ^NTR / Fc and TrkA / Fc chimeras were obtained from R & D Systems (Minneapolis, Minnesota, USA). Furin resistant pro-NGF was synthesized as previously described. (Beattie, MS et al. (2002) Neuron 36, 375-386).

Nervous system bioassay Hippocampal neurons were generated from E16-17 mouse embryos as previously described (Yang, T. et al. (2003) J Neurosci 23, 3353-3363). 25 μl of cell suspension (2000 neurons / well; 12,500 cells / cm ² ), 25 μl of DMEM containing 10% FBS, and different concentrations of recombinant BDNF, NGF, or p75-binding compound with poly-L-lysine Low density culture was initiated in addition to each well of the coated A / 2 plate. For studies with p75 ^{NTR + / +} and p75 ^{NTR − / −} neurons, mice with mutations in exon 3 of the p75NTR gene (Lee, KF et al. (1992) Cell 69, 737-749) Breeded on a similar gene background (> 10 B6 backcross).

  As described above (Longo, FM, Manthorpe, M., Xie, YM, Varon, S. (1997) J Neurosci Res 48, 1-17) Cell viability was assayed by a combination of visual measurements of conversion of MTT to blue formazan product. The number of viable neurons was determined by counting the total number of cells in each well that were morphologically normal and filled with blue product (Longo FM, Manthorpe, M., Xie, YM, Varon, S. (1997) J Neurosci Res 48, 1-17). For each neurotrophin concentration or compound concentration, duplicate wells were counted and the results averaged. The activity of each compound was confirmed by blind counting. The counts were normalized to the number of survival obtained with 25 ng / ml BDNF, or baseline survival. Fitting to dose response curves was done with Sigmaplot from SYSTAT Software Inc. (Richmond, California, USA).

For signal transduction pathway inhibitor studies, LY294002, PD98059 (obtained from EMD Biosciences / Calbiochem, San Diego, California, USA), and SN50 (Alexis Corp., Lausen, From Switzerland) was added to the cultures at final concentrations of 25 μM, 50 μM and 2.5 μg / ml, respectively. For antibody inhibition studies, p75 ^NTR antiserum and control non-immune serum were used at a final dilution of 1: 100 in the presence of BDNF, NGF, or p75-binding compounds. Survival was assayed 48 hours later for all studies applying signal transduction inhibitors, p75 ^NTR antibodies or p75 ^{NTR − / −} neurons.

Protein extraction and Western blot analysis
For assays of Trk, AKT, NFκB, and ERK activation, 6-well plates coated with poly L-lysine from hippocampal cells from E16-17 mice (Corning, Inc., Corning, New York, USA) Incubated in the presence of DMEM containing 10% FBS and then incubated in serum-free DMEM for 2 hours prior to addition of neurotrophin or compound. At the indicated time points, neuronal cells were treated with 20 mM Tris, pH 8.0, 137 mM NaCl, 1% Igepal CA-630, 10% glycerol 1 mM PMSF, 10 μg / ml aprotinin, 1 μg / ml leupeptin 500 μM orthovanadate (Zhou , J., Valletta, JS, Grimes, ML, Mobley, WC (1995) J Neurochem 65, 1146-1156).
The lysate was centrifuged, the supernatant was collected, and the protein concentration was measured using the BCA protein assay reagent obtained from Pierce (Rockford, Illinois, USA). Western blots were performed as previously described (Yang, T. et al. (2003) J Neurosci 23, 3353-3363). Western blot signals were performed using the ECL Chemiluminescence System obtained from Amersham (Piscataway, New Jersey, USA) (Yang, T. et al. (2003) J Neurosci 23, 3353-3363).

Replacement of NGF from p75 ^NTR and TrkA
NGF ELISA was performed as previously described (Longo, FM et al. (1999) J Neurosci Res 55, 230-237). In summary, 96-well plates are incubated overnight at 4 ° C. with 0.1 pmol (1 nM) of p75 / Fc or TrkA / FC recombinant protein from R & D System (Minneapolis, Minnesota, USA), followed by 1 at room temperature. Incubated with blocking buffer for hours. 100 ng / ml pro NGF, or different concentrations of NGF, and p75-binding compound were diluted with sample buffer, added to the wells and incubated for 6 hours with shaking at room temperature. The plates were then washed 5 times with Tris buffer (TBS) containing 0.05% Tween-20 and incubated overnight at 4 ° C. with anti-NGF rabbit polyclonal antibody. After washing 5 times with TBD, the wells were incubated with anti-rabbit IgG HRP conjugate for 2.5 hours at room temperature and washed 5 times. 3,3 ′, 5,5′-tetramethyl-benzidine substrate was added and the absorbance was measured at 450 nm.

NIH3T3 fibroblasts expressing p75 ^NTR antibody racing sky vector or p75 ^NTR (Huang, CS et al. (1999) J Biol Chem 274, 36707-36714) were obtained from Dr. William Mobley (Stanford University, California, USA). Obtained. Cells were grown in monolayers, harvested in PBS containing 2 mM EDTA, pelleted and suspended in ice-cold DMEM HEPES containing 1 mg / ml BSA. 6-9 × 10 ⁶ cells from one confluent 6-well plate were used for each experimental point.
For binding analysis, the p75 ^NTR antibody (1: 100) was allowed to bind (to cells) in the presence or absence of 100 nM 75-binding compound at 4 ° C. under slow rotation for 90 minutes, Thereafter, it was washed 4 times in PBS. The final cell pellet was resuspended in lysis buffer.
Western blot was performed as described above. For detection of p75 ^NTR antibody, blots were probed with horseradish peroxidase-conjugated goat anti-rabbit IgG from Amersham / Pharmacia Biotech (Piscataway, New Jersey, USA). The signal was detected by an ECL chemiluminescence system obtained from Amersham Biosciences (Piscataway, New Jersey, USA). To adjust for variations in the amount of protein loaded, blots were removed and re-probed with a β-actin monoclonal antibody obtained from Sigma (St. Louis, Missouri, USA).

Oligodendrocyte culture, proneutrophin treatment and cell death assay Skin oligodendrocytes from rat children were prepared as previously described (Yoon et al. (1998) J Neurosci 18, 3273-3281, Harrington , AW, Kim, JY, Yoon, SO (2002) J Neurosci 22, 156-166). Cells were treated with 0.05 nM (2.8 ng / ml) recombinant, cleavage resistant pro-NGF. Controls were treated with an equal volume of pro NGF purification buffer containing 350 mM imidazole. 24 hours after the treatment, the cells were fixed and subjected to MBP and TUNEL staining treatment as described above (Beattie, MS et al. (2002) Neuron 36, 375-386). Counts of 200-250 cells per well and a minimum of 600 cells per experimental condition were performed.

Example 34: Computer modeling, pharmacophore creation, virtual and functional screening To create a meaningful pharmacophore that mimics the loop structure that appears to interact with the receptor, two conditions are assumed: (1) The degree of freedom of ligand peptide structure is constrained by being within the protein, and (2) there is little “inductive fit” involving changes in the loop structure at the target receptor subsite, or of small molecule ligands Adapt by flexibility. When applying these conditions, an interacting / activating small molecule conformation is possible that interacts with the receptor in a manner similar to the natural ligand.
Computational studies of active dimeric cyclic peptides that mimic the NGF β-hairpin loop suggest that energetic and structural constraints negate the simultaneous β-hairpin convolution of both peptide subunits. It means acting like a monomer. In addition, based on early virtual screening of 3D conformer libraries, it is unlikely that many functional dimeric non-peptide molecules with a molecular weight of 500 D or less exist.

  Therefore, efforts were focused on finding compounds that mimic a single loop 1 structure. Using the procedure outlined in FIG. 1, compounds were selected by screening for cell viability assays. Computer studies show that in situ, the constrained loop 1 skeleton and the part near the center of the side chain structure have constrained degrees of freedom, and from sample sets from loop molecular dynamics simulations. The selected intermediate structure was extracted and used to create a new pharmacophoric model (FIG. 1a). Guidance on the placement of pharmacophore properties was obtained by considering the inventors' experience with loop phylogeny, side chain chemistry, and synthetic active peptides.

As a first approximation, it is assumed that similar loop 1 domains from different animal species of neurotrophins and different neurotrophin family members should bind to the p75 ^NTR as well. The primary structure of BDNF loop 1 is significantly different from NGF and NT-3, and only the latter two are used for the purpose of reducing the complexity of the pharmacophore. Acting as a hydrogen bond donor (McDonald, I, Thornton, JM, (1994) WWW Edition December 1994) The trend for histidine residues suggests use at position 34, while the change from K to R at position 32 This suggests the use of a positively ionizable property at this position (FIGS. 1b and 1c).

  An average of 35 conformers for each of over 800,000 compounds was screened against a new pharmacophore yielding about 800 that fits within 10 kcal / mol of calculated internal energy (FIG. 1d). This number was reduced to approximately 60 based on visual inspection of compatibility with possible steric hindrances, taking into account the assumption of a shallow receptor binding pocket and maximum functional group flexibility. 35 compounds were obtained first, 23 of which were water soluble.

  In a preliminary study using the chicken DRG neuronal survival assay, 4 of the 23 compounds tested showed significant activity. Further analysis was performed using mouse embryonic hippocampal neurons. In low density and absence of glial cells, the survival of these neurons depended in part on neurotrophin added to the culture.

  Screening of 23 previously tested compounds using these hippocampal cell cultures identified 3 compounds as active (compounds (ii-iv)) and identified as having activity using DRG cultures, and The fourth and fifth active compounds (compounds (i) and (vii)) were identified using DRG and hippocampal assays. These results correspond to 17% for this screening tool. As further support for this method, in a preliminary study based on the model of NGF loop 4 (LM14A), high-efficiency identification of the active compounds was obtained (3 out of 8 compounds screened positive (37%)). .

（式中：最大値＝最大シグナル；ベース＝ベースラインシグナル；［Ｃ］＝化合物濃度；Ｓ＝Schild係数；Hillスロープ＝Hill係数；［NGF］＝NGF濃度；EC₅₀＝最大結合（最大値―ベース）の５０％をもたらすNGF濃度；及びA2＝シフトしてない曲線からEC₅₀の２倍をもたらす化合物濃度）にフィットさせた。ここで、Hillスロープ計算値は、１．０から１．６の範囲であり、及び一般的に１と顕著に違わない。 A regression analysis of NGF-p75 ^NTR binding was performed in the presence of p75-binding compounds. This data was converted to the modified Gaddum / Schild equation (Motulsky, HJ, and Christopoulos, A. (2003) A Practical Guide to Curve Fitting, 2nd edition (San Diego, California, GraphPad Software) using the Sigmaplot nonlinear regression module. , Inc.)

(Where: maximum = maximum signal; base = baseline signal; [C] = compound concentration; S = Schild coefficient; Hill slope = Hill coefficient; [NGF] = NGF concentration; EC ₅₀ = maximum binding (maximum value— NGF concentration yielding 50% of the base); and A2 = compound concentration yielding twice the EC ₅₀ from the unshifted curve). Here, the Hill slope calculation value is in the range of 1.0 to 1.6, and generally not significantly different from 1.

Example 35: Compound Promoting Hippocampal Neuronal Cell Survival Chemically extensive with strong neurotrophin activity using a high-throughput virtual screen based on the neurotrophin loop 1 model and a small in vitro bioassay Was identified (FIG. 1). Approximately 800,000 compounds were obtained by computer screening and in vitro screening, yielding 4 positive compounds (17%) in high yield.

Understand the mechanism of action of the selected compounds and test the ^hypothesis that they work via the target receptor, p75 ^NTR , under culture conditions where NGF promotes neuronal cell survival under fetal hippocampal neurons Cells were used to examine the dose-dependent relationship of the survival promoting activity of p75-binding compounds compared to NGF and BDNF. Since it hardly expresses TrkA in culture (Brann, AB, et al. (1999) J Neurosci 19, 8199-8206; Bui, NT, et al. (2002) J Neurochem 81, 594-605), neurotrophin Activity was mediated mainly by BDNF via TrkB and p75 ^NTR and mainly by NGF via p75 ^NTR .

Addition of compound (i-iv) (FIG. 2a, structure) increased the number of GAP-43 positive-neurite-retaining cells, consistent with an increase in neuronal viability (FIG. 2a, micrograph). The dose response curve of the active compound (FIG. 2b) showed that the EC ₅₀ value was within the range of 100-300 pM and the intrinsic activity was 80-100% of the NGF response. Independently synthesized compounds (iii) and (iv) showed similar results. Compound (v), a compound structurally similar to compound (iii), showed little or no neurotrophin activity. The structures of compounds (i-iv) are shown in Table I.

Each compound by a mechanism unrelated to p75 ^NTR or as a result of modulation of receptor multimer formation and survival signaling by high receptor occupancy or by a compound without neurotrophin activity (eg compound (v)) In contrast, at concentrations above 5 nM, viability decreased to baseline or below (Figure 2b). A response curve similar to the NGF response curve in the hippocampal neuronal system is compatible with activation of survival signaling via the NGF binding region of p75 ^NTR .

  Of the four compounds initially identified, two (compound (iii), caffeine derivatives, and compound (iv), amino acid derivatives) are Lipinski standards (Lipinski, CA (2000) J Pharm Toxicol Methods 44, 235). -249) is expected to have the most "drug-like" features, and blood-brain barrier calculations (Fu, XC, Chen, CX, Liang, WQ, Yu, QS (2001) Acta Pharmacol Sin 22, 663-668; Clark, DE (2002) J Pharm Sci 88, 815-821) was selected for more detailed mechanistic studies. Preliminary studies have shown that compound (iv) has shown significant oral uptake and cerebrovascular barrier penetration. Because of the structural similarity to compound (iii) (FIG. 2a), a relatively inactive compound (v) was selected as a negative control.

Example 36: Trk not a receptor, p75 interacts with ^NT receptor, compounds act through p75 ^NT receptor
To test the interaction between p75-binding compounds and neurotrophin receptors, we examined the effect of increasing compound concentration on the binding between recombinant chimeric proteins p75 ^NTR -Fc and TrkA-Fc and NGF . In these experiments, compound (iv) (Fig. 3a) and compound (iii) (Fig. 3b), not compound (v) (Fig. 3c), significantly shifted the NGF / p75 ^NTR- Fc binding curve to the right. did. The inhibition of NGF binding caused by each active compound is reversed by increasing NGF concentration, which is consistent with the mechanism being at least partially competitive. Gaddum-Schild equation (Motulsky, HJ, and Christopoulos, A. (2003) A Practical Guide to Curve Fitting, 2 ^nd edn. (San Diego, California, GraphPad Software), which describes ligand binding in the presence of inhibitors. , Inc.)), the Schild coefficient obtained was significantly less than 1.0 for both active compounds (compound (iv), 0.58 +/- 0.04; compound (iii), 0.26 +/- 0.01). From this, for example, many ligand-receptor binding sites (Lutz, M., and Kenakin, T. (1999) Quantitative Molecular Pharmacology and Informatics in Drug Discovery (quantitative molecular pharmacology and informatics in drug discovery) ) (Hoboken, New Jersey: John Wiley &Sons); Neubig, RR, Spedding, M, Kenakin, T., and Christopoulos, A. (2003) Pharmacol Rev 55, 597-606) Is suggested.

These results are consistent with a model where the effect of the compound is due to allosteric effects that interact only with a portion of the receptor's NGF binding surface and / or indirectly affect NGF binding. Gaddum-Schild analysis also, A ₂ (i.e., an EC ₅₀ rightward to twice the concentration of compound shifts) gives an indication of the efficacy known as, A _2, when Schild coefficient is 1, the compound K _D be equivalent to. The A ₂ values obtained for compound (iv) and compound (iii) were 1192 +/− 1.2 and 31.6 +/− 1.3 nM, respectively. However, since Schild coefficient different from the remarkably 1 can not measure the true K _D values.

For compound (iv), the EC ₅₀ value for this biological effect is about 150 pM, while the A ₂ value is about 4 orders of magnitude higher. Large differences between small molecule biological potency and binding estimated by ligand replacement are common (Lutz, M., and Kenakin, T. (1999) Quantitative Molecular Pharmacology and Informatics in Drug Discovery (Hoboken, New Jersey: John Wiley & Sons)), which may have several causes: (b) receptor status differences in binding pair function assays; (b) receptors with very low biological effects. Signal amplification after receptor, as seen in occupancy; (c) partial replacement of multivalent ligands by smaller antagonists; and (d) compounds work in a mechanism independent of the target receptor, etc. It is. The latter possibility can be treated using p75 ^NTR- inhibiting antibodies and p75 ^{NTR − / −} neurons to assay for p75 ^NTR dependence. Furthermore, since the active compound has no effect on the binding between TrkA and NGF, the specificity of the p75-binding compound for p75 ^NTR is supported (FIGS. 3d, 3e).

Subsequently, it was determined that p75-binding compound activity was p75 ^NTR dependent. Ab9651 (Longo, FM, Manthorpe, M., Xie, YM, Varon, S., previously reported to inhibit the neurotrophin activity of NGF and NGF loop 1 peptide mimetics in mouse dorsal root ganglion neurons. (1997) J Neurosci Res 48, 1-17) partially inhibits the neurotrophin activity of BDNF (FIG. 3g) and completely inhibits the neurotrophin activity of compound (iii) and compound (iv). However, non-immune antibodies had no effect. Virtually identical results were obtained with another independently generated rabbit polyclonal anti-p75 ^NTR antibody (Ab9650), further confirming the specificity of p75 ^NTR inhibition. Neither antibody produced a change in baseline survival, so antibody production did not promote or inhibit survival in these cultures. These results are consistent with that BDNF acts through both TrkB and p75 ^NTR , whereas NGF and p75-binding compounds act primarily through p75 ^NTR .

Furthermore, the response of p75 ^NTR- deficient (− / −) cells to neurotrophin and p75-binding compounds was examined (FIG. 3h). Baseline viability under these culture conditions was the same between wild-type and deletion cells, but p75 ^NTR -deletion is a partial response to BDNF, and to NGF and p75-binding compounds. Associated with no response, a pattern similar to the results found in the p75 ^NTR antibody study. Finally, in addition to 50 ng / ml NGF, treatment with 5 nM compound (iii) or compound (iv) (although this concentration is the concentration that induces maximal response) has an additional effect on survival. No (data not shown), this further supports the hypothesis that p75-binding compounds act directly through binding to p75 ^NTR .

In spite of the observation that compound (iii) and compound (iv) did not affect NGF-TrkA / Vc binding, p75-binding compound is TrkB (which is Trk of hippocampal neurons) or nominally expressed The question remains whether to activate TrkA (since it is the main mechanism that promotes survival). Also, ligand binding to p75 ^NTR appears to affect Trk activation. In view of these, it was interesting to determine whether p75-binding compounds promote Trk activation. Since Trk activation is demonstrated by Trk ^Y490 phosphorylation, an established marker of Trk activation, compounds (iii) and (iv) were assayed for their ability to activate Trk autophosphorylation. In hippocampal cell cultures, BDNF exposure resulted in strong TRk activation (FIG. 3i), whereas no activation was seen for NGF or p75-binding compounds. The lack of signals associated with NGF a) confirms that these cell cultures produce little or no TrkA, and b) the idea that the trophic effect of NGF is primarily mediated through p75 ^NTR. To support. In 3T3-TrkA cells, NGF exposure revealed the expected TrkA autophosphorylation response, whereas the p75-binding compound again showed no activity (FIG. 3j). These results suggest that activation of the Trk receptor does not play a major role in promoting cell survival by p75-binding compounds.

Example 37: Compound works via p75 ^NTR , in total a) replacement of NGF from p75 ^NTR by active compound (but not by inactive compound), b) presence of unoccluded p75 ^NTR P75-binding compounds interact directly with p75 ^NTR due to the fact that they depend on biological functions, c) lack of Trk interaction and activation, and d) lack of additive effects between NGF and compounds. It is strongly suggested that it acts and works through the p75 ^NTR .
This is compatible with the pharmacophoric model used herein to select p75-binding compounds (Figure 1). Fitting this model as the primary initial selection criterion identified a high proportion of chemically diverse positive compounds from small groups tested in vitro, and similarities in various biochemical and biological assays to show the effect, from the fact of equal, p75-binding compound is not a position other than the p75 ^NTR neurotrophin binding site of the receptor, to interact with p75 ^NTR neurotrophin binding site is suggested.

Pro-survival signaling associated with p75 ^NTR action is reported in P13K and AKT (Roux, PP, Bhakar, AL, Kennedy, TE, Barker, PA (2001) J Biol Chem 276, 23097-23104; Lachyankar, MB, et al (2003) J Neurosci Res 71, 157-172), NFκB (Mamidipudi, V., Li, X., Wooten, MW (2002) J Biol Chem 277, 28010-28018; Carter, BD, et al. (1996) ) Science 272, 542-545; Gentry, JJ, Casaccia-Bonnefil, P., Carter, BD (2000) J Biol Chem 275, 7558-7565; Foehr, ED, et al. (2003) J Neurosci Res 73, 7556 -7563), and activation of ERK (Lad, SP, Neet, KE (2003) J Neurosci Res 73, 614-626). It has been shown that these signaling intermediates can be independently regulated by Trk and p75 ^NTR via pathways with varying degrees of overlap, mutual interference, and different kinetics. Treatment of hippocampal neurons with 20 nM compound (iii) and compound (iv) (a plateau concentration for acute signaling activation) is the same as that induced by both neutrophin proteins (BDNF, NGF) To the extent and the same time course (indicating activation of the NFκB pathway) results in an approximately 1.5-fold increase in NFκB-p65 phosphorylation (FIG. 4a) (Sakurai, H., Chiba, H., Miyoshi , H., Sugita, T., Toriumi, W. (1999) J Biol Chem 274, 30353-30356).

  At the same concentration, compound (v) did not induce NFκB-p65 phosphorylation. Consistent with the activation of NFκB by compound (iii) and compound (iv), a specific peptide inhibitor of NFκB translocation, SN50 (Lin, YZ, Yao, SY, Veach, RA, Torgerson, TR, Hawiger, J (1995) J Biol Chem 270, 14255-14258) does not affect baseline survival but significantly reduces cell viability promoted by compound (iii), compound (iv) and neurotrophin (FIG. 4e).

  In the study of AKT activation, compound (iii) and compound (iv) showed 20 nM and activation similar to that found after 30 minutes by NGF, while BDNF was much larger Showed a response. Furthermore, the onset of activation promoted by compound (iii) and compound (iv) was slower than the onset by NGF (FIG. 4b). Consistent with these findings, the P13 kinase inhibitor LY294002, which inhibits AKT activation, significantly reduced survival in all cases, including baseline survival, without compound (v) treatment or exposure. (Figure 4e).

  Studies of ERK signaling showed that ERK44 activation was induced on a larger scale by neurotrophin (BDNF) than by p75-binding compounds (which show a pronounced but small response) (FIG. 4c). ERK42 activation was generally stronger and greater with BDNF and NGF treatment than with p75-binding compounds. There was a significant loss of signal by 30 minutes, but the active form was more persistent after BDNF treatment (FIG. 4d). Consistent with the greater ERK activation seen with BDNF compared to NGF and p75-binding compounds, the ERK inhibitor PD98059 significantly reduced BDNF-stimulated survival and increased NGF activity. Had a small but significant effect and did not significantly reduce the survival promoted by compound (iii) or compound (iv) (FIG. 4e).

  These observations suggest that unlike NFκB and P13K, ERK activation is not an important factor in promoting survival by p75-binding compounds. This difference may be related to the lower level of ERK activation observed with p75-binding compounds compared to protein ligands (FIG. 4d). P13K activation can promote survival through pathways involving and not involving AKT (Zhang, Y., et al. (2003) J Neurosci 23, 7385-7394) and thus in this system The essential mechanism downstream of P13K remains unclear. Stronger AKT and ERK activation by BDNF may represent the effect of TrkB.

  To further investigate the relationship between compound-mediated AKT and NFκB activation and neuronal survival, compound dose-activation studies were performed (FIGS. 4f, 4g). This result indicates that compound (iv) induces activation of both AKT and NFκB in the concentration range of 0.5 nM to 3 nM, which is similar to that required to promote survival, Consistent with its role in signaling mechanisms that mediate compound-induced survival.

Furthermore, the activation of AKT signaling by NGF and compounds was measured to be completely absent in p75NTR-/-neuronal cultures (Fig. 4h), indicating that NGF and p75-binding compounds failed to activate p75 ^NTR . This is consistent with the hypothesis that it activates AKT survival signaling. Together with evidence that compound-induced survival is p75 ^NTR- dependent (FIGS. 3g, 3h), these findings indicate that p75-binding compounds at least partially contribute to hippocampal neuronal survival in culture (including AKT and NFκB). ^Suggests that it induces through interaction with p75 ^{NTR (} which leads to activation of pro-survival signaling pathways).

Example 38: Compound (iii) and Compound (iv) do not promote cell death of mature oligodendrocytes and inhibit pro-NGF-induced cell death
NGF and p75-binding compounds promote cell survival of cultured hippocampal neurons used in the study herein, but ligand formation of p75 ^NTR by mature NGF or pro NGF is more potent than cell survival promotion in certain cell types. Related to death (Lee, R., Kermani, P, Teng, KK, Hempstead, BL (2001) Science 294, 1945-1948; Casaccia-Bonnefil, P., Carter, BD, Dobrowsky, RT, Chao, MV ( 1996) Nature 386, 716-719). To determine whether a p75-binding compound disclosed herein induces cell death or induces cell death in a system in which neurotrophin induces cell death, it was treated with p75-binding compound and pro-NGF. The survival of mature oligodendrocytes was examined.

Mature oligodendrocytes express p75 ^NTR but do not express TrkA and undergo apoptosis upon treatment with NGF or proNGF (Beattie, MS, et al. (2002) Neuron 36, 375-386; Casaccia-Bonnefil, P., Carter, BD, Dobrowsky, RT, Chao, MV (1996) Nature 386, 716-719; Yoon, SO, Casaccia-Bonnefil, P., Carter, B., Chao, MV (1998) J Neurosci 18, 3273-3281). Unlike NGF or pro-NGF, compound (iii), compound (iv) and compound (v) alone do not promote cell death (FIG. 5a). Furthermore, pro NGF-induced cell death is significantly inhibited by compound (iii) and compound (iv) in the concentration range of 1 to 10 nM, but compound (v) (appears to reduce survival at 10 nM). Is not inhibited (FIG. 5a).

To determine whether p75-binding compounds inhibit proNGF binding to p75, proNGF binding to p75 ^NTR was assayed at a concentration range of 1500 nM to 10,000 nM. Compound (iii) and compound (iv) inhibited pro-NGF binding to the same extent with a reduction of about 30% at the highest concentration (FIG. 5b). Compared to inhibition of pro-NGF-induced cell death, the high concentration required for inhibition of pro-NGF binding suggests the following possibilities: 1) In cell-based assays, co-receptors (eg, Due to the native (original) receptor conformation in the presence of sortilin, pro-NGF-p75 ^NTR interactions are more likely to be disrupted (intracellular) by p75-binding compounds than in in vitro assays; 2) At low concentrations, this compound qualitatively alters pro-NGF binding, but does not change the total binding of pro-NGF and reduces cell death induction; or 3) This compound does not affect pro-NGF binding and p75 ^Induces preferential activation of ^pro- survival signaling by ^NTR . Activation of the preferential survival pathway may result from differences in how the compound changes the receptor structure and the lack of binding of co-receptors such as sortilin expressed in oligodendrocytes. Indeed, previous studies suggest that the involvement of sortilin and p75 ^NTR by pro-NGF promotes efficient ligand binding, receptor complex activation and apoptotic effects (Nykjaer, A., Willnow, TE, and Petersen, CM (2005) Curr Opin Neurobiol 15, 49-57).

Example 39. Compound (iii) pre-incubates Aβ in water for 3 days to form oligomers using an already established procedure that protects Aβ-induced neuronal degeneration . E17 hippocampal neurons were incubated for 5 days and matured before adding Aβ with the test compound. Mature neurons show high Aβ vulnerability.
As a negative control, addition of Aβ _42-1 (30 μM) did not cause cell death. Addition of 10 μM or 30 μM Aβ _1-42 caused about 40% neuronal loss after 3 days of exposure (FIG. 6a). This result is similar to previously reported levels of in vitro Aβ-induced cell death (Michaelis, ML, et al. (2006) J Pharm Exp Ther 312: 659-668). The addition of NGF (100 pg / ml) did not protect against Aβ _1-42 , which is a previously reported finding (Yankner, BA, et al. (1990) PNAS 87: 9020 -9023).

Without compound (NC), addition of Aβ _1-42 results in 40% neuronal loss (FIG. 6b). The presence of inactive compound (v) and compound (iv) did not inhibit Aβ _1-42 toxicity. However, addition of compound (iii) _inhibited Aβ _1-42- induced cell death with a dose-responsive effect, with an EC ₅₀ of about 10 nM. Data are expressed as the ratio of viable cells to total cells present in a given measurement area. Multiple bioassays are used to show the mean +/− SE for at least 20 field areas per condition. Complete inhibitory ability of Aβ-induced denaturation exhibited by compound (iv) at low nanomolar concentrations, this preferred molecular weight (below 500), and favorable Lipinsky score; this is a high priority for preclinical development in an in vivo AD model Indicates a lead compound. Compound (iv) has also been shown to inhibit Aβ-induced degeneration of skin and septal neurons.

Example 40: Compound (iv) is a 3 month toxicological test that inhibits hair loss in middle-aged mice , and age-related hair loss is present in 3 out of 5 vehicle-treated mice, compound (iv) -In treated male mice, it was shown to be present in 0 out of 5 mice. In subsequent follow-up, 4 out of 10 vehicle-treated mice and 0 out of 9 compound (iv) -treated middle-aged male mice showed hair loss at 2 months.
Overall, these studies showed hair loss in 7 out of 15 vehicle-treated mice and 0 out of 14 compound (iv) -treated mice. As a result, the p-value was 0.001 (Fisher's exact test), supporting the existence of significant effects from preclinical studies. This data indicates that p75 ^NTR regulates hair follicle cell death and thereby regulates the hair loss process (known as the regression phase). These findings show for the first time the effectiveness of administration of a small molecule compound targeting the p75 ^NTR for the prevention of hair loss that occurs in aging or pathological conditions (known as alopecia areata).

Overview of Examples 34-40 Targeting one of the receptor groups that interact with a given ligand, some activation of effects via the receptor, which may or may not occur in nature, may occur. Expected. Such differences in signal transduction, including minimal activation of Trk, appear to be clinically useful. For example, the compounds disclosed in the Examples can promote cell survival under conditions where neurotrophin promotes cell death, and excessive sympathetic fiber sprouting by neurotrophin treatment and Trk signal Induction of pain transmission that may occur via transmission can be made difficult (Walsh, GS, Krol, KM, Kawaja, MD (1999) J Neurosci 19, 258-273).

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  The patents and publications mentioned in this specification describe common technology in the art, and according to this specification, for all purposes and each specifically and individually cited. The entire document is incorporated as a cited document as much as it is incorporated. In case of conflict between the cited references and the present specification, the present specification shall control. In order to clarify the embodiments of the present application, special terminology has been used. However, the present invention is not intended to be limited to the specific terms so selected. Nothing in this specification should be considered as limiting the scope of the invention. All examples shown are representative and non-limiting. As those skilled in the art will appreciate under the above teachings, the above-described embodiments may be modified or varied without departing from the invention. Therefore, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims (7)

Pharmaceutically accepted diluent or carrier, and Formula I, IA, IB, II, IIA, IIB, III, IV or the compound represented by IVA or acceptable salts thereof with pharmaceutically, flop prodrug or solvate A pharmaceutical composition comprising a hydrate, wherein the prodrug, when administered to a biological system, generates the compound in one or more steps involving a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, or both Represents all compounds,
The compound represented by Formula I has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ² , R ^{2 ′} , R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ² and R ^{2 ′} may together form ═O, ═S or ═CH ₂ , R ⁵ represents a heterocycloalkyl group, X represents CH ₂ , NH, O or S, n Represents 0, 1, 2, 3, 4, or 5, and m represents 1 or 2.)
The compound represented by the chemical formula IA has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently represents a hydrogen atom or an optionally substituted alkyl group, and n represents 0, 1, 2, , 3, 4 or 5).
The compound represented by the chemical formula IB has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently represents a hydrogen atom or an optionally substituted alkyl group).
The compound represented by Formula II has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V and W each independently represent = CH ₂ , = NH, = O or = S; R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , -OH, -C (= O) OR ^a , -C (= O) NHR ^a , -NHC (= O) R ^a , -NHS (= O) ₂ R ^a or optionally substituted R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted alkyl group, and Z represents a heterocycloalkyl group or a heteroaryl group. Each heterocycloalkyl group or heteroaryl group may be bonded via a heteroatom and optionally have a substituent.
The compound represented by Formula IIA has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; q represents 1, 2, 3 or 4; t represents 0, 1, 2, or 3; Y, V and W each independently represent O or S, and R ⁶ each independently represents —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O ) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, R ¹⁰ and R ¹¹ are each independently Represents a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group. And
The compound represented by the chemical formula IIB has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V and W each independently represent O or S; and R ¹⁰ and R ¹¹ each independently. A hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, —C (= O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, R 'And R "together with the nitrogen atom bonded to these form an optionally substituted heterocyclic aryl group.)
The compound represented by Formula III has the following structure:

(Wherein X represents CH ₂ , NH, O or S, s represents 0, 1, 2, 3 or 4; R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² , R ^{22 ′} and R ²⁴ each independently represents an absent group, a hydrogen atom or an optionally substituted alkyl group, or R ²⁰ and R ^{20 ′} represent May form ═O, ═S or ═CH ₂ together, or R ²⁰ and R ²¹ may form an optionally substituted cycloalkyl group together with the atoms bonded thereto. , Or R ²⁰ and R ²¹ together with the atoms bonded to them may optionally form an aryl group, or R ¹⁹ and R ²⁰ optionally together with the atoms bonded to them substituted may form a which may cycloalkyl group, or R ¹⁹ and R ²⁰ May form a optionally optionally substituted aryl group with the atoms connecting to these, R ²³ is a hydrogen atom, optionally optionally substituted alkyl group, optionally A cycloalkyl group which may have a substituent, or an aryl group which may optionally have a substituent.
The compound represented by Formula IV has the following structure:

(Wherein p represents 1, 2, 3, 4, 5 or 6, Y, V and W each independently represent CH ₂ , NH, O or S, and R ³⁰ , R ³¹ , R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} are each independently absent, have a hydrogen atom, or optionally have a substituent. R ³⁴ and R ³⁶ together with the atoms bonded thereto may optionally form a hydrocarbon ring optionally having a substituent, and E is — CHR ^c R ^d , —NR ^c R ^d , —OR ^c or SR ^c each represents R ^c and R ^d each independently represents a hydrogen atom or an optionally substituted alkyl group. or R ^c and R ^d form a optionally may have a substituent group a heterocyclic group together with the nitrogen atom bonded thereto, or R And R ^d is represented by optionally having a substituent together with the carbon atoms to which they are bonded form a carbocyclic ring group.)
The compound represented by the chemical formula IVA has the following structure:

(In the formula, p represents 1, ₂ , 3, 4, 5 or 6, V represents CH ₂ , NH, O or S, and R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′.} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} each independently represents an absent, a hydrogen atom or an optionally substituted alkyl group, or R ³⁴ and R ³⁶ are May form a carbocyclic group optionally having substituent (s) together with the atoms bonded thereto, and E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c and —SR ^c. R ^c and R ^d each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ^c and R ^d optionally together with a nitrogen atom bonded thereto have a substituent to form a heterocyclic group, or R ^c and R ^d, optionally having a substituent together with the carbon atoms to which they are bonded There form a carbocyclic ring group.) The pharmaceutical compositions represented by. Structural Formula I, IA, consisting IB, II, IIA, IIB, III, IV or the compound represented by IVA or their pharmaceutically acceptable salts, from flop prodrug or solvate thereof, related to p75 expression A pharmaceutical composition for treating a disorder, wherein the prodrug, when administered to a biological system, in a step or steps involving spontaneous chemical reaction, enzyme-catalyzed chemical reaction, or both, Represents all the compounds to be generated,
The compound represented by Formula I has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ² , R ^{2 ′} , R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ² and R ^{2 ′} may together form ═O, ═S or ═CH ₂ , R ⁵ represents a heterocycloalkyl group, X represents CH ₂ , NH, O or S, n Represents 0, 1, 2, 3, 4, or 5, and m represents 1 or 2.)
The compound represented by the chemical formula IA has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently represents a hydrogen atom or an optionally substituted alkyl group, and n represents 0, 1, 2, , 3, 4 or 5).
The compound represented by the chemical formula IB has the following structure:

(Wherein R ¹ , R ^{1 ′} , R ³ and R ⁴ each independently represents a hydrogen atom or an optionally substituted alkyl group).
The compound represented by Formula II has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V and W each independently represent = CH ₂ , = NH, = O or = S; R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , -OH, -C (= O) OR ^a , -C (= O) NHR ^a , -NHC (= O) R ^a , -NHS (= O) ₂ R ^a or optionally substituted R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted alkyl group, and Z represents a heterocycloalkyl group or a heteroaryl group. Each heterocycloalkyl group or heteroaryl group may be bonded via a heteroatom and optionally have a substituent.
The compound represented by Formula IIA has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; q represents 1, 2, 3 or 4; t represents 0, 1, 2, or 3; Y, V and W each independently represent O or S, and R ⁶ each independently represents —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O ) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, R ¹⁰ and R ¹¹ are each independently Represents a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, —C (═O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group. And
The compound represented by the chemical formula IIB has the following structure:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V and W each independently represent O or S; and R ¹⁰ and R ¹¹ each independently. A hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , —OH, —C (= O) OR ^a , —C (═O) NHR ^a , —NHC (═O) R ^a , —NHS (═O) ₂ R ^a or an optionally substituted alkyl group, R 'And R "together with the nitrogen atom bonded to these form an optionally substituted heterocyclic aryl group.)
The compound represented by Formula III has the following structure:

(Wherein X represents CH ₂ , NH, O or S, s represents 0, 1, 2, 3 or 4; R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² , R ^{22 ′} and R ²⁴ each independently represents an absent group, a hydrogen atom or an optionally substituted alkyl group, or R ²⁰ and R ^{20 ′} represent May form ═O, ═S or ═CH ₂ together, or R ²⁰ and R ²¹ may form an optionally substituted cycloalkyl group together with the atoms bonded thereto. , Or R ²⁰ and R ²¹ together with the atoms bonded to them may optionally form an aryl group, or R ¹⁹ and R ²⁰ optionally together with the atoms bonded to them substituted may form a which may cycloalkyl group, or R ¹⁹ and R ²⁰ May form a optionally optionally substituted aryl group with the atoms connecting to these, R ²³ is a hydrogen atom, optionally optionally substituted alkyl group, optionally A cycloalkyl group which may have a substituent, or an aryl group which may optionally have a substituent.
The compound represented by Formula IV has the following structure:

(Wherein p represents 1, 2, 3, 4, 5 or 6, Y, V and W each independently represent CH ₂ , NH, O or S, and R ³⁰ , R ³¹ , R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} are each independently absent, have a hydrogen atom, or optionally have a substituent. R ³⁴ and R ³⁶ together with the atoms bonded thereto may optionally form a hydrocarbon ring optionally having a substituent, and E is — CHR ^c R ^d , —NR ^c R ^d , —OR ^c or SR ^c each represents R ^c and R ^d each independently represents a hydrogen atom or an optionally substituted alkyl group. or R ^c and R ^d form a optionally may have a substituent group a heterocyclic group together with the nitrogen atom bonded thereto, or R And R ^d is represented by optionally having a substituent together with the carbon atoms to which they are bonded form a carbocyclic ring group.)
The compound represented by the chemical formula IVA has the following structure:

(In the formula, p represents 1, ₂ , 3, 4, 5 or 6, V represents CH ₂ , NH, O or S, and R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′.} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} each independently represents an absent, a hydrogen atom or an optionally substituted alkyl group, or R ³⁴ and R ³⁶ are May form a carbocyclic group optionally having substituent (s) together with the atoms bonded thereto, and E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c and —SR ^c. R ^c and R ^d each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ^c and R ^d optionally together with a nitrogen atom bonded thereto have a substituent to form a heterocyclic group, or R ^c and R ^d, optionally having a substituent together with the carbon atoms to which they are bonded There form a carbocyclic ring group.) The pharmaceutical compositions represented by. Formula I:

(Wherein R ¹ , R ^{1 ′} , R ² , R ^{2 ′} , R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ² and R ^{2 ′} may together form ═O, ═S or ═CH ₂ , R ⁵ represents a heterocycloalkyl group, X represents CH ₂ , NH, O, or S; n represents 0, 1, 2, 3, or 5, m is 1 or 2 represents a.) a compound represented by or a pharmaceutically acceptable salt thereof, flop prodrug (provided that the prodrug Represents any compound that, when administered to a biological system, generates the compound in one or more steps involving a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, or both. ) Or a solvate. Formula II:

(Wherein p represents 0, 1, 2, 3, 4, 5 or 6; Y, V and W each independently represent = CH ₂ , = NH, = O or = S; R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or an optionally substituted alkyl group, and R ¹² and R ¹³ each independently represent a hydrogen atom, —NR ^a R ^b , -OH, -C (= O) OR ^a , -C (= O) NHR ^a , -NHC (= O) R ^a , -NHS (= O) ₂ R ^a or optionally substituted R ^a and R ^b each independently represent a hydrogen atom or an optionally substituted alkyl group, and Z is optionally substituted. also represents an heterocycloalkyl group or optionally may have a substituent group heteroaryl compounds represented by.), or their pharmaceutically acceptable salts, flop prodrug (provided that the prodrug The creature When administered to a spontaneous chemical reaction, it refers to a chemical reaction with an enzyme catalyst, or in one or more steps involving both all compounds that generates the compound.) Or solvate. Formula III:

(Wherein X represents CH ₂ , NH, O or S, s represents 0, 1, 2, 3 or 4; R ¹⁹ , R ^{19 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² , R ^{22 ′} and R ²⁴ each independently represents an absent group, a hydrogen atom or an optionally substituted alkyl group, or R ²⁰ and R ^{20 ′} represent May form ═O, ═S or ═CH ₂ together, or R ²⁰ and R ²¹ may form an optionally substituted cycloalkyl group together with the atoms bonded thereto. , Or R ²⁰ and R ²¹ together with the atoms bonded to them may optionally form an aryl group, or R ¹⁹ and R ²⁰ optionally together with the atoms bonded to them substituted may form a which may cycloalkyl group, or R ¹⁹ and R ²⁰ May form a optionally optionally substituted aryl group with the atoms connecting to these, R ²³ is a hydrogen atom, optionally optionally substituted alkyl group, optionally Represents an optionally substituted cycloalkyl group or an optionally substituted aryl group, and R ²² and R ²³ optionally have a substituent together with the atoms bonded thereto. The compound represented by the formula III, which forms an optionally substituted heterocycloalkyl group, is not 2-amino-3-methyl-N- (2-morpholinoethyl) -butanamide), or a pharmaceutically acceptable salt, flop prodrug (provided that the prodrug, when administered to a biological system, spontaneous chemical reaction, chemical reaction with an enzyme catalyst, or in one or more steps involving both the compound All compounds that generate The expressed.) Or solvate thereof. Formula IV:

(Wherein p represents 1, 2, 3, 4, 5 or 6, Y, V and W each independently represent CH ₂ , NH, O or S, and R ³⁰ , R ³¹ , R ³² , R ^{32 ′} R ³³ , R ³⁴ , R ^{34 ′} , R ³⁵ , R ^{35 ′} , R ³⁶ , and R ^{36 ′} are each independently absent, have a hydrogen atom, or optionally have a substituent. R ³⁴ and R ³⁶ together with the atoms bonded thereto may optionally form a hydrocarbon ring optionally having a substituent, and E is — CHR ^c R ^d , —NR ^c R ^d , —OR ^c or SR ^c each represents R ^c and R ^d each independently represents a hydrogen atom or an optionally substituted alkyl group. or R ^c and R ^d form a optionally may have a substituent group a heterocyclic group together with the nitrogen atom bonded thereto, or R And R ^d form a optionally may have a substituent group carbocyclic group together with the carbon atoms bonded thereto. However, the compound represented by Formula IV can, N-(3- (diethylamino) propyl l ) -2- (4,6-dimethyl-5,7-dioxo-4,5,6,7-tetrahydro-1H-benzo [d] imidazol-1-yl) acetamide.) Or pharmaceutically accepted salts thereof, up prodrug (provided that the prodrug, when administered to a biological system, spontaneous chemical reaction, chemical reaction with an enzyme catalyst, or in one or more steps involving both the Represents all compounds that generate a compound ) or solvates. Chemical formula IVA:

(In the formula, p represents 1, ₂ , 3, 4, 5 or 6, V represents CH ₂ , NH, O or S, and R ³² , R ^{32 ′} , R ³³ , R ³⁴ , R ^{34 ′.} , R ³⁵ , R ^{35 ′} , R ³⁶ and R ^{36 ′} each independently represents an absent, a hydrogen atom or an optionally substituted alkyl group, or R ³⁴ and R ³⁶ are May form a carbocyclic group optionally having substituent (s) together with the atoms bonded thereto, and E represents —CHR ^c R ^d , —NR ^c R ^d , —OR ^c and —SR ^c. R ^c and R ^d each independently represent a hydrogen atom or an optionally substituted alkyl group, or R ^c and R ^d optionally together with a nitrogen atom bonded thereto have a substituent to form a heterocyclic group, or R ^c and R ^d, optionally having a substituent together with the carbon atoms to which they are bonded Pharmaceutically acceptable salts of the stomach to form a carbocyclic group.) Represented by the compound, or these compounds flop prodrug (provided that the prodrug, when administered to a biological system, spontaneous chemical reactions, Represents all compounds that generate the compound in one or more steps involving an enzyme-catalyzed chemical reaction, or both .

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