Compounds for the treatment of neurodegenerative and metabolic disorders

Abstract

Provided is a pharmaceutical composition that inhibits NAD consumption or increases NAD synthesis. 【Solution means】For example, it is a pharmaceutical composition containing a pyrazolopyrimidine compound of formula (II) or a pharmaceutically acceptable salt thereof. JPEG2026048976000135.jpg40169 (In the formula, R a1 and R a2 are independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxyl, etc., R b1 , R b2 , and R b3 are independently hydrogen, halo, (C1-C4) alkyl, etc., R c is hydrogen or (C1-C4) alkyl, Ar is a monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4) alkyl, etc., and n = 2, 3, 4, or 5)

Description

Detailed description of the invention

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Application No. 62 / 847,600, filed on 14 May 2019, all of which are incorporated herein by reference for all purposes.

[0002] [Explanation of government support] This invention was carried out with government support under authorization numbers 5R01NS085223 and R21NS093488 granted by the National Institutes of Health. The U.S. Government has certain rights to this invention.

[0003] [Background technology] Many deadly neurodegenerative diseases, including prion diseases such as Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by toxicity resulting from protein misfolding and are called protein misfolding neurodegenerative diseases (PMNDs). The proteins involved in these diseases become misfolded and form aggregates of various sizes. Some of these aggregates are highly toxic to nerve cells, a phenomenon also known as protein toxicity. Protein aggregates can also exhibit "prion-like" properties in the sense that they can propagate from cell to cell and act as seeds to amplify intracellular misfolding and aggregation processes. Such toxic misfolded proteins include the prion protein PrP in CJD, Aβ and tau in AD; α-synuclein and tau in PD; tau, TDP-43 and C9ORF72 in FTD; and SOD1, TDP43, FUS and C9ORF72 in ALS. PD belongs to a broader group of diseases called synucleinopathy, characterized by the accumulation of misfolded α-synuclein aggregates. Lewy body dementia is also a synucleinopathy. FTD belongs to another PMND group called tauopathy, which also includes chronic traumatic encephalopathy (CTE) and progressive supranuclear palsy (PSP). There are also non-neurological diseases that involve protein misfolding; for example, in diabetes, the proteins IAPP and proinsulin form protein aggregates that are toxic to pancreatic β cells.

[0004] The lack of understanding of the mechanisms of neurotoxicity hinders the development of effective treatments for PMND. To study these mechanisms, models using misfolded toxic prion proteins (TPrPs) have been developed, and in particular, TPrPs can reliably induce neuronal cell death in cell culture and after intracerebral injection. 1TPrP induces death in over 60% of cultured nerve cells at nanomolar concentrations, whereas its original folded counterpart, NTPrP, does not. Therefore, this model provides a highly efficient system for studying the mechanisms of neuronal cell death following exposure to misfolded proteins. Knowledge of the specific mechanisms of prion-induced toxicity and methods to inhibit them was considered more broadly applicable to other PMNDs. Thus, as demonstrated herein, TPrP-based studies have spurred the development of novel neuroprotective approaches for treating destructive PMNDs.

[0005] [Summary of the Invention] There are currently no disease-modifying treatments available for any protein misfolding neurodegenerative disease (PMND). Current treatments, if present, alleviate certain disease symptoms but do not slow the progression of the underlying pathogenic mechanisms or halt neuronal loss. In contrast, the compounds described herein can disrupt the fundamental neurotoxic mechanisms associated with changes in NAD metabolism, thereby protecting neurons from further damage. Therefore, the methods described herein can provide a first-class disease-modifying treatment for PMND and other diseases associated with NAD metabolic disorders.

[0006] In various embodiments, methods are provided for inhibiting NAD consumption and / or increasing NAD synthesis in a patient, comprising the step of administering to the patient an effective amount of a compound comprising, for the purpose, a member of any of the species or genus of the chemical structures disclosed and claimed herein.

[0007] In various embodiments, methods are provided for preventing or inhibiting NAD depletion in a patient, or for improving conditions related to altered NAD metabolism in a patient, comprising the step of administering to the patient an effective amount of a compound comprising, for the purpose, a member of any of the species or genus of the chemical structures disclosed and claimed herein. The conditions may include metabolic disorders, diabetes, aging, neurodegenerative diseases, neurodegeneration associated with multiple sclerosis, hearing loss or retinal disorders, cerebral or cardiac ischemia, renal failure, traumatic brain injury, or axonal damage.

[0008] In various embodiments, a method is provided to provide protection from the toxicity of misfolded proteins in a patient, comprising the step of administering to the patient an effective amount of a compound comprising a member of any of the species or genus of the chemical structures disclosed and claimed herein.

[0009] In various embodiments, a method is provided for preventing or treating a protein misfolding neurodegenerative disease in a patient, comprising the step of administering to the patient an effective amount of a compound comprising, for the purpose, a member of any of the species or genus of the chemical structures disclosed and claimed herein. The disease may be a prion disease such as Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD) or other synucleinopathies, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), or a tauopathy such as frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP).

[0010] Furthermore, novel compounds that may be useful in the methods described herein are provided.

[0011] In various embodiments, compounds having formula (I),

[0012] [ka]

[0013] Or a pharmaceutically acceptable salt thereof is provided.

[0014] In formula (I): Each R 1 And R 2 Is independently H, (C1-C4) alkyl, or (C1-C4) alkoxy; and Each R 3 Is independently selected from H, (C1-C4) alkyl optionally substituted with OH, (C1-C4) alkoxy, or heteroaryl (provided that both of R 3 Are not hydrogen); or both of R 3 Together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring containing at least one additional heteroatom selected from O, S, S=O, S(=O)=O, or NR, where R is (C1-C4) alkyl optionally substituted with -OH or (C1-C4) alkoxyl.

[0015] In various embodiments, a compound having formula (II),

[0016]

Chemical formula

[0017] Or a pharmaceutically acceptable salt thereof is provided.

[0018] In formula (II): Each R a1 And R a2 Is independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxyl, (C1-C4) haloalkoxyl, 2- to 4-membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; <00004​​​​​​​​​​, or (C1-C4) haloalkyl; or R b2 and R b3 Together they form aryl or heteroaryl compounds; Each R c and R d These are independently hydrogen or (C1-C4) alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, or heteroaryl; and n = 2, 3, 4, or 5.

[0019] In various embodiments, a compound having formula (III),

[0020] [ka]

[0021] Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0022] In formula (III): L 1 These are bonds, C1-C4 alkylenes, or 2-4 member heteroalkylenes; R 1 is a monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, alkylaryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, alkylaryl, or heteroaryl is optionally substituted with one or more selected from halo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxyl, -C(=O)(C1-C4)alkyl, -C(=O)N(R)2, or -C(=NR)(C1-C4)alkyl, where (C1-C4)alkyl is either unsubstituted or substituted with a heterocycloalkyl; Each R is independently H, -OH, (C1-C4)alkyl, or (C1-C4)alkoxyl, or two Rs, together with the bonded nitrogen atom, form a heterocycloalkyl group, optionally containing an additional O atom in the heterocyclyl ring; R 2 It occurs 0, 1, or 2 times, and is a (C1-C4) alkyl, (C1-C4) haloalkyl, or SO2N(R) 4 )2 and Each R 3 and R 4 These are independently H or (C1-C4) alkyl.

[0023] In various embodiments, a compound having formula (IV),

[0024] [ka]

[0025] Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0026] In formula (IV): R 1 These are hydrogen, (C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, and -C(O)NHNHR. 6 -C(O)NR 6 -((C1-C4)Alkylene)-NHR 6 -C(O)NR 6 (C1-C4) alkyl, or -C(O)NR 6 -Cycloalkylene-NHR 6 and; R 3 is hydrogen or (C1-C4) alkyl; Each R 2 , R 4 , R 5 These are independently hydrogen, halo, (C1-C4)alkyl, -C(O)O-(C1-C4)alkyl, (C1-C4)alkoxyl, (C1-C4)haloalkyl, or CN; and Each R 6is either hydrogen or (C1-C4) alkyl.

[0027] In various embodiments, a compound having formula (V),

[0028] [ka]

[0029] Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0030] In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, CN, -S(O)2NH2, oxo, -NH2, (C1-C4)alkoxyl, or -NHC(O)(C1-C4)alkyl; Each R 1 and R 2 R is independently hydrogen, (C1-C4)alkyl, aryl, or heteroaryl (where the aryl or heteroaryl is optionally substituted with a halo or (C1-C4)alkyl), or bonded to nitrogen. 1 and R 2 Together they form a 5-6 member heterocycloalkyl group; and R 3 This is hydrogen or a hydroxy-(C1-C4) alkyl group.

[0031] Other aspects of the present invention are disclosed below.

[0032] [Brief explanation of the drawing] Figure 1 shows the primary neuroprotective assay and confirmatory NAD quantification assay in a 384-well plate format. PK1 neuroblastoma cells (2000 cells / well) were treated with 2.5 μg / ml TPrP for 3 days at the indicated doses (in μM), in the presence or absence of either NAD or the screening hit DMCM, as shown. TPrP is described in Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 Prepared as described. DMSO content was 0.3%. Five replicates and standard deviations are shown. Top panel: CellTiter-Glo(Promega) bioluminescent cell viability assay. Bottom panel: NAD+ / NADH-Glo TM NAD quantitative assay using (Promega).

[0033] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2A: Carbazole; Figure 2B: Pyrazolopyrimidine; Figure 2C: Aminothiazole; Figure 2D: Triazolophthalazine; Figure 2E: Aminophthalazine; Figure 2F: Flavonoid (Nobiletin); Figure 2G: Alkaloid (Palmatine); Figure 2H: 3-Heteroarylquinoline (DMPQ).

[0034] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-GloTM Quantitative analysis was performed using (Promega).

[0035] Figure 3 shows GABA, which is structurally unrelated to DMCM. A This study demonstrates a lack of neuroprotection by R inhibitors. PK1 cells (1500 cells / well, 96-well plate) were treated with flumazenil (50 nM) for 24 hours, and then exposed for 4 days with or without TPrP (3 μg / ml) and DMCM (0.5 or 5 μM). (TPrP is described in Zhou et al., Proc Natl Acad Sci USA 109, 3113-3118 (2012)). 1 Preparation was carried out as described. Cell viability was measured using CellTiter-Glo® (Promega). The lack of protection by flumazenil against TPrP toxicity was repeated in a 10-point dose response experiment (0.3–164 nM, not shown). In this experiment, GABA A Due to R inhibition, IC 50 Flumazenil was used at a dilution of 100 times.

[0036] Figure 4 shows GABA A This study demonstrates that the R-inactive DMCM analog (DMCM-10049) and the aminoamide DMCM-8137 possess neuroprotective effects. DMCM-8137 and DMCM-10049 exhibit nearly identical dose-response profiles in a TPrP neuroprotective assay. Cells (1500 cells / well, 96-well plate) were exposed to 5 μg / ml TPrP and the indicated doses of the compounds for 4 days. (TPrP is referenced from Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012)). 1 The cells were prepared as described in [the relevant document]. Cell viability was measured using CellTiter-Glo® (Promega).

[0037] Figure 5 shows that DMCM rescues TPrP-induced toxicity in primary neurons. Primary mouse cortical neurons (Life Technologies) were exposed to 12 μg / ml TPrP for 5 days and treated with the indicated DMCM or NAD. The assay was performed in a 96-well plate format. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The samples were prepared as described. Data from 3 replicates are shown ± standard deviation. Cell viability was measured using CellTiter-Glo® (Promega). DMCM and NAD treatment also suppressed neuritis and neuronal vacuolation induced by TPrP exposure (not shown).

[0038] Figure 6 shows that DMCM reduces ribosylation of ADP, an excess protein induced by misfolded proteins. PK1 cells were treated with 5 μg / ml TPrP in the presence of 9 nM FK866 (to inhibit NAD synthesis from nicotinamide present in the culture medium) and 40 μM biotin-NAD (Trevigen). Cells were harvested 2 or 3 days after treatment. Cell lysates were analyzed using SDS-PAGE, and ADP-ribosylated and biotinylated proteins were identified using streptavidin-HRP. Bands corresponding to TPrP-specific ADP-ribosylation at approximately 80 and 130 kD were reduced in the presence of DMCM (compare lanes 1 and 2 at each point). DMCM had no effect in the absence of TPrP (lanes 3 and 4 at each point). 10 μg of protein was added per lane.

[0039] Figure 7 shows that DMCM-10049 preserves dendritic spines and pα-syn in a cellular PD model. *This shows a reduction in levels. Human stem cell-derived nerve cells (30 days after differentiation) were seeded with 50 μg / ml of pre-formed α-synuclein fibrils (PFFs), treated with 2 μM DMCM-10049 or vehicle, and fixed after 17 days for analysis. Control cells were not seeded with PFFs. A: Dendritic spines were labeled with the marker F-actin using Phalloidin-iFluor488 (Abcam). B: pα-syn * (Red, antibody GTX50222, GeneTex) + DAPI (blue) staining. Quantification was performed using ImageJ (NIH), and statistical analysis was performed using one-way ANOVA (Prism7). The mean and standard deviation of 8 images (A) or 6 images (B) per condition are shown. **** P<0.0001; *** P<0.001; ns = not statistically significant.

[0040] Figure 8 shows the therapeutic effect of DMCM-10049 on a mouse model of Parkinson's disease. Tg(SNCA * A53T) mice were administered DMCM-10049 at a dose of 50 mg / kg / day in drinking water starting at 9 months of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. The median survival time was 411 days in the control group (n=48) and 488 days in the treatment group (n=16). Survival time was significantly extended (log-rank test, p=0.01 for Prism7).

[0041] Figure 9 shows the therapeutic effect of DMCM-10049 on a mouse model of ALS.

[0042] Tg(SOD1 *G93A) mice were administered DMCM-10049 at a dose of 50 mg / kg / day in drinking water starting at 70 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. The median survival time was 165 days in the control group (n=7) and 177 days in the treatment group (n=11). Survival time was significantly extended (log-rank test, p=0.0007 for Prism7).

[0043] Figure 10 shows that oral batalanib (SR5-1457) treatment delays motor function impairment in a mouse model of ALS. Mice (all female) were administered 50 mg / kg of batalanib daily in drinking water starting at 47 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. Rotarod and hanging wire tests were performed as described. 2,3 The mean ± standard error is shown. Statistical analysis was performed using two-way ANOVA, n=12. * p<0.05; ** p<0.01; *** The procedure was performed with p<0.001.

[0044] Figure 11 shows that in batalanib analogs, the SAR for neuroprotective / NAD recovery effects does not correlate with the SAR for VEGFR inhibition. VEGFR-active and inactive compounds related to batalanib (SR5-1457), including methyl ketone SR1-134005, were prepared and tested in this assay. Dose-response curves are shown for a counterscreen intended to detect compounds that nonspecifically increase luminescence / cell viability in the absence of neuroprotection (red) and NAD levels (black), as well as TPrP (green). The assay was performed in a 1536-well plate format as described in the caption of Figure 2.

[0045] Figure 12 shows the difference in GABA levels with batalanib (SR1-134005) in a mouse model of ALS. AIt shows the therapeutic effect of R-active 3-methyl ketone analogs. Tg(SOD1 * G93A) mice were administered SR1-134005 at a dose of 6 mg / kg / day in drinking water starting at 100 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. Muscle strength was measured using a hanging wire test. Mean ± standard error is shown. The difference between the treatment group (n=14) and the control group (n=19) was significant (p<0.001 for all except at 145 days, unpaired multiple t-test, Prism7).

[0046] Figure 13 shows the significantly lower GABA levels in a mouse model of Parkinson's disease treated with batalanib (SR1-134005). A This study demonstrates the therapeutic effect of an R-active 3-methyl ketone analog. Transgenic (Tg) mice (SNCA*A53T) were administered SR1-134005 at a dose of 25 mg / kg / day in drinking water starting at 8 months of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. The median survival time was 411 days in the control group (n=58) and 462 days in the treatment group (n=16). Survival time was significantly extended (log-rank test: p=0.03, Prism7).

[0047] Figure 14 shows neuroprotection in a cellular PD / synucleinopathy model. Mouse stem cell-derived neurons (8 days after differentiation) were seeded with PFF (A, B: 4 μg / ml; C, D: 3 μg / ml) and treated with the indicated dose of the test compound or vehicle DMSO for the last two days of differentiation. Control cells were not seeded with PFF. Cells were imaged using a phase-contrast microscope. Neurite length was quantified using the ImageJ NeuronJ plugin (NIH), and statistical analysis was performed in pairs by comparing compound-treated cells with the DMSO control group (Student's t-test, Prism8). Mean and standard errors for four irradiation fields per condition are shown. Each irradiation field contained approximately 50-100 neurons. The displayed image corresponds to a representative area of ​​one irradiation field.**** P<0.0001; *** P<0.001; ** P<0.01; * P<0.05; ns = not statistically significant.

[0048] Figure 15 shows the lack of PARP-1 inhibition by carbazole (DMCM-10049), aminophthalazine (SR1-134005, also known as SR-005), pyrazolopyrimidine (SR1-293229, also known as SR-229), triazolophthalazine (SR5-22843, also known as SR-843), and flavonoid (nobiletin). ABT-888 is a known PARP1 inhibitor that acts as a pharmacological control group for the assay. "Control" indicates that the assay was performed in the absence of the compound. The assay was performed using the BPS Bioscience PARP1 chemiluminescence assay kit according to the manufacturer's instructions.

[0049] Figure 16 shows that aminophthalazine batalanib and SR1-134005 (also known as SR-005) are NAMPT activators. The compounds were tested using a colorimetric quantitative NAMPT activity assay (Abcam, ab221819). Each data point represents two replicate samples. A, B: Activation of NAMPT by SR-005, but not by DMCM, SR-229, SR-259, SR-186, or nobiletin. The compounds were tested at 5 μM (A) or 20 μM (B). C, D: Dose-dependent activation of NAMPT by SR-005 (C, 0.5 and 2.5 μM; D, 5 and 20 μM). E: Dose-dependent activation of NAMPT by batalanib. Pazopanib is a potent inhibitor of VEGFR-1, -2, and -3 and does not activate NAMPT at 10 μM. This data adds to the prior evidence that the NAD-recovering effects of batalanib and SR-005 are not related to VEGFR activity.

[0050] [Detailed explanation] Misfolded toxic prion protein TPrP induces severe depletion of neuronal NAD. Severe depletion of neuronal NAD is a cause of cell death because NAD supplementation leads to complete recovery of cells exposed to TPrP damage in vitro and in vivo, despite continued exposure to TPrP. 2 Intranasal NAD treatment improved motor function and activity in mice with prion disease. Furthermore, it was found that NAD depletion in TPrP-exposed neurons was at least partially due to excessive consumption of cellular NAD during a metabolic reaction called mono-ADP-ribosylation. 2 Poly-ADP-ribosylation inhibitors (known as PARP inhibitors) have long been developed as anticancer agents. Available selective PARP inhibitors do not mitigate the NAD depletion and neuronal cell death caused by TPrP, demonstrating the need to identify novel compounds that can disrupt the mechanisms in misfolded protein-induced toxicity. Such mechanisms may also act in cases of other disorders associated with NAD metabolic imbalances, as described herein.

[0051] Using TPrP as a highly neurotoxic prototype amyloid-forming misfolded protein, we developed a high-throughput screening (HTS) assay to identify compounds effective in a) preventing neuronal cell death and b) preventing TPrP-induced NAD depletion (Figure 1).

[0052] The HTS campaign was conducted at Scripps Florida using a subset of the Scripps Drug Discovery Library (SDDL). Several potent, novel, and chemically manageable small molecules were identified that, when used in doses ranging from low nanomolar to low micromolar levels, could provide complete neuroprotection and preservation of NAD levels. Among the highly active compounds were DMCM and allosteric GABA. A Receptor (GABA) AR) modulators and vatalanib, a VEGF receptor (VEGFR) tyrosine kinase inhibitor, are among those being studied in clinical trials for cancer treatment. This effort also identified six other classes of neuroprotective molecules.

[0053] Examples of active compounds are provided below: 1) Carbazole (e.g., SR1-75869, also known as DMCM);

[0054] [ka]

[0055] 2) Pyrazolopyrimidine (e.g., SR1-293229);

[0056] [ka]

[0057] 3) Aminothiazole (e.g., SR1-477186);

[0058] [ka]

[0059] 4) Triazolophthalazine (e.g., SR1-115259);

[0060] [ka]

[0061] 5) Aminophthalazines (e.g., SR5-1457, also known as batalanib, also known as CGP79787, and also SR1-134005 (batalanib with much less GABA) A R-active analog));

[0062] [ka]

[0063] 6) Flavonoids (e.g., nobiletin, also known as SR1-712262);

[0064] [ka]

[0065] 7) Alkaloids (including isoquinoline, aporphine, and ergot alkaloids) (an example is the isoquinoline alkaloid, also known as palmatine chloride, or SR1-841226);

[0066] [ka]

[0067] 8) 3-Heteroarylquinolines (e.g., DMPQ, also known as SR1-597975)

[0068] [ka]

[0069] The activity of the above compound series is characterized in detail in Figures 2A–2H. Each member of the series is highly potent in neuroprotective assays designed to reflect their potential for the successful treatment of several neurodegenerative diseases, as described herein. Furthermore, many possess properties advantageous for lead development (e.g., pain-free). 4 The drug similarity of Lipinski and Veber 5,6 (Complies with the rules of [the organization / group]).

[0070] <Definition> The abbreviations used herein have their conventional meanings within the technical fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with standard rules of chemical valence known in the technical field of chemistry.

[0071] When substituents are identified by the usual chemical formula written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left (for example, -CH2O- is equivalent to -OCH2-).

[0072] The term "alkyl," unless otherwise specified, means a straight (i.e., unbranched) or branched carbon chain (or carbons), or a combination thereof, either alone or as part of another substituent, which may be fully saturated, monovalent, or polyvalent unsaturated, and may contain monovalent, divalent, and polyvalent groups. Alkyls can contain a specified number of carbons (e.g., C1-C1). 10 (where n means 1 to 10 carbon atoms). Alkyl is a chain that is not cyclized. Examples of saturated hydrocarbon groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("Pr"), isopropyl ("iPr"), n-butyl ("Bu"), t-butyl ("t-Bu"), isobutyl, sec-butyl, methyl, homologs and isomers (e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.). Unsaturated alkyl groups have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl group bonded to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety may also be an alkenyl moiety. The alkyl moiety may also be an alkynyl moiety. The alkyl moiety may be completely saturated. An alkenyl may contain one or more double bonds, plus two or more double bonds and / or one or more triple bonds. An alkynyl may contain one or more triple bonds, plus two or more triple bonds and / or one or more double bonds.

[0073] The term "alkylene" means a divalent group derived from an alkyl group, either alone or as part of another substituent, unless otherwise specified, such as -CH2CH2CH2CH2-. Typically, the alkyl (or alkylene) group has 1 to 24 carbon atoms, and is preferred herein if it has 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" is generally a short-chain alkyl or alkylene group having 8 or fewer carbon atoms. The term "alkenylene" means a divalent group derived from an alkene, either alone or as part of another substituent, unless otherwise specified.

[0074] The term "heteroalkyl," alone or in combination with other terms, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), where the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is bonded to the remainder of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive (e.g., -CH2-NH-OCH3 and -CH2-O-Si(CH3)3). The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two arbitrarily distinct heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three arbitrarily distinct heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four arbitrarily distinct heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five arbitrarily distinct heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight arbitrarily distinct heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with other terms, means a heteroalkyl group containing at least one double bond unless otherwise specified.A heteroalkenyl may optionally contain one or more double bonds, plus two or more double bonds and / or one or more triple bonds. The term "heteroalkynyl," alone or in combination with other terms, means a heteroalkyl group containing at least one triple bond, unless otherwise specified. A heteroalkynyl may optionally contain one or more triple bonds, plus two or more triple bonds and / or one or more double bonds.

[0075] Similarly, the term "heteroalkylene," unless otherwise specified, refers to a divalent group derived from a heteroalkyl group, either alone or as part of another substituent, including, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy one or both ends of the chain (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R' represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include groups that bond to the remainder of a molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. When “heteroalkyl” is enumerated, followed by a list of specific heteroalkyl groups such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are enumerated for clarity. Therefore, the term “heteroalkyl” in this specification should not be interpreted as excluding specific heteroalkyl groups such as -NR'R''.

[0076] The terms "cycloalkyl" and "heterocycloalkyl," alone or in combination with other terms, refer to the cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Cycloalkyls and heterocycloalkyls are not aromatic. Furthermore, in the case of heterocycloalkyls, the heteroatom may occupy a position where the heterocycle is bonded to the rest of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyls include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl. "Cycloalkylene" and "heterocycloalkylene" refer to divalent groups derived from cycloalkyl and heterocycloalkyl, respectively, either alone or as part of another substituent.

[0077] In several embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term “heterocyclyl” means monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and the ring is saturated or unsaturated but not aromatic. A 3 or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may contain 0 or 1 double bond and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A 6 or 7-membered ring may contain 0, 1, or 2 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is linked to the parent molecule via any carbon or nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Typical examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolinyl, isoxazolinyl, isoxazolinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, Examples include, but are not limited to, oxazolidinyl, piperadinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorphonyl (thiomorpholine sulfone), thiopyranyl, and trithianil. A heterocyclyl bicyclic heterocycle is a monocyclic heterocycle condensed with any of phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. A heterocyclyl bicyclic heterocycle is linked to the parent molecule via any carbon or nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclils include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In several embodiments, the heterocyclil group is optionally substituted with one or two groups that are independently oxo or thia. In certain embodiments, the bicyclic heterocyclil is a 5 or 6-membered monocyclic heterocyclil, a 5 or 6-membered monocyclic cycloalkyl, a 5 or 6-membered monocyclic cycloalkenyl, a 5 or 6-membered monocyclic heterocyclil, or a 5 or 6-membered monocyclic heteroaryl condensed to a phenyl ring, where the bicyclic heterocyclil is optionally substituted with one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) condensed with either (i) one ring system selected from the group consisting of bicyclic aryls, bicyclic heteroaryls, bicyclic cycloalkyls, bicyclic cycloalkenyls, and bicyclic heterocyclyls; or (ii) one of two other ring systems independently selected from the group consisting of phenyls, bicyclic aryls, monocyclic or bicyclic heteroaryls, monocyclic or bicyclic cycloalkyls, monocyclic or bicyclic cycloalkenyls, and monocyclic or bicyclic heterocyclyls. The polycyclic heterocyclyl is bonded to the parent molecule via any carbon or nitrogen atom contained within the base ring. In several embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) condensed with (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) one of two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazine-10-yl, 9,10-dihydroacridine-9-yl, 9,10-dihydroacridine-10-yl, 10H-phenoxazine-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinoline-2-yl, 12H-benzo[b]phenoxazine-12-yl, and dodecahydro-1H-carbazole-9-yl.

[0078] The term "halo" or "halogen" means, alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. Furthermore, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl compounds. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0079] The term "aryl," unless otherwise specified, means a polyunsaturated, aromatic, hydrocarbon substituent, which may be one or more rings (preferably 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or covalently bonded. A fused ring aryl refers to a group of rings that are fused together, where at least one fused ring is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom such as N, O, or S, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes a fused ring heteroaryl group (i.e., a group of rings that are fused together, where at least one fused ring is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings that are fused together, one ring having 5 members and the other ring having 6 members, where at least one ring is a heteroaryl ring. Similarly, a 6,6-fused heteroarylene refers to two fused rings, one having 6 members and the other having 6 members, where at least one ring is a heteroaryl ring. A 6,5-fused heteroarylene also refers to two fused rings, one having 6 members and the other having 5 members, where at least one ring is a heteroaryl ring. Heteroaryl groups can be bonded to the rest of the molecule via carbon or heteroatoms.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridadinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 3-pyrazolyl, 2-imidazolyl Examples include lyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Each substituent of the above aryl and heteroaryl ring systems is selected from the permissible substituent group listed below. "Arylene" and "heteroarylene" refer to divalent groups derived from aryl and heteroaryl, respectively, either alone or as part of another substituent. The heteroaryl substituent may have an -O- bonded to the ring heteroatom nitrogen.

[0080] symbol

[0081] [ka]

[0082] The symbol indicates the bonding point of the chemical part to the rest of the molecule or chemical formula.

[0083] The term “pharmaceutically acceptable salt” includes salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. If the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired base in either a suitable or appropriate inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. If the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired acid in either a suitable or appropriate inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Similarly, examples include salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of this disclosure contain both basic and acidic functional groups that enable the conversion of the compound into either a base addition salt or an acid addition salt.

[0084] The term "EC" as used herein 50"Effective concentration" or "median effectiveness concentration" refers to the concentration of a molecule (e.g., small molecule, drug, antibody, chimeric antigen receptor, or bispecific antibody) that can induce an intermediate response between the baseline response and the maximal response after a specific exposure period. In some embodiments, EC 50 This is the concentration of the molecule (for example, small molecules, drugs, antibodies, chimeric antigen receptors, or bispecific antibodies) that accounts for 50% of the maximum possible effect of that molecule.

[0085] As used herein, the term “neurodegenerative disorder” refers to a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases that can be treated by the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia with telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, chronic traumatic encephalopathy, Cockayne syndrome, corticobasar degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Shainker syndrome, Huntington's disease, HIV-related dementia, and Kennethiazia. These include Dee's disease, Krabbe disease, Kuhl's disease, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, myalgic encephalomyelitis, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinal ataxia (multiple types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or tabes dorsalis.

[0086] The term “treating” or “treatment” means any measure of success in treating and improving an injury, disease, pathology, or condition, including any objective or subjective parameters such as abatement; remission; reduction of symptoms, or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or debilitation; mitigating the debilitation of the final stage of degeneration; or improvement of the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric assessment. The term “treating” and its cognates may include prevention of injury, pathology, condition, or disease. In several embodiments, treatment is prevention. In several embodiments, treatment does not include prevention.

[0087] As used herein (and as well understood in the art), “treating” or “treatment” also broadly includes any approach to obtain a beneficial or desired outcome (including clinical outcomes) in the condition of a subject. Beneficial or desired clinical outcomes include, but are not limited to, reduction or improvement of one or more symptoms or conditions, whether partial or whole, detectable or undetectable; reduction of disease severity; stabilization of the disease condition (i.e., no worsening); prevention of transmission or spread of the disease; delay or slowing of disease progression; improvement or mitigation of the disease condition; reduction of disease recurrence; and remission. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of disease. Treatment can prevent the onset of disease, suppress the spread of disease, alleviate the symptoms of disease, completely or partially eliminate the underlying cause, shorten the duration of disease, or a combination of these.

[0088] The term "prevent" refers to a reduction in the incidence of disease symptoms in a patient. As mentioned above, prevention is either complete (no detectable symptoms are observed) or partial, resulting in fewer symptoms being observed than in the case of no treatment.

[0089] "Patient" or "subject requiring it" refers to a living organism that is suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In several embodiments, the patient is human.

[0090] An "effective dose" is the amount of a compound sufficient to achieve a specified purpose compared to the absence of the compound (for example, the administered compound achieving an effect, treating a disease, reducing enzyme activity, enhancing enzyme activity, reducing a signaling pathway, or reducing one or more symptoms of a disease or condition). An example of an "effective dose" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, and is also called a "therapeutic effective dose." A "reduction" (and its grammatical equivalent) of a symptom or symptoms means a decrease in the severity or frequency of a symptom(s), or the elimination of a symptom(s). The “prophylactic effective dose” of a drug is the amount of drug administered to a subject that, when administered, produces the intended prophylactic effect (e.g., preventing or delaying the onset (or recurrence) of injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of injury, disease, pathology, or condition, or its symptoms). Complete prophylactic effect does not necessarily occur with a single dose, but may occur only after a series of doses. Therefore, the prophylactic effective dose may be administered in one or more doses. “Activation reduction dose,” as used herein, refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. “Functional disruption dose,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.The exact amount depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0091] For any compound described herein, the therapeutically effective dose can first be determined by a cell culture assay. The target concentration would be the concentration of the active compound that can achieve the method described herein, when measured using the method described herein or a method known in the art.

[0092] As is well known in the art, therapeutically effective doses for human use can also be determined from animal models. For example, doses for humans can be formulated to achieve concentrations that have been found to be effective in animals. Doses for humans can be adjusted, as described above, by monitoring the efficacy of the compound and adjusting the dose upward or downward. Adjusting the dose to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0093] The term “therapeutic effective dose,” as used herein, refers to the amount of therapeutic agent sufficient to improve the disorder as described above. For example, for a given parameter, a therapeutic effective dose may represent an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as an increase or decrease of “~ times.” For example, a therapeutic effective dose may have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more compared to a control.

[0094] Dosage may vary depending on the patient and the requirements of the compound used. In the context of this disclosure, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response over time. The size of the dose is also determined by the presence, nature, and severity of any adverse side effects. Determining the appropriate dose for a particular situation is within the scope of the practitioner's skill. Generally, treatment is initiated with a dose lower than the optimal dose of the compound. The dose is then gradually increased until the optimal effect is achieved under the circumstances. Dosage and intervals can be individually adjusted to provide an effective level of the compound for the specific clinical manifestation being treated. This will provide a treatment plan that is appropriate to the severity of the individual disease state.

[0095] As used herein, “administer” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, subarachnoid, intranasal or subcutaneous administration, or implantation of a slow-release device (e.g., a mini osmotic pump) into the subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other methods of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, and transdermal patches. In some embodiments, administration does not include the administration of any activators other than those listed.

[0096] As used herein, the term “cell” means a cell that performs sufficient metabolic or other functions to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art (e.g., including the presence of an intact membrane, staining with a specific dye, the ability to produce offspring, or, in the case of germ cells, the ability to combine with a secondary germ cell to produce viable offspring). Cells may include prokaryotes and eukaryotes. Examples of prokaryotes include, but are not limited to, bacteria. Examples of eukaryotes include, but are not limited to, yeast cells, as well as cells derived from plants and animals (e.g., mammals, insects (e.g., Spodoptera), and human cells). Cells may be useful if they are naturally non-adherent or have been treated, for example, by trypsin treatment to prevent adhesion to a surface.

[0097] <Compound> In one embodiment, the Specified Provision provides a compound that may provide complete neuroprotection and protection of non-neuronal cell types, as well as preservation of NAD levels. The compound may be very potent in a) preventing neuronal cell death and / or cell death; and b) preventing TPrP-induced NAD depletion (as identified by neuroprotective assays, for example, when used in doses ranging from low nanomolar to low micromolar levels).

[0098] In one embodiment, the compound has formula (I).

[0099] [ka]

[0100] In formula (I), Each R 1 And R2 is independently hydrogen, (C1-C4) alkyl, or (C1-C4) alkoxy; and Each R 3is independently selected from hydrogen, (C1-C4) alkyl optionally substituted with hydrogen, OH, (C1-C4) alkoxy, or heteroaryl (provided that 3 both are not hydrogen); or both R 3 form a 5- to 7-member heterocyclyl ring containing at least one additional heteroatom selected from O, S, S=O, S(=O)=O, or NR together with the nitrogen atom to which they are attached, where R is (C1-C4) alkyl optionally substituted with -OH or (C1-C4) alkoxyl.

[0101] The compounds of formula (I) include all pharmaceutically acceptable salt forms.

[0102] In several embodiments, R 1 is methyl.

[0103] In several embodiments, R 2 is methyl.

[0104] In several embodiments, one of R 3 is hydrogen and the other R 3 is

[0105]

Chemical formula

[0106] is.

[0107] In some compounds of formula (I), when R 1 and R 2 are methyl, one of R 3 is hydrogen and the other R 3 is [[ID=5�]]

[0108]

Chemical formula

[0110] In some compounds of formula (I), R 1 and R 2 are methyl, the two Rs bonded to the nitrogen atom 3 do not form any of

[0111]

Chemical formula

[0112] .

[0113] In one aspect, the compound has formula (II).

[0114]

Chemical formula

[0115] In formula (II), each R a1 and R a2 is independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxyl, (C1-C4) haloalkoxyl, 2-4 membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R b1 , R b2 , and R b3 is independently hydrogen, halo, (C1-C4) alkyl, -S(O)2R d , -S(O)₂OR d , or (C1-C4) haloalkyl; or R b2 and R b3 together form aryl or heteroaryl; each R c and R d is independently hydrogen or (C1-C4) alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, or heteroaryl; and n = 2, 3, 4, or 5.

[0116] The compound of formula (II) includes all pharmaceutically acceptable salt forms.

[0117] In multiple embodiments, R b1 R is hydrogen. In some embodiments, R b1 is a C1-C4 alkyl group. In some embodiments, R b1 is methyl. In some embodiments, R b1 is ethyl. In some embodiments, R b1 is a halo. In some embodiments, R b1 is -F. In some embodiments, R b1 is a (C1-C4) haloalkyl. In several embodiments, R b1 is -CF3. In some embodiments, R b1 -S(O)2R d In some embodiments, R b1 It is -S(O)2CH3.

[0118] In multiple embodiments, R b2 R is hydrogen. In some embodiments, R b2 is methyl. In some embodiments, R b3 R is hydrogen. In some embodiments, R b3 is methyl. In some embodiments, R c R is hydrogen. In some embodiments, R c is methyl. In some embodiments, R d R is hydrogen. In some embodiments, R d It is methyl.

[0119] In multiple embodiments, Rb2 and R b3 Together, they form phenyl.

[0120] In multiple embodiments, R a2 R is hydrogen. In some embodiments, R a2 is (C1-C4)alkyl. In some embodiments, R a2 It is methyl.

[0121] In several embodiments, the compound has the following formula:

[0122] [ka]

[0123] R a1 and R b1 This is described herein. e z is independently a halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, or heteroaryl, where z is 0, 1, 2, 3, 4, or 5.

[0124] In several embodiments, z is 0, 1, 2, or 3.

[0125] In multiple embodiments, R b1 This is hydrogen, methyl, ethyl, -F, -CF3, or -S(O)2Me.

[0126] In multiple embodiments, R a2 It is hydrogen or methyl.

[0127] In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0128] In multiple embodiments, R a1 is (C1-C4)alkyl. In some embodiments, R a1is methyl. In some embodiments, R a1 is ethyl. In some embodiments, R a1 is isopropyl. In some embodiments, R a1 is t-butyl. In some embodiments, R a1 is a (C1-C4) haloalkyl. In several embodiments, R a1 is -CF3. In some embodiments, R a1 R is a heterocycloalkyl. In some embodiments, R a1 teeth

[0129] [ka]

[0130] In some embodiments, R a1 is -CH2-O-CH3. In several embodiments, R a1 It is phenyl.

[0131] In several embodiments, Ar is a phenyl optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, or heteroaryl compounds.

[0132] In some embodiments, Ar is

[0133] [ka]

[0134] In some embodiments, Ar is

[0135] [ka]

[0136] That is the case.

[0137] In several embodiments, Ar is

[0138]

Chemical formula

[0139] In some compounds of formula (II), R a2 , R b1 , R b2 , R b3 , and R c are hydrogen, n is 3, and Ar is phenyl (unsubstituted or substituted with -CH3 or -OMe), then R a1 is neither difluoromethyl nor trifluoromethyl.

[0140] a2 , R b1 , R b2 , R b3 , and R c are hydrogen, n is 3, and Ar is -F, Br,

[0141]

Chemical formula

[0142] <000089,8>phenyl substituted with a1 is not trifluoromethyl.

[0143] In several embodiments, the compounds of formula (II) include the following.

[0144]

Chemical formula

[0145] In one embodiment, the compound has formula (III),

[0146] [ka]

[0147] In formula (III), L 1 These are bonds, C1-C4 alkylenes, or 2-4 member heteroalkylenes; R 1 is a monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, alkylaryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, alkylaryl, or heteroaryl is optionally substituted with one or more selected from halo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxyl, -C(=O)(C1-C4)alkyl, -C(=O)N(R)2, or -C(=NR)(C1-C4)alkyl, where (C1-C4)alkyl is either unsubstituted or substituted with a heterocycloalkyl; Each R is independently hydrogen, -OH, (C1-C4)alkyl, or (C1-C4)alkoxyl, or two Rs together with the bonded nitrogen atom form a heterocycloalkyl, optionally containing an additional O atom in the heterocyclyl ring; R 2 It occurs 0, 1, or 2 times, and is a (C1-C4) alkyl, (C1-C4) haloalkyl, or SO2N(R) 4 )2; Each R 3 and R 4 These are independently H or (C1-C4) alkyl.

[0148] The compound of formula (III) includes all pharmaceutically acceptable salt forms.

[0149] In multiple embodiments, L 1 L is a bond. In some embodiments, L1 is methylene. In some embodiments, L 1 is -CH2CH2-O-.

[0150] In some embodiments, R 1 is

[0151]

Chemical formula

[0152] as follows.

[0153] In some embodiments, R 2 does not occur. In some embodiments, R 2 occurs once.

[0154] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is methyl.

[0155] In some embodiments, the compound includes the following formula.

[0156]

Chemical formula

[0157] [[ID=�3]]R 1 and R 2 are described herein.

[0158] In some of the compounds of formula (III), when L 1 is a bond, R 2 does not occur, and R 3 is hydrogen, R 1 is

[0159]

Chemical formula

[0160] not; and In some compounds of formula (III), L 1 is methylene, and R 2 This does not occur, and R 3 If R is hydrogen, 1 teeth

[0161] [ka]

[0162] isn't it.

[0163] In several embodiments, the compound of formula (III) includes the following:

[0164] [ka] JPEG2026048976000037.jpg225169JPEG2026048976000038.jpg138169

[0165] In several embodiments, the compound has formula (IV).

[0166] [ka]

[0167] In formula (IV): R 1 These are hydrogen, (C1-C4)alkyl, -C(O)OH, -C(O)O-(C1-C4)alkyl, and -C(O)NHNHR. 6 -C(O)NR 6 -((C1-C4)Alkylene)-NHR 6 -C(O)NR 6 (C1-C4) alkyl, or -C(O)NR 6 -Cycloalkylene-NHR 6 and; R 3 is hydrogen or (C1-C4) alkyl; and Each R 2 , R4 , R 5 These are independently hydrogen, halo, (C1-C4)alkyl, -C(O)O-(C1-C4)alkyl, (C1-C4)alkoxyl, (C1-C4)haloalkyl, or CN; and Each R 6 is either hydrogen or (C1-C4) alkyl.

[0168] The compound of formula (IV) includes all pharmaceutically acceptable salt forms.

[0169] In multiple embodiments, each R 4 and R 5 R is independently hydrogen or a (C1-C4) alkoxyl. In some embodiments, each R 4 and R 5 is -OMe. In some embodiments, R 4 is hydrogen, R 5 is -OMe. In some embodiments, R 5 is hydrogen, R 4 It is -OMe.

[0170] In multiple embodiments, R 1 R is hydrogen, (C1-C4) alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is -C(O)OH or -C(O)OCH3. In some embodiments, R 1 is a C(O)NH(C1-C4) alkyl group. In several embodiments, R 1 It is -C(O)NHCH3.

[0171] In multiple embodiments, R 1 is -C(O)NH-((C1-C4)alkylene)-NH2 or -C(O)NH-cycloalkylene-NH2. In several embodiments, R 1 is -C(O)NH-CH2CH2-NH2, -C(O)NCH3-CH2CH2-NHCH3,

[0172] [ka]

[0173] , or -C(O)NHNH2.

[0174] In multiple embodiments, R 3 It is hydrogen or methyl.

[0175] In multiple embodiments, R 2 R is hydrogen, (C1-C4)alkyl, or -C(O)O-(C1-C4)alkyl. In some embodiments, R 2 R is hydrogen. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is -C(O)OCH3. In several embodiments, R 2 The expression is -C(O)OCH2CH3.

[0176] In multiple embodiments, R 6 R is independently hydrogen. In some embodiments, R 6 It is independently methyl.

[0177] In some compounds of formula (IV), R 4 and R 5 is -OMe, R 3 is hydrogen, R 2 If R is ethyl, 1 It is not -COOMe.

[0178] In some compounds of formula (IV), R 4 is -OMe, R 5 is hydrogen, R 1 and R 2 If R is hydrogen, 3 It is not methyl.

[0179] In some compounds of formula (IV), R 2 , R 3 , R 4 , and R 5 If R is hydrogen, 1 It is not -C(O)NHCH3.

[0180] In several embodiments, the compound of formula (IV) includes the following:

[0181] [ka]

[0182] In several embodiments, the compound has formula (V).

[0183] [ka]

[0184] In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, CN, -S(O)2NH2, oxo, -NH2, (C1-C4)alkoxyl, or -NHC(O)(C1-C4)alkyl; Each R 1 and R 2 R is independently hydrogen, (C1-C4)alkyl, aryl, or heteroaryl (where the aryl or heteroaryl is optionally substituted with a halo or (C1-C4)alkyl), or bonded to nitrogen. 1 and R 2 Together they form a 5-6 member heterocycloalkyl group; and R 3 This is hydrogen or a hydroxy-(C1-C4) alkyl group.

[0185] The compound of formula (V) includes all pharmaceutically acceptable salt forms.

[0186] In multiple embodiments, R 1 and R 2 R is hydrogen. In some embodiments, R 1 and R 2 One of them is hydrogen, and the other is a (C1-C4) alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl. In several embodiments, R 1 and R 2 These are independently (C1-C4) alkyl groups. For example, R 1 and R 2 R is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl. In some embodiments, R 1 and R 2 It is methyl.

[0187] In multiple embodiments, R 1 and R 2 One of the atoms is hydrogen, and the other is phenyl, which can be optionally substituted with F, Cl, Br, or (C1-C4) alkyl groups.

[0188] In multiple embodiments, R 1 and R 2 One is hydrogen, and the other is phenyl.

[0189] [ka]

[0190] That is the case.

[0191] In multiple embodiments, R bonded to nitrogen 1 and R 2 They are both,

[0192] [ka]

[0193] They form heterocycloalkyl groups of 5-6 members, such as those shown.

[0194] In multiple embodiments, R 3 R is hydrogen. In some embodiments, R 3 R is a hydroxy-(C1-C4)alkyl. In several embodiments, R 3 It is -CH2-OH.

[0195] In several embodiments, Ar is pyridyl, phenyl, naphthyl, or thiazolyl, which is optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, -CN, -S(O)2-NH2, -NH2, (C1-C4)alkoxyl, or -NHC(O)alkyl. In several embodiments, Ar

[0196] [ka]

[0197] That is the case.

[0198] In several embodiments, the compound has the following formula:

[0199] [ka]

[0200] R 1 , R 2 And Ar are as described herein.

[0201] In some compounds of formula (V), R 1 , R 2 and R 3 If is hydrogen, then Ar is

[0202] [ka]

[0203] Neither of the above.

[0204] In several embodiments, the compound of formula (V) includes the following:

[0205] [ka] JPEG2026048976000049.jpg238169JPEG2026048976000050.jpg237169

[0206] <Method> In one embodiment, a method is provided for inhibiting NAD consumption and / or increasing NAD synthesis in a patient, the method comprising administering an effective amount of a compound described herein to the patient.

[0207] The compound may inhibit the protein ADP-ribosylation reaction. The compound may inhibit NAD cleavage by protein deacetylase or glycohydrolase. The compound may increase NAD synthesis. The patient has or is at risk of suffering from a protein misfolding neurodegenerative disease or other protein misfolding disease.

[0208] Protein misfolding neurodegenerative diseases include prion diseases, Parkinson's disease or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, or tauopathy, while protein misfolding disorders include diabetes mellitus.

[0209] In one embodiment, a method is provided for preventing or inhibiting NAD depletion in a patient. In another embodiment, a method is provided for improving a condition related to altered NAD metabolism in a patient. The method comprises the step of administering an effective amount of a compound described herein to a patient.

[0210] The aforementioned conditions include metabolic disorders, aging, degenerative diseases, neurodegenerative diseases, neurodegeneration associated with multiple sclerosis, hearing loss, retinal disorders or multiple sclerosis, cerebral or cardiac ischemia, renal failure, kidney disease, traumatic brain injury, or axonal damage.

[0211] In one embodiment, a method is provided for providing protection from the toxicity of misfolded proteins in a patient. The method comprises the step of administering an effective amount of a compound described herein to a patient. The patient suffers from a prion disease, Parkinson's disease or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, tauopathy or diabetes.

[0212] In one embodiment, a method is provided for preventing or treating protein misfolding neurodegenerative diseases in patients. The method comprises the step of administering an effective amount of a compound described herein to a patient. Protein misfolding neurodegenerative diseases include prion diseases, Parkinson's disease or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, or tauopathy.

[0213] [Neurological protection and GABA] A R inhibition is one of two distinct activities of DMCM. DMCM (whose structure has been previously shown and is also shown in the examples), a member of the carbazole series, has a known mode of action: GABA A It is an inverse agonist of all subtypes of R. 7 It binds to the benzodiazepine (BZ) site. Therefore, it is a convulsive agent in vivo. Because its convulsive activity is not resistant to neuroprotective substances, it cannot be directly reused. 8 Another pharmacological modulator that binds to the BZ site is flumazenil (Ro 15-1788). 9,10 It has been tested. This does not rescue TPrP-induced toxicity, does not compete with the effects of DMCM (Figure 3), and neuroprotection is not achieved with GABA. A This suggests that it is highly likely to be unrelated to endogenous activity in R.

[0214] Preliminary SAR studies showed DMCM activity and neuroprotection versus GABA. A This was done to further test the conclusion that the R bond is different. Figure 4 shows hydrazineamide 1, an analog of DMCM (DMCM-10049), which is GABA A Lacks R activity (most GABA A Efficacy reduced by more than 100 times compared to the R subtype. 11 It has been reported that... However, it showed neuroprotective activity very similar to that of DMCM (Figure 4). When DMCM was treated with a diamine containing 1,4-cis-diaminocyclohexane, aminoamides such as compound 2 (DMCM-8137) were obtained. This compound was also neuroprotective (Figure 4). Furthermore, it is designed to have a handle to allow conjugation for target identification (Figure 4).

[0215] In summary, these studies suggest that DMCM is GABA A This study demonstrates that DMCM acts on targets other than R to confer neuroprotection, and this finding enables the optimization of DMCM analogs as neuroprotective agents lacking the activity of the parent compound. DMCM exhibits neuroprotective effects in primary neurons (see Figure 5).

[0216] [DMCM prevents excessive mono-ADP-ribosylation induced by TPrP.] TPrP is used to mono-ADP-ribosylation of excess proteins. 2 It has been demonstrated that the NAD consumption reaction induces at least partial NAD depletion. Figure 6 shows that DMCM prevents this excessive protein ADP-ribosylation.

[0217] DMCM exhibits neuroprotective effects in a cell model of Parkinson's disease (PD).

[0218] Parkinson's disease, like prion diseases, arises from the misfolding and aggregation of proteins (in this case, α-synuclein). Therefore, the neuroprotective properties of HTS-derived compounds were investigated in cellular models of PD-induced neurodegeneration (Figures 7 and 14). In these models, neurons exposed to pre-formed α-synuclein fibrils (PFFs) underwent synaptic and dendritic spine loss, as well as neurite shortening and loss (see Figure 7, PFF-exposed neurons vs. control cells). Neurons seeded with PFFs accumulated α-synuclein fibrils and formed specific types of α-synuclein aggregates (pα-syn) that are toxic to cells. *12 It accumulates (called pα-syn). Figure 7 shows that DMCM hydrazineamide, named DMCM-10049, preserves the dendritic spines of nerve cells exposed to PFF and toxic pα-syn * This indicates a reduction in the amount of [something].

[0219] [Therapeutic effects of DMCM-10049 in a mouse model of Parkinson's disease.] Furthermore, DMCM has been used in vivo as a tool compound with good PK properties. 5、7-9、13、14 Therefore, DMCM-10049 was used in a mouse model of PD (which has the α-synuclein mutation that causes familial PD in humans, Tg(SNCA) * The study was conducted in A53T mice. Treatment with DMCM-10049 significantly extended the survival time of these mice (Figure 8).

[0220] [Therapeutic effects of DMCM-10049 in a mouse model of ALS.] DMCM-10049 was used in a mouse model of ALS (with SOD1 mutation, Tg(SOD1) * G93A) Mouse 15 The study was conducted in the following cases: Mutant SOD1 accounts for 15-20% of familial ALS cases and 1-2% of clearly sporadic ALS cases, while misfolded SOD1 is found in ALS patients without the mutation. 16Treatment with DMCM-10049 significantly extended the survival time of these mice (Figure 9).

[0221] [Detailed study of the batalanib series (aminophthalazine series).] Batalanib (also known as SR5-1457) is an orally administered antitumor agent that has recently been undergoing late-stage clinical development. 17ー21 This is a receptor tyrosine kinase inhibitor, particularly a potent VEGFR inhibitor, which is highly cell-permeable and possesses overall superior PK properties in humans and rodents. 22-24 This compound has high neuroprotective properties, EC 50 =39.9nM (TPrP toxicity relief) and EC 50 The result was 195 nM (NAD assay). Due to its high potency and excellent PK properties (including high brain permeability and high oral bioavailability), the inventors chose to rapidly advance this compound into in vivo neuroprotective research.

[0222] As shown in Figure 10, batalanib treatment in ALS mice significantly improved motor function and muscle strength, as evaluated using the rotorod and hanging wire tests. However, no extension of survival time was observed (treatment group 160±2 days vs. control group 157±2 days).

[0223] While batalanib was used in this initial proof-of-concept study, this specific compound is not suitable for direct reuse because it can potently inhibit VEGFR. VEGFR gives off anti-angiogenic effects that are thought to be involved in its antitumor properties. This is because VEGF / VEGFR-2 signaling is known to be neuroprotective (and therefore blocking VEGFR is expected to cause mild neurotoxicity rather than neuroprotection). 25 Therefore, it may be inferred that the neuroprotective mechanism of this compound is independent of known activity vs. VEGFR. VEGFR-2 overexpression is associated with Tg(SOD1 *VEGF administration is known to delay neurodegeneration of spinal motor neurons in G93A mice, and in ALS models, it delays muscle weakness. 26-28 It has been shown to be neuroprotective in the PD model. 29、30 Therefore, the VEGFR inhibitory activity of batalanib should be counterproductive to neuroprotective purposes, and thus batalanib would be an unsuitable option for reuse in the treatment of ALS, or more generally, any neurodegenerative disease requiring chronic treatment. The NAD-conserving activity identified herein is likely to counteract (and prevail over) the intrinsic VEGFR effect. Analogues lacking VEGFR activity should be better candidates for neuroprotective lead.

[0224] Figure 11 shows batalanib analogues that are known to be inactive with VEGFR, or at least have very low affinity for VEGFR. Note: Flt-1 and KDR are subtypes of VEGFR, also known as VEGFR-1 and VEGFR-2, respectively. As shown, the activity of these compounds regarding neuroprotective / NAD regeneration effects does not correlate with their activity against VEGFR inhibition. 24 For example, SR1-134005 (second structure, Figure 11), a methyl ketone-containing structural analog of batalanib, is more than six times more potent than batalanib as a neuroprotective agent (6.3 nM vs. 39.9 nM), but this same compound is 13 times less potent than batalanib as a VEGFR-1 inhibitor (1 μM vs. 77 nM). Similarly, the analog SR1-151915 (third structure) exhibits approximately half the neuroprotective activity of batalanib (EC2). 50 It retains (=71.4nM), but this same compound is also an insufficient VEGFR inhibitor (IC). 50 (>1 μM). Conversely, the analog SR1-151911 (fourth structure) has much lower neuroprotectiveness (only 44% neuroprotection at 6.4 μM), but moderate VEGFR activity (IC). 50It has a strength of 793 nM (compared to VEGFR-1, approximately 20 times less than batalanib, and more potent in VEGFR than SR1-134005 and SR1-151915).

[0225] Furthermore, other commercially available potent VEGFR inhibitors structurally unrelated to batalanib (lenvatinib, pazopanib, tivozanib, and sorafenib) showed no neuroprotective activity in the TPrP assay up to 10 μM (data not shown).

[0226] Clearly, the ability to distinguish between these two activities (neuroprotective and antitumor effects mediated by VEGFR inhibition) led us to validate SR1-134005, a batalanib analog with low VEGF-R activity, in an ALS mouse model.

[0227] [Therapeutic effects of SR1-134005 in a mouse model of ALS.] SR1-134005, a methyl ketone analog of batalanib (exhibiting approximately 13-fold reduced VEGFR-1 activity compared to batalanib, Figure 11), provides the same overall in vivo benefits as batalanib, and is also effective at 8-fold lower doses (Figure 12). These in vivo results support our in vitro findings that SR1-134005 is a more potent neuroprotective agent than batalanib, and that its neuroprotection is dissociated from VEGFR inhibition, which is presumed to be a factor in the antitumor effects observed in this class of compounds.

[0228] [Therapeutic effects of SR1-134005 in a mouse model of Parkinson's disease.] Treatment with SR1-134005, a methyl ketone analog of batalanib, is effective in reducing Tg(SNCA). * The A53T) mouse lifespan was significantly extended (Figure 13).

[0229] [Neuropneumoprotective effects of pyrazolopyrimidine (SR1-293229), aminothiazole (SR1-477186), triazolophthalazine (SR1-115259), aminophthalazine (batalanib), and flavonoids (nobiletin, apigenin) in a cellular model of Parkinson's disease (PD), a synucleinopathy.] Similar to our observations using the carbazole series, compounds from other lead series protected against α-synuclein PFF-induced neurodegeneration in cultured nerve cells. These include pyrazolopyrimidine (SR1-293229), aminothiazole (SR1-477186), triazolophthalazine (SR1-115259), aminophthalazine (batalanib), and flavonoids (nobiletin, apigenin). Figure 14 illustrates the protective effect and shows that the lead compounds prevent neurite loss induced by PFF exposure.

[0230] [NAD rescue by carbazole, aminophthalazine, pyrazolopyrimidine, triazolophthalazine, and flavonoid series is not due to PARP-1 inhibition.] Figure 15 shows that at least five of the lead series described herein are not PARP-1 inhibitors.

[0231] [Aminophthalazines (batalanib and SR1-134005) are NAMPT activators.] TPrP has been shown to induce excessive ADP-ribosylation and enable the design of compound screening strategies to capture compounds that can restore physiological NAD levels. Figure 6 shows that this can be achieved by preventing excessive ADP-ribosylation. Figure 16 shows that this can also be achieved by enhancing NAD synthesis, as one of our lead series, aminophthalazine batalanib and "SR-005," act by activating NAMPT (the rate-limiting enzyme in NAD synthesis).

[0232] For the first time, it has been shown that failure of NAD metabolism is a fundamental mechanism of neurotoxicity induced by misfolded amyloid-forming protein (TPrP), and that NAD supplementation is neuroprotective. 2 Therefore, with the hypothesis that other conditions could be effectively treated using compounds that can restore significant NAD levels by any mechanism, NAD-restoring compounds were screened for relief from protein toxicity. In fact, NAD dysregulation is now a common condition in AD. 31,32 aging 33-36 Neuronal degeneration associated with multiple sclerosis 37 Hearing loss 38 , retinal damage 39 Traumatic brain injury 40 , and axonal damage 41 It is also recognized as being involved in a large decrease in NAD levels, which is associated with a degenerative kidney state. 42 It is found in [location]. Increased NAD, such as increased NAD synthesis due to NAD administration or enzyme overexpression, is associated with cerebral ischemia. 43 myocardial ischemia / reperfusion injury 44、45 and acute kidney injury 42 It has been shown to reduce the risk.

[0233] NAD metabolism has also been shown to be altered in mouse models of type 2 diabetes (T2D). 46、47 The alteration of NAD metabolism in diabetes can be explained by our findings that misfolded proteins induce NAD dysregulation. In fact, diabetes is caused by pancreatic β-cells 48 It has been shown to be a protein misfolding disorder characterized by pancreatic β-cell dysfunction and death associated with the deposition of aggregated island amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin. 48 Amyloid IAPP deposition is a common feature of diabetes with various etiologies. 49 Like other proteins involved in protein misfolding disorders, IAPP forms toxic oligomers. 48Furthermore, proinsulin, a precursor of insulin, is also prone to misfolding in β-cells. Proinsulin misfolding is associated with the progression of type 2, type 1, and several monogenic forms of diabetes. 48、50、51 Finally, pancreatic β-cells share some physiological characteristics with nerve cells. 52 Therefore, the compounds described herein will also be used to mitigate pancreatic cell dysfunction and death in diabetic cell models, as a demonstration of the potential for treating diabetes in humans, and to achieve therapeutic benefits in animal models of diabetes. For this purpose, the inventors have used rodent-derived insulin-secreting cell lines (e.g., MIN-6 and INS-1 cells) 52、53 Using ); the inventors anticipate changes in their β-cell function, NAD levels, and viability upon exposure to misfolded and / or aggregated forms of IAPP and / or proinsulin. Furthermore, the inventors anticipate that such changes will be corrected by treatment with the compounds described herein. The therapeutic benefits of the compounds are demonstrated in rodent models (e.g., T2D) 54 Regarding high-fat diet mice, ob / ob mice and db / db mice (leptin deficiency and resistance, respectively), and type 1 diabetes mice were also included. 55、56 This will likely be evaluated in streptozotoxin-treated mice, non-obese diabetic (NOD) mice, and biobreeding diabetes-prone (BB) rats.

[0234] The NAD used here refers to both the oxidized (NAD+) and reduced (NADH) forms of the cofactor. NAD is particularly important as a coenzyme for regulating energy metabolic pathways such as glycolysis, the TCA cycle, and oxidative phosphorylation leading to ATP production. Furthermore, NAD acts as a substrate for signal transduction and post-translational protein modification called ADP-ribosylation.

[0235] Physiological cellular NAD levels are due to the balance of activity between NAD synthases and NAD-consuming enzymes. Therefore, it is hypothesized that NAD imbalances induced by misfolded proteins (and assessed by our phenotypic assays) may result in either impaired NAD biosynthesis or increased NAD consumption.

[0236] In mammalian cells, NAD is primarily synthesized via the salvage pathway using its precursor nicotinamide (NAM). The rate-limiting enzyme in NAD synthesis via the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT). Other NAD synthesis pathways include the de novo pathway, which utilizes the precursor tryptophan, and the Preiss-Handler pathway, which utilizes the precursor nicotinic acid (NA).

[0237] On the other hand, NAD is consumed during the following cellular reactions: 1) production of cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) (calcium-releasing second messengers) from NAD by enzymes called NAD hydrolase or ADP-ribosyl cyclases (CD38 and CD157); 2) sirtuin-mediated protein deacetylation; and 3) protein ADP-ribosylation (transfer of one or more ADP-ribose moieties of NAD to non-proteins by mono / oligo-ADP-ribose transferase (mART) or poly-ADP-ribose transferase (called PARP)).

[0238] TPrP induces excessive ADP-ribosylation of cellular proteins, and furthermore, toxicity has been shown not to be mitigated by selective PARP1 inhibitors. Therefore, these studies have revealed a novel mechanism of neurotoxicity, at least in part, related to imbalances in NAD metabolism due to excessive mono- or oligo-ADP-ribosylation reactions. As described above, the HTS campaign and follow-up assays that led to the identification of the eight compound series presented herein are phenotypic-dependent. Thus, this study deliberately agnosticated the mechanisms underlying the preservation of NAD levels and viability in cells exposed to protein toxicity. This design was intended to identify compounds that modulate NAD levels by any mechanism of action, such as enhancing NAD synthesis or preventing excessive NAD degradation / consumption, and to include non-PARP1 inhibitors. Our data show the following: 1) All protective compounds presented herein are neuroprotective and preserve cellular NAD levels; 2) At least five of these compounds are not PARP-1 inhibitors (Figure 15); 3) As proof of concept, one or more test compounds prevent excessive ADP-ribosylation induced by misfolded proteins (Figure 6), and one or more test compounds are NAMPT activators (Figure 16).

[0239] [Examples] Example 1: Cell viability assay and NAD quantification assay The following table shows the structures of specific examples of compounds useful for carrying out the methods of the present invention, related to corresponding data such as compound identification name, molecular weight, compound properties, and biological results.

[0240] The biological activity of the test compound was evaluated using two assays: a cell viability assay (CellTiter-Glo®) to assess the compound's ability to prevent neuronal cell death induced by the misfolded protein TPrP, and an NAD quantification assay (NAD+ / NADH-Glo) to assess the compound's ability to prevent NAD depletion induced by the misfolded protein TPrP. TMThe effective concentration (EC) was quantified at ). 50 The value is shown. The procedure is to calculate the survival rate EC. 50 and NAD EC 50 For compounds showing both, see Figure 2 (1536-well plate format) (Tables 1-8), and survival rate EC 50 For compounds where only one compound is shown, the results were as described in Figure 4 (96-well plate format) (Tables 9-12).

[0241] [Table 1] JPEG2026048976000052.jpg167169 JPEG2026048976000053.jpg74169

[0242] [Table 2] JPEG2026048976000055.jpg192169 JPEG2026048976000056.jpg148169

[0243] [Table 3]

[0244] [Table 4] JPEG2026048976000059.jpg102169

[0245] [Table 5] JPEG2026048976000061.jpg203169

[0246] Table 6 JPEG2026048976000063.jpg188169 JPEG2026048976000064.jpg194169 JPEG2026048976000065.jpg103169

[0247] Table 7 JPEG2026048976000067.jpg127169

[0248] Table 8

[0249] Table 9 JPEG2026048976000070.jpg187169 JPEG2026048976000071.jpg228169 JPEG2026048976000072.jpg201169 JPEG2026048976000073.jpg181169 JPEG2026048976000074.jpg220169 JPEG2026048976000075.jpg219169 JPEG2026048976000076.jpg204169

[0250] Table 10 JPEG2026048976000078.jpg216169 JPEG2026048976000079.jpg194169 JPEG2026048976000080.jpg172169 JPEG2026048976000081.jpg201169 JPEG2026048976000082.jpg223169

[0251]

Table 11

[0252]

Table 12

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Brief Description of the Drawings

[0254] [Figure 1]Figure 1 shows primary neuroprotective assays and confirmatory NAD quantification assays in a 384-well plate format. PK1 neuroblastoma cells (2000 cells / well) were treated with 2.5 μg / ml TPrP for 3 days at the indicated doses (in μM), in the presence or absence of either NAD or a screening hit DMCM, as shown. TPrP was prepared as described by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012)1. DMSO was 0.3%. Five replicates and standard deviations are shown. Top panel: CellTiter-Glo(Promega) bioluminescent cell viability assay. Bottom panel: NAD quantification assay using NAD+ / NADH-Glo™(Promega). [Figure 2A] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of the eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2A Carbazole.

[0255] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2B]Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2B Pyrazolopyrimidine.

[0256] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2C] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of the eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2C Aminothiazole.

[0257] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2D] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of the eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2D Triazolophthalazine.

[0258] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2E] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of the eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2E: aminophthalazine.

[0259] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2F] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counter screen for naive cells; blue: NAD quantification counter screen for naive cells): Figure 2F: Flavonoid (nobiletin).

[0260] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2G]Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counterscreen for naive cells; blue: NAD quantification counterscreen for naive cells): Figure 2G Alkaloid (palmatine).

[0261] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1 The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 2H] Figures 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H show the structures and dose-response curves of eight lead compounds (red: cell viability in the presence of TPrP; black: NAD quantification in the presence of TPrP; green: cell viability counterscreen for naive cells; blue: NAD quantification counterscreen for naive cells): Figure 2H 3-heteroarylquinoline (DMPQ).

[0262] Cell viability assays were performed in 1536-well plates. PK1 neuroblastoma cells (80 cells / well) were treated with 4 μg / ml TPrP for 3 days in a total volume of 5 μl. TPrP was identified by Zhou et al., Proc Natl Acad Sci USA 109,3113-3118 (2012). 1The preparation was carried out as described. The compound was added in 30 nl volume in 0.6% DMSO at 10 time points by titration at 4 log. Cell viability was measured using CellTiter-Glo® (Promega). NAD was measured using NAD+ / NADH-Glo TM Quantitative analysis was performed using (Promega). [Figure 3] Figure 3 shows the lack of neuroprotection by a GABAAR inhibitor structurally unrelated to DMCM. PK1 cells (1500 cells / well, 96-well plate) were treated with flumazenil (50 nM) for 24 hours and then exposed for 4 days with or without DMCM (0.5 or 5 μM) added to TPrP (3 μg / ml). TPrP was prepared as described by Zhou et al., Proc Natl Acad Sci USA 109, 3113-3118 (2012)1. Cell viability was measured using CellTiter-Glo® (Promega). The lack of protection by flumazenil against TPrP toxicity was repeated in a 10-point dose response experiment (0.3–164 nM, not shown). In this experiment, flumazenil was used at 100 times its IC50 for GABAAR inhibition. [Figure 4] Figure 4 shows that the GABAAR-inactive DMCM analog (DMCM-10049) and the aminoamide DMCM-8137 exhibit neuroprotective effects. DMCM-8137 and DMCM-10049 show nearly identical dose-response profiles in the TPrP neuroprotective assay. Cells (1500 cells / well, 96-well plate) were exposed to 5 μg / ml of TPrP and the indicated doses of the compounds for 4 days. TPrP was prepared as described by Zhou et al., Proc Natl Acad Sci USA 109, 3113-3118 (2012)1. Cell viability was measured using CellTiter-Glo® (Promega). [Figure 5]Figure 5 shows that DMCM rescues TPrP-induced toxicity in primary neurons. Primary mouse cortical neurons (Life Technologies) were exposed to 12 μg / ml TPrP for 5 days and treated with indicated DMCM or NAD. The assay was performed in 96-well plate format. TPrP was prepared as described by Zhou et al., Proc Natl Acad Sci USA 109, 3113-3118 (2012)1. Data for 3 replicates ± standard deviation are shown. Cell viability was measured using CellTiter-Glo® (Promega). DMCM and NAD treatment also suppressed neuritis and neuronal vacuolation induced by TPrP exposure (not shown). [Figure 6] Figure 6 shows that DMCM reduces ribosylation of ADP, an excess protein induced by misfolded proteins. PK1 cells were treated with 5 μg / ml TPrP in the presence of 9 nM FK866 (to inhibit NAD synthesis from nicotinamide present in the culture medium) and 40 μM biotin-NAD (Trevigen). Cells were harvested 2 or 3 days after treatment. Cell lysates were analyzed using SDS-PAGE, and ADP-ribosylated and biotinylated proteins were identified using streptavidin-HRP. Bands corresponding to TPrP-specific ADP-ribosylation at approximately 80 and 130 kD were reduced in the presence of DMCM (compare lanes 1 and 2 at each point). DMCM had no effect in the absence of TPrP (lanes 3 and 4 at each point). 10 μg of protein was added per lane. [Figure 7]Figure 7 shows that DMCM-10049 preserves dendritic spines and reduces pα-syn* levels in a cellular PD model. Human stem cell-derived neurons (30 days after differentiation) were seeded with 50 μg / ml of pre-formed α-synuclein fibrils (PFFs), treated with 2 μM DMCM-10049 or vehicle, and fixed after 17 days for analysis. Control cells were not seeded with PFFs. A: Dendritic spines were labeled with the marker F-actin using Phalloidin-iFluor488 (Abcam). B: pα-syn* (red, antibody GTX50222, GeneTex) + DAPI (blue) staining. Quantification was performed using ImageJ (NIH), and statistical analysis was performed using one-way ANOVA (Prism7). Mean and standard deviation of 8 images (A) or 6 images (B) per condition are shown. ****P<0.0001; ***P<0.001; ns = not statistically significant. [Figure 8] Figure 8 shows the therapeutic effect of DMCM-10049 on a mouse model of Parkinson's disease. Transgenic (SNCA*A53T) mice were administered DMCM-10049 at a dose of 50 mg / kg / day in drinking water starting at 9 months of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The control group was given the same mixture without the compound. The median survival time was 411 days in the control group (n=48) and 488 days in the treatment group (n=16). Survival time was significantly extended (log-rank test, p=0.01 for Prism7). [Figure 9] Figure 9 shows the therapeutic effect of DMCM-10049 on a mouse model of ALS.

[0263] Tg(SOD1 *G93A) mice were administered DMCM-10049 at a dose of 50 mg / kg / day in drinking water starting at 70 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. The median survival time was 165 days in the control group (n=7) and 177 days in the treatment group (n=11). Survival time was significantly extended (log-rank test, p=0.0007 for Prism7). [Figure 10] Figure 10 shows that oral batalanib (SR5-1457) treatment delays motor function impairment in a mouse model of ALS. Mice (all female) were administered 50 mg / kg of batalanib daily in drinking water starting at 47 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. Rotarod and hanging wire tests were performed as described²,³. Mean ± standard error is shown. Statistical analysis was performed using two-way ANOVA, n=12; *p<0.05; **p<0.01; ***p<0.001. [Figure 11] Figure 11 shows that in batalanib analogs, the SAR for neuroprotective / NAD recovery effects does not correlate with the SAR for VEGFR inhibition. VEGFR-active and inactive compounds related to batalanib (SR5-1457), including methyl ketone SR1-134005, were prepared and tested in this assay. Dose-response curves are shown for a counterscreen intended to detect compounds that nonspecifically increase luminescence / cell viability in the absence of neuroprotection (red) and NAD levels (black), as well as TPrP (green). The assay was performed in a 1536-well plate format as described in the caption of Figure 2. [Figure 12]Figure 12 shows the therapeutic effect of a much lower dose of GABAAR-active 3-methyl ketone analog compared to batalanib (SR1-134005) in a mouse model of ALS. Tg (SOD1*G93A) mice were administered 6 mg / kg / day of SR1-134005 in drinking water starting at 100 days of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. Muscle strength was measured using a hanging wire test. Mean ± standard error is shown. The difference between the treatment group (n=14) and the control group (n=19) was significant (p<0.001 for all except at 145 days, unpaired multiple t-test, Prism7). [Figure 13] Figure 13 shows the therapeutic effect of a much lower dose of GABAAR-active 3-methyl ketone analog compared to batalanib (SR1-134005) in a mouse model of Parkinson's disease. Tg (SNCA*A53T) mice were administered 25 mg / kg / day of SR1-134005 in drinking water starting at 8 months of age. Unsweetened strawberry-flavored gelatin (Royal®) was used to mask the flavor, and 4% DMSO was used to solubilize the compound. The vehicle control group was given the same mixture without the compound. The median survival time was 411 days in the control group (n=58) and 462 days in the treatment group (n=16). Survival time was significantly extended (log-rank test: p=0.03, Prism7). [Figure 14]Figure 14 shows neuroprotection in a cellular PD / synucleinopathy model. Mouse stem cell-derived neurons (8 days after differentiation) were seeded with PFF (A, B: 4 μg / ml; C, D: 3 μg / ml) and treated with the indicated dose of the test compound or vehicle DMSO for the last two days of differentiation. Control cells were not seeded with PFF. Cells were imaged using a phase-contrast microscope. Neurite length was quantified using the ImageJ NeuronJ plugin (NIH), and statistical analysis was performed in pairs by comparing compound-treated cells with the DMSO control group (Student's t-test, Prism8). Mean and standard errors for four irradiation fields per condition are shown. Each irradiation field contained approximately 50-100 neurons. The displayed image corresponds to a representative area of ​​one irradiation field. ****P<0.0001;***P<0.001;**P<0.01;*P<0.05;ns=not significant. [Figure 15] Figure 15 shows the lack of PARP-1 inhibition by carbazole (DMCM-10049), aminophthalazine (SR1-134005, also known as SR-005), pyrazolopyrimidine (SR1-293229, also known as SR-229), triazolophthalazine (SR5-22843, also known as SR-843), and flavonoid (nobiletin). ABT-888 is a known PARP1 inhibitor that acts as a pharmacological control group for the assay. "Control" indicates that the assay was performed in the absence of the compound. The assay was performed using the BPS Bioscience PARP1 chemiluminescence assay kit according to the manufacturer's instructions. [Figure 16]Figure 16 shows that aminophthalazine batalanib and SR1-134005 (also known as SR-005) are NAMPT activators. The compounds were tested using a colorimetric quantitative NAMPT activity assay (Abcam, ab221819). Each data point represents two replicate samples. A, B: Activation of NAMPT by SR-005, but not by DMCM, SR-229, SR-259, SR-186, or nobiletin. The compounds were tested at 5 μM (A) or 20 μM (B). C, D: Dose-dependent activation of NAMPT by SR-005 (C, 0.5 and 2.5 μM; D, 5 and 20 μM). E: Dose-dependent activation of NAMPT by batalanib. Pazopanib is a potent inhibitor of VEGFR-1, -2, and -3 and does not activate NAMPT at 10 μM. This data adds to the prior evidence that the NAD-recovering effects of batalanib and SR-005 are not related to VEGFR activity.

Claims

1. A pharmaceutical composition comprising a compound of formula (II), formula (IV), or formula (V) below, or a pharmaceutically acceptable salt thereof, for use in a method for inhibiting NAD consumption and / or increasing NAD synthesis in a patient, The aforementioned method, Pyrazolopyrimidine compound of formula (II) 【Chemistry 1】 or the effective amount of its pharmaceutically acceptable salt (In formula (II): Each R ａ１ and R ａ２ are each independently hydrogen, (C １ -C ４ ), alkyl, (C １ -C ４ ), haloalkyl, (C １ -C ４ ), alkoxyl, (C １ -C ４ ), haloalkoxyl, a 2- to 4-membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ｂ１ , R ｂ２ , and R ｂ３ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , or (C １ -C ４ ) is a haloalkyl; or R ｂ２ and R ｂ３ Together they form aryl or heteroaryl compounds; Each R ｃ and R ｄ These are independently hydrogen or (C １ -C ４ ) is alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) optionally substituted with haloalkoxyls or heteroaryls; and n = 2, 3, 4, or 5); Compound of formula (IV), 【Chemistry 2】 or the effective amount of its pharmaceutically acceptable salt (In formula (IV): R １ is hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O-(C １ -C ４ ) Alkyl, -C(O)NHNHR ６ , -C(O)NR ６ - ((C １ -C ４ )Alkilen)-NHR ６ , -C(O)NR ６ (C １ -C ４ ) alkyl, or -C(O)NR ６ -Cycloalkylene-NHR ６ And; R ３ is hydrogen or (C １ -C ４ ) is alkyl; Each R ２ , R ４ , R ５ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -C(O)O-(C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) are haloalkyl or CN; and Each R ６ is hydrogen or (C １ -C ４ (It is alkyl); or Compound of formula (V), 【Transformation 3】 or the effective amount of its pharmaceutically acceptable salt (In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, CN, -S(O) ２ NH ２ , oxo, -NH ２ , (C １ -C ４ ) Alkoxyl, or -NHC(O)(C １ -C ４ ) optionally substituted with alkyl; Each R １ and R ２ Independently, hydrogen, (C １ -C ４ ) Alkyl, aryl, or heteroaryl (where aryl or heteroaryl is halo or (C) １ -C ４ (Optionally substituted with alkyl), or R bonded to nitrogen １ and R ２ Together they form a 5-6 member heterocycloalkyl group; and R ３ is hydrogen, or hydroxyl (C １ -C ４ (It is alkyl.) A pharmaceutical composition comprising the step of administering to the patient.

2. The pharmaceutical composition according to claim 1, wherein the compounds of formulas (II), (IV), and (V) inhibit the ADP-ribosylation reaction of proteins.

3. The pharmaceutical composition according to claim 1, wherein the compounds of formulas (II), (IV), and (V) inhibit NAD cleavage by a protein deacetylase or glycohydrolase.

4. The pharmaceutical composition according to claim 1, wherein the compounds of formulas (II), (IV), and (V) increase NAD synthesis.

5. The pharmaceutical composition according to claim 1, wherein the patient suffers from or is at risk of suffering from a protein misfolding neurodegenerative disease or another protein misfolding disease.

6. The pharmaceutical composition according to claim 5, wherein the protein misfolding neurodegenerative disease includes prion disease, Parkinson's disease or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, or tauopathy, and the protein misfolding disease includes diabetes mellitus.

7. A pharmaceutical composition comprising a compound of formula (II), formula (IV), or formula (V) below, or a pharmaceutically acceptable salt thereof, for use in a method for preventing or inhibiting NAD depletion in a patient, or in a method for improving a condition related to altered NAD metabolism in a patient, The aforementioned method, Pyrazolopyrimidine compound of formula (II) 【Chemistry 4】 or the effective amount of its pharmaceutically acceptable salt (In formula (II): Each R ａ１ and R ａ２ is independently hydrogen, (C １ -C ４ ), alkyl, (C １ -C ４ ), haloalkyl, (C １ -C ４ ), alkoxyl, (C １ -C ４ ), haloalkoxyl, a 2- to 4-membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ｂ１ , R ｂ２ , and R ｂ３ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , or (C １ -C ４ ) is a haloalkyl; or R ｂ２ and R ｂ３ Together they form aryl or heteroaryl compounds; Each R ｃ and R ｄ These are independently hydrogen or (C １ -C ４ ) is alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) optionally substituted with haloalkoxyls or heteroaryls; and n = 2, 3, 4, or 5); Compound of formula (IV), 【Transformation 5】 or the effective amount of its pharmaceutically acceptable salt (In formula (IV): R １ is hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O-(C １ -C ４ ) Alkyl, -C(O)NHNHR ６ , -C(O)NR ６ - ((C １ -C ４ )Alkilen)-NHR ６ , -C(O)NR ６ (C １ -C ４ ) alkyl, or -C(O)NR ６ -Cycloalkylene-NHR ６ And; R ３ is hydrogen or (C １ -C ４ ) is alkyl; Each R ２ , R ４ , R ５ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -C(O)O-(C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) are haloalkyl or CN; and Each R ６ is hydrogen or (C １ -C ４ (It is alkyl); or Compound of formula (V), 【Transformation 6】 or the effective amount of its pharmaceutically acceptable salt (In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, CN, -S(O) ２ NH ２ , oxo, -NH ２ , (C １ -C ４ ) Alkoxyl, or -NHC(O)(C １ -C ４ ) optionally substituted with alkyl; Each R １ and R ２ Independently, hydrogen, (C １ -C ４ ) Alkyl, aryl, or heteroaryl (where aryl or heteroaryl is halo or (C) １ -C ４ (Optionally substituted with alkyl), or R bonded to nitrogen １ and R ２ Together they form a 5-6 member heterocycloalkyl group; and R ３ is hydrogen, or hydroxyl (C １ -C ４ (It is alkyl.) A pharmaceutical composition comprising the step of administering to the patient.

8. The pharmaceutical composition according to claim 7, wherein the aforementioned condition includes metabolic disorders, aging, degenerative diseases, neurodegenerative diseases, neurodegeneration associated with multiple sclerosis, hearing loss, retinal disorders or multiple sclerosis, ischemia of the brain or heart, renal failure, kidney disease, traumatic brain injury, or axonal damage.

9. A pharmaceutical composition comprising a compound of formula (II), formula (IV), or formula (V) below, or a pharmaceutically acceptable salt thereof, for use in a method of providing protection from the toxicity of misfolded proteins in a patient, The aforementioned method, Pyrazolopyrimidine compound of formula (II) 【Transformation 7】 or the effective amount of its pharmaceutically acceptable salt (In formula (II): Each R ａ１ and R ａ２ Independently, hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) Haloalkoxyl, 2-4 member heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ｂ１ , R ｂ２ , and R ｂ３ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , or (C １ -C ４ ) is a haloalkyl; or R ｂ２ and R ｂ３ Together they form aryl or heteroaryl compounds; Each R ｃ and R ｄ These are independently hydrogen or (C １ -C ４ ) is alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) optionally substituted with haloalkoxyls or heteroaryls; and n = 2, 3, 4, or 5); Compound of formula (IV), 【Transformation 8】 or the effective amount of its pharmaceutically acceptable salt (In formula (IV): R １ is hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O-(C １ -C ４ ) Alkyl, -C(O)NHNHR ６ , -C(O)NR ６ - ((C １ -C ４ )Alkilen)-NHR ６ , -C(O)NR ６ (C １ -C ４ ) alkyl, or -C(O)NR ６ -Cycloalkylene-NHR ６ And; R ３ is hydrogen or (C １ -C ４ ) is alkyl; Each R ２ , R ４ , R ５ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -C(O)O-(C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) are haloalkyl or CN; and Each R ６ is hydrogen or (C １ -C ４ (It is alkyl); Compound of formula (V), 【Chemistry 9】 or the effective amount of its pharmaceutically acceptable salt (In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, CN, -S(O) ２ NH ２ , oxo, -NH ２ , (C １ -C ４ ) Alkoxyl, or -NHC(O)(C １ -C ４ ) optionally substituted with alkyl; Each R １ and R ２ Independently, hydrogen, (C １ -C ４ ) Alkyl, aryl, or heteroaryl (where aryl or heteroaryl is halo or (C) １ -C ４ (Optionally substituted with alkyl), or R bonded to nitrogen １ and R ２ Together they form a 5-6 member heterocycloalkyl group; and R ３ is hydrogen, or hydroxyl (C １ -C ４ (It is alkyl.) A pharmaceutical composition comprising the step of administering to the patient.

10. The pharmaceutical composition according to claim 9, wherein the patient suffers from a prion disease, Parkinson's disease or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, tauopathy, or diabetes.

11. A pharmaceutical composition comprising a compound of formula (II), formula (IV), or formula (V) below, or a pharmaceutically acceptable salt thereof, for use in a method for preventing or treating protein misfolding neurodegenerative diseases in patients, Pyrazolopyrimidine compound of formula (II) 【Chemistry 10】 or the effective amount of its pharmaceutically acceptable salt (In formula (II): Each R ａ１ and R ａ２ Independently, hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) Haloalkoxyl, 2-4 member heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ｂ１ , R ｂ２ , and R ｂ３ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , or (C １ -C ４ ) is a haloalkyl; or R ｂ２ and R ｂ３ Together they form aryl or heteroaryl compounds; Each R ｃ and R ｄ These are independently hydrogen or (C １ -C ４ ) is alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) optionally substituted with haloalkoxyls or heteroaryls; and n = 2, 3, 4, or 5); Compound of formula (IV), 【Chemistry 11】 or the effective amount of its pharmaceutically acceptable salt (In formula (IV): R １ is hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O-(C １ -C ４ ) Alkyl, -C(O)NHNHR ６ , -C(O)NR ６ - ((C １ -C ４ )Alkilen)-NHR ６ , -C(O)NR ６ (C １ -C ４ ) alkyl, or -C(O)NR ６ -Cycloalkylene-NHR ６ And; R ３ is hydrogen or (C １ -C ４ ) is alkyl; and Each R ２ , R ４ , R ５ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -C(O)O-(C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) are haloalkyl or CN; and Each R ６ is hydrogen or (C １ -C ４ (It is alkyl); or Compound of formula (V), 【Chemistry 12】 or the effective amount of its pharmaceutically acceptable salt (In formula (V): Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, CN, -S(O) ２ NH ２ , oxo, -NH ２ , (C １ -C ４ ) Alkoxyl, or -NHC(O)(C １ -C ４ ) optionally substituted with alkyl; Each R １ and R ２ Independently, hydrogen, (C １ -C ４ ) Alkyl, aryl, or heteroaryl (where aryl or heteroaryl is halo or (C) １ -C ４ (Optionally substituted with alkyl), or R bonded to nitrogen １ and R ２ Together they form a 5-6 member heterocycloalkyl group; and R ３ is hydrogen, or hydroxyl (C １ -C ４ (It is alkyl.) A pharmaceutical composition comprising the step of administering to the patient.

12. The pharmaceutical composition according to claim 11, wherein the protein misfolding neurodegenerative disease includes prion disease, Parkinson's disease or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, or tauopathy.

13. The compounds of formula (II) include any one of these structures and their pharmaceutically acceptable salt forms: 【Chemistry 13】 【change】 【change】 【change】 【change】 【change】 The compounds of formula (IV) include any one of these structures and their pharmaceutically acceptable salt forms: 【Chemistry 14】 【change】 The compound of formula (V) 【Chemistry 15】 【change】 【change】 【change】 It is one of the following: A pharmaceutical composition according to any one of claims 1 to 12.

14. Compounds having formula (II) 【Chemistry 16】 or a pharmaceutically acceptable salt thereof (Here: Each R ａ１ and R ａ２ Independently, hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) Haloalkoxyl, 2-4 member heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ｂ１ , R ｂ２ , and R ｂ３ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , or (C １ -C ４ ) is a haloalkyl; or R ｂ２ and R ｂ３ Together they form aryl or heteroaryl compounds; Each R ｃ and R ｄ These are independently hydrogen or (C １ -C ４ ) is alkyl; Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) optionally substituted with haloalkoxyls or heteroaryls; and n = 2, 3, 4, or 5, However, R ａ２ , R ｂ１ , R ｂ２ , R ｂ３ , and R ｃ is hydrogen, n is 3, and Ar is phenyl (unsubstituted or -CH). ３ Or if it is replaced with -OMe, R ａ１ is neither difluoromethyl nor trifluoromethyl, and However, R ａ２ , R ｂ１ , R ｂ２ , R ｂ３ , and R ｃ is hydrogen, n is 3, Ar is -F, Br, 【Chemistry 17】 If it is a phenyl substituted with R ａ１ (It is not trifluoromethyl).

15. R ｂ１ Hydrogen, halo, C １ -C ４ Alkyl, (C １ -C ４ ) Haloalkyl, or -S(O) ２ R ｄ The compound according to claim 14.

16. R ｂ１ methyl, ethyl, -F, -CF ３ , or -S(O) ２ CH ３ The compound according to claim 15.

17. Each R ｂ２ , R ｂ３ , R ｃ , and R ｄ The compound according to claim 14, wherein is independently hydrogen or methyl.

18. R ｂ２ and R ｂ３ The compound according to claim 14, wherein together they form phenyl.

19. The compound according to claim 14, wherein n is 2, 3, or 4.

20. R ａ１ However, (C １ -C ４ ) alkyl, (C １ -C ４ The compound according to any one of claims 14 to 19, wherein the compound is a haloalkyl, a heterocycloalkyl, a 2- to 4-membered heteroalkyl, or an aryl.

21. R ａ１ However, methyl, ethyl, isopropyl, t-butyl, -CF ３ , [Chemistry 18] -CH ２ -O-CH ３ The compound according to claim 20, which is , or phenyl.

22. The aforementioned compound, 【Chemistry 19】 The formula has: Here, R ｂ１ is hydrogen, methyl, ethyl, -F, -CF ３ , or -S(O) ２ Me is; R ａ２ The compound according to any one of claims 14 to 21, wherein is hydrogen or methyl.

23. Ar is phenyl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ The compound according to any one of claims 14 to 22, optionally substituted with a haloalkoxyl or heteroaryl.

24. Ar is, 【Chemistry 20】 The compound according to any one of claims 14 to 23.

25. The aforementioned compound, 【Chemistry 21】 【change】 【change】 【change】 A compound according to claim 14, selected from the above.

26. Compounds having formula (IV), 【Chemistry 22】 or a pharmaceutically acceptable salt thereof (Here: R １ is hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O-(C １ -C ４ ) Alkyl, -C(O)NHNH ２ , -C(O)NH-((C １ -C ４ )Alkilen)-NH ２ , -C(O)NH(C １ -C ４ ) Alkyl, or -C(O)NH-cycloalkylene-NH ２ And; R ３ is hydrogen or (C １ -C ４ ) is alkyl; and Each R ２ , R ４ , and R ５ These are independently hydrogen, halo, (C １ -C ４ ) alkyl, -C(O)O-(C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxyl, (C １ -C ４ ) Haloalkyl or CN, However, R ４ and R ５ is -OMe, R ３ is hydrogen, R ２ If R is ethyl, １ It's not COOME. However, R ４ is -OMe, R ５ is hydrogen, R １ and R ２ If R is hydrogen, ３ It is not methyl, and However, R ２ , R ３ , R ４ , and R ５ If hydrogen, R １ ha-C(O)NHCH ３ isn't it).

27. Each R ４ and R ５ The compound according to claim 26, wherein is independently hydrogen or -OMe.

28. R １ However, hydrogen, (C １ -C ４ ) alkyl, -C(O)OH, -C(O)O(C １ -C ４ ) Alkyl, -C(O)NH-CH ２ CH ２ -NH ２ , -C(O)NCH ３ -CH ２ CH ２ - NHCH ３ , 【Chemistry 23】 or -C(O)NHNH ２ The compound according to any one of claims 26 to 27.

29. R ３ The compound according to any one of claims 26 to 28, wherein the compound is hydrogen or methyl.

30. R ２ However, hydrogen, (C １ -C ４ ) alkyl, or -C(O)O(C １ -C ４ The compound according to any one of claims 26 to 29, wherein it is alkyl.

31. The aforementioned compound, 【Chemistry 24】 A compound according to claim 26, selected from the above.

32. Compounds having formula (V), 【Chemistry 25】 or a pharmaceutically acceptable salt thereof (Here, Ar is a monocyclic or bicyclic aryl or heteroaryl, and one or more halos, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, CN, -S(O) ２ NH ２ , oxo, -NH ２ , (C １ -C ４ ) Alkoxyl, or -NHC(O)(C １ -C ４ ) optionally substituted with alkyl; Each R １ and R ２ Independently, hydrogen, (C １ -C ４ ) Alkyl, aryl, or heteroaryl (where aryl or heteroaryl is halo or (C) １ -C ４ (Optionally substituted with alkyl), or R bonded to nitrogen １ and R ２ Together they form a 5-6 member heterocycloalkyl group; and R ３ is hydrogen, or hydroxyl (C １ -C ４ ) is alkyl, However, R １ , R ２ and R ３ If hydrogen is, then Ar is 【Chemistry 26】 (Neither of the above).

33. R １ and R ２ Independently, hydrogen, (C １ -C ４ ) alkyl, or phenyl (F, Cl, Br, or (C １ -C ４ The compound according to claim 32, wherein it is optionally substituted with alkyl.

34. R bonded to nitrogen １ and R ２ Together, 【Chemistry 27】 The compound according to claim 32, which forms a compound.

35. R ３ However, hydrogen, or -CH ２ The compound according to any one of claims 32 to 34, wherein it is -OH.

36. The aforementioned compound, 【Chemistry 28】 A compound according to any one of claims 32 to 35, having the formula.

37. Ar is, 【Chemistry 29】 The compound according to any one of claims 32 to 36.

38. The aforementioned compound, 【Transformation 30】 【change】 【change】 A compound according to claim 32, selected from the above.

39. A pharmaceutical composition comprising the compound described in any one of claims 14 to 38.

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