BR112021004938A2 - methods and compositions for treating damage associated with aging using ccr3 inhibitors - Google Patents

Abstract

The present invention relates to methods for ameliorating neurodegenerative diseases with CCR3 modulating agents. The methods include administering a therapeutically effective amount of the CCR3 modulating agent to the subject, with a concomitant improvement in cognitive, motor or other neurodegenerative function affected. Cognitive and motor diseases in which the methods of the invention can improve cognition include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy.

Description

Descriptive Report of the Patent of Invention for "METHODS AND COMPOSITIONS FOR THE TREATMENT OF ASSO-

CIAED WITH AGING USING CCR3 INHIBITORS". |. Cross Reference to Related Requests

[0001] Pursuant to 35 USC 8 119 (e), this application claims priority for the filing date of United States Provisional Patent Application No. 62/737,017, filed September 26, 2018, of which description is incorporated herein by reference. Il. Introduction

[0002] The following is offered as background information only and is not admitted to be the state of the art of the present invention.

[0003] Aging is an important risk factor for several human diseases, including cognitive impairment, cancer, arthritis, vision loss, osteoporosis, diabetes, cardiovascular disease and stroke. In addition to normal synapse loss during natural aging, synapse loss is an early pathological event common to many neurodegenerative conditions and is the best correlate of the neuronal and cognitive damage associated with such conditions. Thus, aging remains the most dominant risk factor for dementia-related neurodegenerative diseases such as Alzheimer's disease (AD) (Bishop, NA et al., Neural Mechanisms of Aging and Cognitive Decline. Nature 464 (7288) , 529-535 (2010); Heeden, T. et al., Insights into the Aging Mind: A View From Cognitive Neuroscience. Nat. Rev. Neurosci. 5(2), 87-96 (2004); Mattson, MP, et al., Ageing and Neuronal Vulnerability: Nat. Rev. Neurosci. 7 (4), 278-294 (2006)). Aging affects all tissues and functions in the body, including the central nervous system, and a decline in functions such as cognition and motor activity can seriously affect quality of life.

[0004] The treatment of cognitive and motor decline associated with neurodegeneration has achieved limited success in preventing and reversing damage. Therefore, it is important to identify new treatments to maintain cognitive integrity when protecting, combating or reversing the effects of aging. Unfortunately, drug treatments for cognitive and motor impairment face significant obstacles. For example, it is believed that for treatments such as small molecules to be effective in treating cognitive decline and motor activity, they must cross the blood-brain barrier (Blood-Brain Barrier, BBB). Transport across the BBB is the exception, not the rule, and 98% of all small molecules do not cross it (Pardridge, William M, The Blood-brain Barrier: Bottleneck in Brain Drug Development, NeuroRx: The J of the Society for Experimental NeuroTherapeutics Experimental, 2: 3-14, 2005). As a result, therapies for neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are limited; in fact, Alzheimer's disease has one of the highest failure rates in the clinical development of any area of the disease (99.6% failure in the last 20 years) (Id.; and Burke, M., Renewed Focus on Dementia Checked by Drug Challenges, ChemistryWorld, 3 July 2014). These BBB-permeable drugs that are approved to treat cognitive disorders such as Alzheimer's disease, such as donepezil, exhibit temporary effects and do not work in all patients (Banks, WA, Drug Delivery to the Brain in Alzheimer's Di sease: Consideration of the Blood-Brain Barrier, Adv. Drug. Deliv. Rev. 64(7): 629-39 (2012); and Burke, M. supra). Similarly, levodopa, which treats the symptoms of Parkinson's disease, such as defi-

motor cits and crosses the BBB, eventually loses its effectiveness. An additional obstacle to treatments that cross the BBB is the fact that making compounds more lipophilic (which tends to make them more penetrating into the BBB) also often results in increased blood removal, leading to a decrease in bio - availability. Therefore, increased lipophilicity compensates for the plasma area under the curve (Area Under the Curve, AUC), minimizing cerebral absorption (Pardridge, William M, supra). Ill. Summary

[0005] The present invention overcomes these drawbacks. For example, Compound 1, a compound of the invention, exhibited resistance to crossing the BBB at significant concentrations, yet unexpectedly results in amelioration of symptoms associated with age-related neurodegeneration and age-related motor decline. Thus, the present invention can act in a peripheral way, abandoning what was considered a requirement for effective cognitive action pharmaceutical products, that is, it works directly on the central nervous system. And while certain embodiments of the invention can cross the BBB at significant concentrations, their ability to antagonize the CCL11/CCR3 pathway offers an alternative mechanism of action to current therapy for cognitive and motor impairments.

[0006] The compounds of the invention act as antagonists of chemokine receptor 3 with c-c motif (CCR3), the receptor for Eotaxin-1. Eotaxin-1 (CCL11) is a protein that is present at increased levels in blood plasma with aging and has been shown to cause reductions in cognitive function (Villeda et al., The Aging Systemic Milieu Negatively Regulates Neurogenesis and Cognitive Function, Nature, 477(7362): 90-94 (2011)). Eotaxin/CC11 acts mainly on the protein-coupled CCR3 receptor

G, which is expressed in eosinophils in the periphery and in neurons and glial cells in the central nervous system. (Kia, M. et al., Immunohistochemical Study of the B-Chemokine Receptors CCR3 and CCR5 and Their Ligands in the Normal and Alzheimer's Disease Brains, Am. J. Pathol. 153 (1); 31-37 (1998) ). In Alzheimer's, CCR3 levels have been observed to be increased in the CNS (Id.) Thus, it would be expected that the cognitive effects of CCR3 antagonization in Alzheimer's and related disorders would be mediated by the eotaxin-1/ interaction CCR3 located in the center. However, Compound 1 (a compound of the invention) unexpectedly resulted in improved cognitive function and stimulation of neurogenesis despite its inability to cross the BBB at significant concentrations.

Methods of treating patients with impairments associated with aging, neurodegenerative disease and associated cognitive and motor decline are provided, including by way of example and not limitation, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia , Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy, and so on. Aspects of the methods include modulating CCR3, the major CCL11/eotaxin-1 receptor by administering a therapeutically effective amount of the CCR3 antagonists of the invention. Methods include administering an effective therapeutic dose of CCR3 antagonists to individuals or patients, as well as monitoring specific clinical parameters. Also included are methods of treating neurodegenerative diseases and cognitive and motor decline associated with an agent that acts peripherally, that is, does not cross the blood-brain barrier, in significant concentrations and yet exhibits improvement in the disease, such as improvement in cognitive or motor activity.

[0008] Methods of using a diagnostic or complementary diagnostic test in relation to impairments associated with aging are also provided. By way of example and not limitation, such complementary diagnoses or diagnoses include devices that can determine or detect the presence of a subset of an individual's white blood cells. The diagnostic or complementary diagnostic device can also determine or detect the presence, relative or absolute concentration, relative or absolute number of eosinophils in the blood or tissues of an individual. Such diagnostic or complementary diagnostic devices can be used in conjunction with [ l. IV. Incorporation by Reference

[0009] All publications, patents and patent applications mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each publication or patent application were specific and individually indicated as being incorporated by reference. V. Brief Description of Figures

[0010] Figure 1A shows the sum of doublecortin (DCX) positive cells in the hippocampus of 2 month and 18 month old C57B1/6 mice treated with IgG (n = 18 for both groups); 18-month-old mice treated with Compound 1 for 2 weeks at a high (n = 16) or low (n = 31) dose; and 18-month-old mice treated with Compound 1 ("Comp. 1") for 4 weeks at a low dose (n = 16). Data shown are mean + s.e.m., where *P < 0.05, **P < 0.001.

[0011] Figure 1B shows the sum of positive cells for 5-

bromo-2'-deoxyuridine (BrdU) in the hippocampus of 2-month and 18-month-old C57B1/6 mice treated with IgG (n = 19 for both groups); 18-month-old mice treated with Compound 1 for 2 weeks at high (n = 16) or low (n = 24) doses. Data shown are mean + s.e.m., where ***P< 0.001.

[0012] Figure 2A shows the effect of Compound 1 on the time spent by young and old C57B1/6 mice in the new (N) versus familiar/old ("F" or "O") arm during a maze test in Y. 2-month-old mice were treated for 2 weeks with IgG (n = 18). 18-month-old mice were treated with: IgG for 2 weeks (n = 18); Compound 1 at a high dose for 2 weeks (n = 15); Compound 1 at a low dose for 2 weeks (n = 31); or Compound 1 at a low dose for 4 weeks (n = 16). Data shown are mean + s.e.m., where **P < 0.05, ***P < 0.01

[0013] Figure 2B shows the effect of Compound 1 on the total number of visits made by young and old C57B1/6 mice in the new (N) versus familiar (F) arm during a labyrinth test in Y. 2-month-old mice were treated for 2 weeks with IgG (n = 18). 18-month-old mice were treated with: IgG for 2 weeks (n = 18); Compound 1 at a high dose for 2 weeks (n = 15); Compound 1 at a low dose for 2 weeks (n=31); or Compound 1 at a low dose for 4 weeks (n = 16). Data shown are mean + s.e.m., where *P < 0.05, **P < 0.01, ***P < 0.001.

[0014] Figure 3 shows the effect of Compound 1 on entry hits ("number of visits") in the new and familiar arms of C57B1/6 mice in the Y-maze test. each arm was represented for each treatment group and subjected to the paired t-test. 3-month-old mice (n = 15) received a subcutaneous infusion of vehicle (veh) via an Alzet minipump (0.5 uL/hr) for four weeks, with one replacement. 16.5-month-old mice received a subcutaneous infusion of vehicle (veh, n = 16) or 50 mg/mL of Compound 1 (n = 16) via an Alzet minipump (0.5 uL/hour) for four weeks with a spare. Data shown are mean + s.e.m.; *P< 0.05.

[0015] Figure 4A shows the effect of Compound 1 on the mean time taken by C57B1/6 mice to find the target hole in the Barnes Labyrinth test. Mean times were plotted for each treatment group. 3-month-old mice (n = 18) received a subcutaneous infusion of vehicle (veh) via an Alzet minipump (0.5 uL/hour) for four weeks with one replacement. 16.5-month-old mice received a subcutaneous infusion of vehicle (veh, n = 15) or 50 mg/mL of Compound 1 (n = 15) via an Alzet minipump (0.5 uL/hour) for four weeks with a spare. The data shown is the mean t s.e.m.

[0016] Figure 4B shows the effect of Compound 1 on the difference in latency to find the target hole between the last and the first experiment of the last day of the Barnes maze test in C57B1/6 mice. Differences were plotted for each treatment group and data submitted to an unpaired t-test. 3-month-old mice (n = 18) received a subcutaneous infusion of vehicle (veh) via an Alzet minipump (0.5 uL/hour) for four weeks with one replacement. 16.5-month-old mice received a subcutaneous infusion of vehicle (veh, n = 15) or 50 mg/mL of Compound 1 (n = 15) via an Alzet minipump (0.5 uL/hour ) for four weeks-

but with a throw-in. Data shown are mean + s.e.m.

[0017] Figure 5 shows the effect of Compound 1 on neurogenesis in C57B1/6 mice by detecting BrdU-positive cells from all sections in the dentate gyrus. The number of BrdU-positive cells in the dentate gyrus was plotted for each treatment group and data subjected to an unpaired t-test between the 16.5-month-old groups. 3-month-old mice (n = 17) received a subcutaneous infusion of vehicle (veh) via an Alzet minipump (0.5 uL/hr) for four weeks with one replacement. 16.5-month-old mice received a subcutaneous infusion of vehicle (veh, n = 17) or 50 mg/mL of Compound 1 (n = 17) via an Alzet minipump (0.5 ul/hour) during four weeks with a replacement. Data shown are mean + s.e.m.; *P < 0.05.

[0018] Figure 6 shows the levels of Compound 1 detected in the CSF of C57B1/6 mice in both the young (n = 2) and old (n = 3) group (the levels were both below 10 nM). Compound 1 levels were detected using mass spectrometry.

Figure 7 depicts the distribution (measured as area under the curve (AUC)) of Compound 1 in the tissues of C57B1/6JO01aHsd mice over a period of time. The compound was labeled with a carbon-14 marker and measurements were taken at 1, 24 and 168 hours.

[0020] Figure 8 represents the pharmacokinetic profiles of Compound 1 after per os (P.O.) dosing. Blood plasma of 2-month-old male C57B1/6 mice that received mg/kg or 150 mg/kg by oral gavage was measured for Compound 1 at 20 minutes, 2 hours, 8 hours and 12 hours after ad - ministry. The plasma concentration after drug administration was plotted over time.

[0021] Figure 9 shows the effect of Compound 1 on exploratory preference during the Open Field test in young C57B1/6 mice. Exploratory preference was represented as the ratio of time spent in the periphery vs. center and the data were submitted to a one-way ANOVA. 2-month-old mice were treated with: vehicle p.o. b.i.d. (n=11); Composite 1 p.o. b.i.d. 30 mg/kg (n=12); vehicle p.o. b.i.d. plus mouse recombinant CCL11 (eotaxin-1 or "rmE") i.p. (n=14); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 14). Data shown are mean + s.e.m.; **P< 0.01.

[0022] Figure 10A shows the effect of Compound 1 on time spent in the young versus familiar arms in the Y-maze test in young C57B1/6 mice. Time spent in the new versus familiar arms was plotted for each treatment group and the data were subjected to a paired t-test. 2 month old mice were treated with: vehicle p.o. b.i.d. (n=13); Compound 1 p.o. b.i.d. 30 mg/kg (n=14); vehicle p.o. b.i.d. plus mouse recombinant CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 15). Data shown are mean + s.e.m.; **P< 0.01.

[0023] Figure 10B illustrates the effect of Compound 1 on the proportion of time spent in the new versus familiar arm in the Y-maze test in young C57B1/6 mice. Proportions were plotted for each treatment group and data were submitted to a post-hoc Kruskal-Wallis ANOVA test. 2 month old mice were treated with: vehicle p.o. b.i.d. (n=12); Compound 1 p.o. b.i.d. 30 mg/kg (n=14); vehicle p.o. b.i.d.

plus mouse recombinant CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 15). Data shown are mean + s.e.m.; *P < 0.05.

[0024] Figure 10C illustrates the effect of Compound 1 on the proportion of number entries made in the young versus familiar arm in the Y-maze test in young C57B1/6 mice. Proportions were plotted for each treatment group and data were submitted to a t-test between vehicle and treatment with mouse recombinant CCL11. 2-month-old mice were treated with: vehicle p.o. b.i.d. (n=13); Composite 1 p.o. b.i.d. 30 mg/kg (n=14); vehicle p.o. b.i.d. plus mouse recombinant CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 15). Data shown are mean + s.e.m.; *P < 0.05.

[0025] Figure 11A shows the effect of Compound 1 on the mean latency to find the target hole during the Barnes Labyrinth test in young C57B1/6 mice. Mean latencies were represented as time units for each treatment group in each experiment. 2 month old mice were treated with: vehicle p.o. b.i.d. (n=13); Compound 1 p.o. b.i.d. 30 mg/kg (n=14); vehicle p.o. b.i.d. plus mouse recombinant CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 15). Data shown are mean + s.e.m.

[0026] Figure 11B shows the effect of Compound 1 on the latency to find the target hole during the Barnes Labyrinth test in young C57B1/6 mice. The mean latencies of the last three experiments for each treatment group were plotted and the data were submitted to an unpaired t-test.

2 month old mice were treated with: vehicle p.o. b.i.d. (n=13); Compound 1 p.o. b.i.d. 30 mg/kg (n=14); vehicle p.o. b.i.d. plus mouse recombinant CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg/kg plus mouse recombinant CCL11 (n = 15). Data shown are mean + s.e.m.; *P<0.05.

[0027] Figure 12A shows the effect of Compound 1 on memory for the new arm in the Y-maze by the number of entries made to the new arm relative to the total entries. 24 month old mice were treated with Compound 1 p.o. b.i.d. 30 mg/kg or vehicle. Data shown are mean + s.e.m.; **P<0.01.

[0028] Figure 12B shows the effect of Compound 1 on the total distance traveled in the Y-maze as a measure of locomotor activity. 24 month old mice were treated with Compound 1 p.o. b.i.d. 30 mg/kg or vehicle. Data shown are mean + s.e.m.; *P < 0.05.

[0029] Figure 13A shows the effect of Compound 1 on entry accessions ("number of visits") in the new and familiar arms for C57B1/6 mice in the Y-maze test in 24-month-old mice . The number of visits to each arm was represented for each treatment group and submitted to a paired t-test. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were submitted to the Y-maze test. All mice received, for 5 consecutive days, an injection of BrdU at 50 mg/kg IP immediately before starting the treatment. Data shown are mean + s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 new versus familiar arm using Student's t-test for pairs.

of.

[0030] Figure 13B shows the effect of Compound 1 on the proportion of the number of entries made in the new versus familiar arm in the Y-maze test in 24-month-old mice. Proportions were plotted for each treatment group and data were subjected to a t-test between vehicle treatment and Compound 1 treatment. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously. BID (twice a day) for 21 days. Three weeks later, the mice were submitted to the Y-maze test. All mice received, for 5 consecutive days, an injection of BrdU at 50 mg/kg IP immediately before starting the treatment. The data shown are the mean t+ s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 compared to control by Student's t-test.

[0031] Figure 13C shows the effect of Compound 1 on the time spent in the new versus familiar arm in the Y-maze test in 24-month-old C57B1/6 mice. Time spent in the new versus familiar arms was plotted for each treatment group and the data were subjected to a paired t-test. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were submitted to the Y-maze test. All mice received, for 5 consecutive days, an injection of BrdU at 50 mg/kg IP immediately before starting the treatment. Data shown are mean + s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 new versus familiar arm by paired Student's t-test.

[0032] Figure 13D shows the effect of Compound 1 on the proportion of time spent ("duration") in the new versus familiar arm in the Y-maze test in 24-month-old C57B1/6 mice. Proportions were plotted for each treatment group and data were submitted to a t-test. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were submitted to the Y-maze test. All mice received, for 5 consecutive days, an injection of BrdU at 50 mg/kg IP immediately before starting the treatment. Data shown are mean + s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 compared to control by Student's t-test.

[0033] Figure 13E shows the effect of Compound 1 on mean speed during the Y-maze test of 24-month-old C57B1/6 mice. Mean velocities were plotted for each treatment group and data were subjected to a t-test. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were submitted to the Y-maze test. All mice received, for 5 consecutive days, an injection of BrdU at 50 mg/kg IP immediately before starting the treatment. Data shown are mean + s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001 compared to control by Student's t-test.

[0034] Figure 14A shows the effect of Compound 1 on the mean time taken by C57B1/6 mice of 24 months to find the target hole in the Barnes Labyrinth test. Mean times were plotted for each treatment group. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily)

for 21 days. Three weeks later, the mice underwent the Barnes Labyrinth test. Data shown are mean + s.e.m.; *“P < 0.05 compared with the control using Student's t-test.

[0035] Figure 14B shows the effect of Compound 1 on velocity in 24-month-old C57B1/6 mice in the Barnes Maze test, on average, across all experiments for each treatment group. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were submitted to the Barnes Labyrinth test. Data shown are mean + s.e.m.; *P < 0.05 compared to control using Student's t-test.

[0036] Figure 15A shows the effect of Compound 1 on the distance walked in the Open Field test in 24-month-old C57B1/6 mice. The mean distance walked was plotted for each treatment group. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice were subjected to the Open Field test. Data shown are mean + s.e.m.

[0037] Figure 15B shows the effect of Compound 1 on velocity in the Open Field test in 24-month-old C57B1/6 mice. The mean speed of mice was represented for each treatment group. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, the mice underwent open field testing. Data shown are mean + s.e.m.

[0038] Figure 16A shows the effect of Compound 1 on nitric oxides.

TNFalpha cytokine levels in the plasma of 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Inflammatory cytokine levels tend to be lower in mice treated with Compound 1 than in mice treated with vehicle.

[0039] Figure 16B shows the effect of Compound 1 on IL6 cytokine levels in the plasma of 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Inflammatory cytokine levels tend to be lower in mice treated with Compound 1 than in mice treated with vehicle.

[0040] Figure 16C shows the effect of Compound 1 on the levels of cytokine IL1beta in the plasma of 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Inflammatory cytokine levels tend to be lower in mice treated with Compound 1 than in mice treated with vehicle.

[0041] Figure 16D shows the effect of Compound 1 on IL5 cytokine levels in the plasma of 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Inflammatory cytokine levels tend to be lower in mice treated with Compound 1 than in mice treated with vehicle.

[0042] Figure 16E shows the effect of Compound 1 on IL17 cytokine levels in the plasma of 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Inflammatory cytokine levels tend to be lower in mice treated with Compound 1 than in mice treated with vehicle.

[0043] Figure 17 shows the effect of Compound 1 on activated microglia in 24-month-old C57B1/6 mice. 23-month-old mice were dosed with vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of CD68+ activated microglia are lower in mice treated with Compound 1 than in mice treated with vehicle.

[0044] Figure 18 shows the effect of compound 1 on the percentage of eosinophils in the complete count of white blood cells (leukocytes) in 24-month-old C57BlI/6 mice treated with control saline solution or 30 mg/ kg of Compound 1 over 3 weeks BID, SQ. Compound 1 decreased the endogenous age-related increase in blood eosinophils.

[0045] Figure 19 shows the effect of Compound 1 on the percentage of eosinophils in the complete count of white blood cells (leukocytes) in hairless mice at 3 months of age treated with saline control or 30 mg/kg of Compound 1 for 2 weeks BID, PO. Compound 1 decreased the oxazolone-induced increase in blood eosinophils.

[0046] Figure 20 shows the results of Compound 1 in a rotarod test for motor coordination. 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an osmotic pump. Treated mice were more successful than vehicle-treated mice in a binomial test, *P < 0.05.

[0047] Figure 21 shows the results of Compound 1 in the T-maze test for memory. 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an osmotic pump. Treated mice were more successful than vehicle treated mice in a binomial test, *P < 0.05.

Figure 22A shows the results of Compound 1 on overnight faecal production. 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an osmotic pump. The weight of the fecal granules was measured overnight. Mice treated with Compound 1 had significantly lower fecal production compared to mice treated with vehicle by Student's t-test, *P < 0.05.

[0049] Figure 22B shows the results of Compound 1 on overnight water intake. 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an osmotic pump. Total water intake was measured overnight. Mice treated with Compound 1 drank significantly more water compared to mice treated with vehicle by Student's t-test, *P < 0.05.

[0050] Figure 22C shows the results of Compound 1 on overnight food intake. 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an osmotic pump. Total food consumed was measured during the night. There were no differences in total overnight food intake between the two groups.

[0051] Figure 23 shows the effect of Compound 1 (Comp. 1) on the number of activated microglia positive for CD68 (CD68+) in the brain of three-month-old mice treated with LPS and treated with Compound 1 during 18 days. Mice treated with Compound 1 exhibited a decrease in CD68+ immunoreactivity and therefore a reduction in gliosis.

Figures 24A and 24B show the effect of Compound 1 on anxiety in the Open Field test in three-month-old mice treated with IP LPS for 4 weeks and treated with Compound 1 orally BID (two times a day) for 1 week. Treatment with LPS increased the preference for the Campo Aberto periphery, indicating an increase in anxiety. Compound 1 treatment decreased LPS-induced anxiety in the Open Field test. Data shown are mean + s.e.m; *P < 0.05 through Student's t-test.

Figures 25A and 25B show the effect of Compound 1 on the number of entries into the new and familial arms in the Y-maze test for 3 month old C57B1/6 mice treated with LPS. The number of visits to each arm was plotted for each treatment group and subjected to a paired t-test. The 3-month-old mice were dosed with vehicle or LPS IP for 6 weeks and dosed with vehicle control or Compound 1 orally BID (twice daily) for 3 weeks. Mice treated with Compound 1 showed a significant preference for the new arm, whereas mice treated with vehicle did not. Data shown are mean + s.e.m.; **P < 0.01, *P < 0.05, new versus familiar arm by paired Student's t-test.

Figures 26A and 26B show the effect of Compound 1 on IL1beta mRNA in the brain of three-month-old C57B1/6 mice treated with LPS and/or Compound 1. Mice were dosed with vehicle control or LPS IP for 7 weeks, and administered with vehicle or Compound 1 orally BID (twice daily) for 4 weeks. Tissues were collected and RNA was prepared from cortical brain tissues. ILibeta mRNA levels were measured by qPCR and data are presented in relation to vehicle control. There was a trend toward increased IL1beta mRNA levels for LPS treatment and a significant decrease for Compound 1 treatment. Data shown are mean + s.e.m; *P < 0.05 through Student's t-test.

Figures 27A and 27C show the effect of Compound 1 on microglial activation in the hippocampus of three-month-old C57B1/6 mice treated with LPS and/or Compound

1. Mice were dosed with vehicle control or LPS IP for 7 weeks and dosed with vehicle or Compound 1 orally BID (twice daily) for 4 weeks. Tissues were collected and brain sections were subjected to immunohistochemistry for CD68, a marker for activated microglia. There was an increasing trend in CD68 levels for LPS treatment and a robust decreasing trend for Compound 1 treatment. Data shown are mean + s.e.m.

Figures 28A and 28C show the effect of Compound 1 on total microglia in the hippocampus of three-month-old C57B1/6 mice treated with LPS and/or Compound 1. The mice were dosed with vehicle control or LPS IP for 7 weeks and dosed with vehicle or Compound 1 orally BID (twice daily) for 4 weeks. Tissues were collected and brain sections were subjected to immunohistochemistry for Iba1, a marker for microglia. There was a significant increase in Iba1 for LPS treatment and a decreasing trend for Compound 1 treatment. Data shown are mean + s.e.m.; ***P < 0.001, *P < 0.05, through Student's t-test.

Figures 29A and 29B show the effect of Compound 1 on total astrocytes in the hippocampus of three-month-old C57B1/6 mice treated with LPS and/or Compound 1. Mice were dosed with vehicle control or LPS IP for 7 weeks and dosed with vehicle or Compound 1 orally BID (twice daily) for 4 weeks. Tissues were collected and brain sections were subjected to immunohistochemistry for GFAP, a marker for astrocytes. There was a decreasing trend for Compound 1 treatment. Data shown are mean t s.e.m.

[0058] Figure 30 represents the dosing regimen for three groups of C57BL/6 mice treated with: (1) DE LPS and Compound 1 controls; (2) LPS plus vehicle control for Compound 1; or (3) LPS plus Compound 1. All three groups were treated with controls, LPS or Compound 1 for three consecutive consecutive days. The graph shows the results of histological analysis of mouse brains in a model of LPS-induced acute inflammation. Microgliosis was measured by determining the percentage of lba-1 positive area in the hippocampus. Data presented are mean + s.e.m; *P < 0.05, ***P < 0.001; One-way common ANOVA was used to test statistical significance with Dunnett's post-hoc multiple comparison test between treatment groups.

[0059] Figure 31 represents the dosing regimen for three groups of C57BL/6 mice treated with: vehicle controls; vehicle treated LPS; or Compound 1. The graph shows the results of histological analysis of mouse brains in a model of LPS-induced acute inflammation. Microgliosis was measured by determining the percentage of positive area for lba-1 in the hi-

pocampo. Data presented are mean + s.e.m; *P < 0.05, ****P < 0.0001; One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups.

[0060] Figure 32 represents the treatment study timeline for a mouse MPTP model of Parkinson's disease. There were two arms in the study: the first arm tested gait and fine kinematic motor function after 10 days of treatment, while the second arm tested immune cell infiltration after 3 days of treatment.

[0061] Figure 33A shows a thermal correlation map describing the degree of correlation for ninety-seven gait parameters in a gait test and fine motor kinematics of C57BI/6J mice after ten days of treatment with Compound 1 in the 11th day of study. Ten main components are presented, showing how the original parameters are correlated in datasets. The more intensity there is for each parameter, the more strongly the parameter is implied in the corresponding main component. Red is a positive correlation and blue is a negative correlation with respect to the 10 individual principal components (x-axis). The left-hand y-axis shows overall groupings for the individual variables on the right-hand y-axis. For example, "ILC" refers to intralimb coordination, "Tail B" refers to the base of the tail.

[0062] Figure 33B shows the fine motor skills and gait properties of C57BI/6J mice on study day 11 after 10 days of treatment with Compound 1. This is illustrated as an overall mouse gait analysis score C57BI/6J treated with MPTP. The differences between the treatment groups in each of the 10 main components were combined.

on a composite score and the difference for the vehicle-treated control group is shown. There was a significant difference in overall gait for the MPTP treatment (*p < 0.05) and there was no significant difference with the Compound treatment

1.

[0063] Figure 34 depicts forepaw toe release (one of the gait properties assessed in the principal component analysis) of C57BI/6J mice on day 11 of the study after 10 days of treatment with Compound 1. C57BI/6J mice on study day 11 after 10 days of Compound 1 treatment. Data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 (30 mg/kg), n = 13). Statistical significance: *p < 0.05, Group 2: MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (t-test unpaired).

[0064] Figure 35 represents the forepaw swing velocity (one of the gait properties evaluated in the principal component analysis) of C57BI/6J mice on day 11 of the study after 10 days of treatment with Compound 1. The data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 (30 mg/kg), n = 13). Statistical significance: *p < 0.05, Group 2: MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (unpaired t-test).

[0065] Figure 36 represents the ankle range of motion (one of the gait properties assessed in the principal component analysis) of C57BI/6J mice on day 11 of the study after 10 days of treatment with Compound 1. data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 (30 mg/kg), n = 13). Statistical significance: *p < 0.05, Group 2:

MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (unpaired t-test).

[0066] Figure 37 reports the acute effects of MPTP and Compound 1 on T cell trafficking to the brain after 3 days of treatment with Compound 1. The total number of CD3 positive T cells counted is shown. in the substantia nigra from 3 sections of 30 µm for each mouse. Data presented are mean + s.e.m; ***P<0.001; One-way ANOVA, Sidak post-hoc multiple comparison test.

Figures 38A and 38B report the acute effects of MPTP and Compound 1 on microgliosis after 3 days of treatment with Compound 1. Figure 38A shows the degree of CD68 positive area measured in the striatum (n = 7 for solution saline + vehicle; n = 8 for MPTP + vehicle; n = 7 for MPTP + Compound 1). Figure 38B shows the degree of CD68 positive area measured in the pars compact of substantia nigra (n = 7 for saline + vehicle; n = 8 for MPTP + vehicle; n = 8 for MPTP + Compound 1). Data presented are mean + s.e.m; **P < 0.01, ***P < 0.001, ***P < 0.0001; One-way ANOVA, Sidak post-hoc multiple comparison test.

[0068] Figure 39 depicts plasma eotaxin-1 levels in 6-month-old Line 61 synuclein-overexpressing transgenic mice. The levels of eotaxin-1 (CCL11) in non-transgenic (NTg) mice versus transgenic for Line 61 sinuclein (Tg) were represented in concentrations of pg/mL.

[0069] Figure 40 reports the results of a wire suspension test for mice (transgenic (Tg) and non-transgenic (nTg) - age-matched littermates) for Line 61 synuclein. shown the mean times of suspension in wire per group, with animals from group C (non-transgenic, tra-

with vehicle) exhibiting significantly longer wire suspension time. Animals in group A (transgenic, treated with Compound-1) exhibited a significantly longer wire suspension time compared to group B (transgenic, treated with vehicle). Data are displayed as mean + SEM of all animals per group; ***P<0.001; Dunn's post-test; *P < 0.05 Mann Whitney test for group A vs. group B.

[0070] Figure 41 reports the results of a mouse grip strength test (transgenic (Tg) and non-transgenic (nTg) - age-matched littermates) for Line 61 synuclein. g] by group is shown. Animals in group A and C (transgenic, treated with Compound 1 and non-transgenic, treated with vehicle, respectively) showed a significantly greater grip strength compared to group B (transgenic, treated with vehicle). Data are displayed as mean + SEM of all animals per group. The groups were compared with transgenic animals treated with vehicle (group B); Unilateral ANOVA followed by Bonferroni post-test.

[0071] Figure 42 reports the number of mice from each treatment group that were able to cross the beam in a beam walk test. N = 15 mice in Group A, 14 mice in Group B, and 15 mice in Group C (groups depicted in Figure 40). All mice were able to traverse the easiest beam in Assay 1, whereas no mice in Treatment Group B were able to traverse the most difficult beam in Assay 5. (Assay 1 = 13 mm rectangular beam; Assay 2 = beam 10 mm rectangular; Test 3 = 28 mm cylindrical beam; Test 4 = 16 mm cylindrical beam; Test 5 = 11 mm cylindrical beam).

[0072] Figure 43 reports the results of five assays for cross-beam slides for three groups of mice (Group A, transgenics treated with Compound 1; Group B, transgenics treated with vehicle; and Group C, non-transgenic tra. - ted with vehicle). Only mice that crossed the beam entirely were included in the analysis. The graphs represent the average number of slips [n] per group and each graph represents a trial (1-5). Data are mean + SEM of all animals per group. The groups were compared to group B; One-way ANOVA followed by Bonferroni post-test. Statistics for Assay 5 could not be obtained as no mice from Group B were able to cross the beam.

[0073] Figures 44A and 44B report the peripheral blood eosinophil count. Figure 44A reports the percentage of eosinophils (of all white blood cells) in the peripheral blood of three groups of mice (Tg Cmpd 1 = transgenics treated with Compound 1; Tg Veh = transgenics treated with vehicle; nNTG Veh; nNTG Veh = non-GMO treated with vehicle). Data were compared using a t-test. Figure 44B reports the absolute peripheral blood eosinophil counts of three groups of mice (Tg Cmpd 1 = transgenics treated with Compound 1; Tg Veh = transgenics treated with vehicle; Veh nTG = non-transgenics treated with vehicle). Data were compared using a t-test.

Figures 45A to 45G report the effect of Compound 1 on neuroinflammation. Figure 45A reports the quantified CD68-positive area in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 12, and 15, respectively). Figure 45B reports the quantified CD68-positive area in the striatum of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice

it; and transgenic mice treated with Compound 1 (n = 15, 11, and 16, respectively). Figure 45C reports the quantified Iba-1 positive area in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 13, and 16, respectively). Figure 45D reports the quantified Iba1i positive area in the striatum of: non-transgenic mice treated with vehicle; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 15, 11, and 16, respectively). Data are mean +/- s.e.m .; *P < 0.05. Figure 45E reports the quantified GFAP-positive area in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 13, and 15, respectively). Figure 45F reports the GFAP-positive area quantified in the striatum of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 15, 13 and 15, respectively). Figure 45G reports the quantified Iba-1 positive area in the pars compact of the substantia nigra of vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1. Data are mean +/- s.e.m .; *P < 0.05.

[0075] Figures 46A and 46B report the effect of Compound 1 on circulating levels of cytokines IL-4 and IL-6 in: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 15, and 17, respectively). Figure 46A reports the measured IL-4 levels in end-stage cardiac plasma from all three groups. Figure 46B reports the measured IL-6 levels in end-stage cardiac plasma from all three groups. Data shown are mean +/- s.e.m; *P < 0.05, **P < 0.01; One-way ANOVA, post-hoc Dunnett's multiple comparison test.

Figures 47A to 47D show the effects of Compound 1 on EAE-induced markers in the cerebellum of C57BL/6 mice. EAE resulted in an increase in CD3 and CD8 positive infiltrating T cells in the cerebellum. Figure 47A shows an increase in CD3 positive infiltrating T cells in the cerebellum which is significantly reduced after treatment with Compound 1 for 9 days. Figure 47B shows an increase in CD8 positive infiltrating cytotoxic T cells in the cerebellum which is significantly reduced after treatment with Compound 1 for 9 days. Figure 47C shows a significant increase in the positive area for Iba-1 in the cerebellum after EAE, which was significantly reduced in the cerebellum after 9 days of treatment. Figure 47D shows a significant increase in the CD68-positive area in the cerebellum after EAE, which was significantly reduced in the cerebellum after 9 days of treatment. Data shown are mean +/- s.e.m; *P < 0.05, **P < 0.01; One-way ANOVA, Dunnett's post-hoc multiple comparison test.

[0077] Figure 48 represents human eotaxin-1 concentrations in a proteomic screen. Relative concentrations of human eotaxin-1 were measured in a commercially available affinity-based assay (SomaLogic). Plasma samples from each of the 18, 30, 45, 55, and 66-year-old donors were represented.

Figure 49A depicts the effect of Compound 1 on the inhibition of eosinophil shape change. Whole blood from humans treated with Compound 1 was incubated with recombinant eotaxin to trigger the change in eosinophil shape.

them. Inhibition of shape change was plotted against plasma concentrations of Compound 1.

Figure 49B depicts the effect of Compound 1 on CCR3 internalization. Whole blood from humans treated with Compound 1 was incubated with recombinant eotaxin to trigger CCR3 internalization and labeled with anti-CCR3 antibody. Inhibition of CCR3 uptake by Compound 1 was plotted as a function of Compound plasma concentrations

1. VI. Detailed Description

Aspects of the invention include methods of treating neurodegenerative diseases/damages associated with aging. The damage associated with aging can manifest itself in several different ways, for example, as cognitive damage and/or physiological damage associated with aging, for example, in the form of damage to Organs central or peripheral organs of the body such as, but not limited to: injury cell, tissue damage, organ dysfunction, shortening of the life cycle associated with aging and carcinogenesis, where specific organs and tissues of interest include, but are not limited to, the skin, neuron, muscle, pancreas, brain, kidney, lung, stomach, intestine, spleen, heart, adipose tissue, testes, ovary, uterus, liver and bone; in the form of reduced neurogenesis, etc.

[0081] In some modalities, the damage associated with aging is a damage associated with aging in the cognitive capacity of an individual, that is, a cognitive damage associated with aging. By cognitive ability or "cognition" is understood mental processes that require attention and concentration, tasks and complex concepts of learning, memory (acquisition, retention and retrieval of new information in the short and/or long term), processes.

information management (dealing with information collected by the five senses), spatial vision function (visual perception, deep perception, use of mental images, copying drawings, building objects or shapes), producing and understanding language, verbal fluency ( word search), problem solving, decision making, and executive functions (planning and prioritization). By "cognitive decline" is meant a progressive decrease in one or more of these abilities, for example, a decline in memory, language, thinking, judgment, etc. By "an impairment of cognitive ability" and "cognitive impairment" is meant a reduction in cognitive ability in relation to a healthy individual, for example, a healthy individual who is the same age or in relation to the individual's ability to an earlier time, eg 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years or more earlier. Cognitive impairments associated with aging include impairments of cognitive ability that are typically associated with aging including, for example, cognitive impairment associated with the natural aging process, for example, mild cognitive impairment (Mild Cognitive Impairment, M.C.1.); and cognitive impairment associated with an aging-associated disorder, that is, a disorder that is seen with increasing frequency as senescence progresses, eg, a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease , dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, and so on.

[0082] By "treatment", it is understood that at least one improvement of one or more symptoms associated with an aging-associated harm that afflicts the individual is achieved, where improvement is used in a broad sense to refer to at least one reduction

tion in the magnitude of a parameter, for example, a symptom associated with the harm to be treated. Likewise, treatment also includes situations in which a pathological condition, or at least the symptoms associated with it, is completely inhibited, for example, prevented from happening or stopped, for example, terminated, so that the adult mammal no longer suffers from the damage or at least the symptoms that characterize the damage. In some cases, "treatment", "treating" and so on refer to obtaining the desired pharmacological and/or physiological effect. The effect can be prophylactic in terms of total or partial prevention of a disease or symptom thereof and/or it can be therapeutic in terms of partial or complete cure of a disease and/or adverse effect attributable to the disease. "Treatment" can be any treatment of a disease in an individual and includes: (a) preventing the occurrence of the disease in an individual who may be predisposed to the disease but has not yet been diagnosed as having the disease; (b) inhibit the disease, that is, stop its development; or (c) alleviating the disease, that is, causing regression of the disease. Treatment can result in a variety of different physical manifestations, eg modulation of gene expression, increased neurogenesis, tissue or organ rejuvenation, etc. Ongoing disease treatment, where the treatment stabilizes or reduces the patient's undesirable clinical symptoms, occurs in some modalities. Such treatment can be carried out before complete loss of function in the affected tissues. The therapy in question can be given during the symptomatic stage of the disease and, in some cases, after the symptomatic stage of the disease.

[0083] In some cases where the harm associated with aging is cognitive decline associated with aging, treatment using the methods of the present invention slows down or reduces the progression of cognitive decline associated with aging.

In other words, the individual's cognitive abilities decline more slowly, if at all, if treatment is followed by the methods described, than before or in the absence of treatment by the methods described.

In some cases, treatment using the methods of the present invention stabilizes an individual's cognitive abilities.

For example, the progression of cognitive decline in an individual suffering from cognitive decline associated with aging is stopped after treatment using the methods described.

As another example, cognitive decline in an individual, eg an individual 40 years of age or older, who is believed to be suffering from cognitive decline associated with aging, is prevented by following treatment using the methods described.

In other words, no (additional) cognitive damage is observed.

In some cases, treatment using the methods of the present invention reduces or reverses cognitive impairment, for example, as seen by improving cognitive abilities in an individual suffering from cognitive decline associated with aging.

In other words, the cognitive abilities of the individual who suffer from cognitive decline associated with aging following the treatment through the described methods are better than they were before the treatment through the described methods, that is, they improve with the treatment .

In some cases, treatment using the methods of the present invention abrogates cognitive impairment.

In other words, the cognitive abilities of the individual suffering from cognitive decline associated with aging are restored, for example, to their level when the individual was around 40 years of age or younger, following treatment using the methods described, for example, as evidenced by improved cognitive abilities in an individual suffering from cognitive decline associated with aging.

[0084] In some cases where the damage associated with aging is motor damage or decline associated with aging, treatment by the methods of the present invention slows or reduces the progression of damage or decline associated with aging. In other words, the individual's motor skills decline more slowly, if at all, after treatment using the methods described than before or in the absence of treatment using the methods described. In some cases, treatment using the methods of the present invention stabilizes an individual's motor skills. For example, the progression of motor decline in an individual who suffers from aging-associated motor decline is stopped following treatment using the methods described. As another example, motor decline in an individual, for example, an individual 40 years of age or older, who is believed to be suffering from aging-associated motor decline, is avoided after treatment using the methods described. In other words, no (additional) motor impairment is observed. In some cases, treatment using the methods of the present invention reduces or reverses motor impairment, for example, as seen by improving coordination or motor skills in an individual suffering from aging-associated motor decline. In other words, the motor skills of individuals who suffer from aging-associated motor decline after treatment using the described methods are better than they were before treatment using the described methods, that is, they improve with the treatment. . In some cases, treatment by the methods of the present invention abrogates the motor damage. In other words, the motor coordination or abilities of the individual who suffers from motor decline associated with aging are restored,

for example, at its level when the individual was about 40 years old or younger, after treatment using the methods described, for example, as evidenced by an improvement in coordination or motor skills in an individual suffering from aging-associated motor decline .

[0085] In some cases, treatment of an adult mammal according to the methods results in an alteration in a central organ, for example, an organ of the central nervous system, such as the brain, spinal cord, etc., where the alteration can manifest itself in several different ways, for example, as described in more detail below including, but not limited to, molecular, structural and/or functional, for example, in the form of increased neurogenesis.

Methods of treating dysfunction caused by neurodegenerative disease are provided, the method comprising administering the compounds of the formulas described below. One embodiment of the invention comprises a method of improving cognitive or motor activity in individuals who have a brain-associated or cognition-associated or motor disease, the method comprising administering a therapeutically effective amount of a compound of the chemical formulas described below. . Further embodiments of the invention comprise a method of enhancing neurogenesis in individuals having a disease associated with the brain or associated with cognition, the method comprising administering a therapeutically effective amount of a compound of the chemical formulas described below. Additional embodiments of the invention comprise a method of alleviating or treating disease symptoms associated with brain or cognition, the method comprising administering a therapeutically effective amount of a compound of the chemical formulas below. Additional modalities of the invention include

in methods of alleviating the symptoms of a disease associated with the central nervous system, the method comprising administering a therapeutically effective amount of a primarily peripherally acting agent of the chemical formulas below. Other additional embodiments of the invention include methods of improving motor activity in an individual who has age-related motor dysfunction or methods which comprise administering a therapeutically effective amount of a compound of the chemical formulas described below. The methods of the invention may also comprise monitoring improvement in age-related diseases including, for example, improvement in cognition, motor activity, neurogenesis and so forth in an individual diagnosed with having one or more such diseases or disorders.

[0087] Additional embodiments of the invention include administering a therapeutically effective amount of a compound, wherein the compound is in the form of co-crystals or salts of the formulas described below. Other embodiments of the invention include administering a therapeutically effective amount of a compound, wherein the compound is in the form of individual optical isomers, a mixture of individual enantiomers, a racemate, or enantiomerically pure compounds. Additional embodiments of the invention also include administering a therapeutically effective amount of a compound, wherein the compound is in the form of pharmaceutical compositions and formulations also described below.

[0088] Additional embodiments of the invention that treat aging-associated motor impairment or decline include modifying agents that inhibit the eotaxin/CCR3 pathway. Such modifying agents use not only compounds of the formulas described below, but other eotaxin and CCR3 inhibitory agents. Modifying agents that are considered include, by way of example, and not limitation, compounds of the formulas described below and other inhibitors of CCR3 small molecules (e.g., bipiperidine derivatives described, e.g., in the U.S. Patent -American No.

7,705,153, cyclic amine derivatives described, for example, in U.S. Patent No. 7,576,117 and the CCR3 antagonists described in Pease JE and Horuk R., Expert Opin Drug Discov (2014) 9 (5 ): 467-83, all incorporated herein by reference in full); anti-eotaxin antibodies; anti-CCR3 antibodies; aptamers that inhibit the expression or function of eotaxin or CCR3 (methods of producing such aptamers include U.S. Patent Nos. 5,270,163, 5,840,867, 6,180,348); antisense oligonucleotides or siRNAs that inhibit the expression or function of eotaxin or CCR3 (for example, described in U.S. Pat.

6,822,087); soluble CCR3 receptor protein (eg, "decoys"); and so on.

[0089] Methods of using a diagnostic test or complementary diagnostic test in relation to the described aging-associated harms are also provided. One modality of such a diagnostic or complementary diagnostic test is an in vitro diagnostic test. One modality of in vitro diagnostic testing is a complementary device used with a particular therapeutic product. Particular therapeutic product modalities include, for example, and without limitation, a small molecule CCR3 inhibitor, an anti-CCR3 antibody, small molecule inhibitors for the CCR3 ligand Eotaxin-1, an anti-Eotaxin-1 antibody, and RNA antisense to either Eotaxin-1 or CCR3.

[0090] By way of example and not limitation, such diagnoses or complementary diagnoses include determining or detecting the presence of a subset of white blood cells in an individual. Complementary diagnoses or diagnoses may also be to determine the presence, relative or absolute concentration, relative or absolute number of eosinophils in an individual's blood, tissue, or other samples. Blood can be obtained, for example, through venipuncture or other similar methods. Other samples may include, by way of example and not limitation, sputum, cerebrospinal fluid or tissue biopsies.

[0091] Methods of detecting or determining the presence, absolute or relative concentration or relative or absolute number of white blood cells, such as eosinophils, neutrophils, lymphocytes, basophils and monocytes, are known to those skilled in the art. Methods for determining the presence, absolute or relative concentration, or relative or absolute number of eosinophils are also known to those skilled in the art. See Walsh G.M., Eosinophils—Methods and Protocols ISBN: 9781493910151, which is incorporated herein by reference in its entirety. Such methods include, by way of example and not limitation: (1) complete blood count with 5-part differential using a hematology analyzer (see, eg, O'Neil et al., Laboratory Hematology 7 : 116-124 (2001) and the US Centers for Disease Control Laboratory Methods (available at https://wwwn.cdc.gov/nchs/data/nhanes/2013-2014/labmethods/CBC H MET COMPLETE BLOOD COUNT. pdf); (2) quantitative sputum eosinophil count using hematoxylin and eosin (H and E) stained smear preparation (see eg Bandyopadhyay A. et al. Lung India. Apr-Jun 2013; ( 2): 117123); (3) flow cytometric quantification of eosinophils using antibodies specific for various immune cells, such as CD45, CD125, CD193, F4/80 and Siglec-8 (Abcam, San Francisco, CA ) (see, for example, Yu YRA et al., Am J Respir Cell Mol Biol. Jan 2016; 54 (1): 13-24 and Cossarizza A. et al., Eur. J. Immu-

nol. 2017, 47: 1584-1797); (4) eosinophil autofluorescence quantified using flow cytometry (see, for example, Guenther G. et al., J Immunol, May 1, 2015, 194 (Supplement 1) 206-12 and Thurau AM et al., Cytometry 23: 159-58 (1996)); (5) isolation of eosinophils from whole blood using Dextran 70, Ficoll-Paque and antibody-based magnetic separation of colloid cells (see, eg, Munoz NM et al., Nature Protocols, 2613-20 (2006) ); Akuthota P. et al., Curr Protoc Immunol!l 98 (1): pages

7.31.1-7.31.8, 2012; and Akuthota P. et al., Methods Mol Biol 1178: 13-(2014)); (6) histological staining by general staining (eosin or similar dye) or staining based on antibodies against specific eosinophil protein (Major Basic Protein (MBP), Eosinophil Cationic Protein (Eosinophil Cationic Protein, ECP), but - eosinophilic xidase (Eosinophil Peroxidase, EPO), Eosinophil Derived Neurotoxin (EDN), SiglecF (or Siglec8), among others) (see, for example, Koller DY et al, Allergy 54 (10): 1094-9 (1999) and Akuthota P., Capron K., Weller PF (2014) Eosinophil Purification from Peripheral Blood in: Walsh G. (eds) Eosinophils, Methods in Molecular Biology (Methods and Protocols), vol. Humana Press, New York, NY); (7) histological staining of processes spatially associated with eosinophils, such as degranulation, Eosinophilic Extracellular Traps (Eosinophil Extracellular Traps, EETs) and/or specific proteins among them (Galectin 10, for example).

[0092] Diagnostic or complementary diagnostic devices may incorporate such methods to determine the presence, absolute or relative concentration or relative or absolute number of eosinophils. In determining the presence, absolute or relative concentration, or relative or absolute number of eosinophils, the devices can be used with other methods of the invention. By way of example,

By and not limitation, such other methods may include the methods of treating aging-associated neurodegenerative disorders/diseases recited herein. In some modalities, the damage associated with aging is an damage associated with aging in an individual's cognitive capacity, that is, damage associated with aging. Such damage associated with aging may include, by way of example and not limitation, a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis. pla, glaucoma, myotonic dystrophy, vascular dementia, and so on. Such aging-associated damage can include cognitive damage and/or motor impairment or decline.

An embodiment of the invention includes treating a subject diagnosed with an impairment associated with aging with a therapeutically effective amount of at least one of the compounds of the invention described herein in conjunction with a complementary diagnostic or diagnostic device. Another embodiment of the invention includes treating said subject with a therapeutically effective amount of Compound 1 described herein in conjunction with a diagnostic device. Said modalities of devices can be used, for example, to determine or detect the presence, absolute or relative concentration or absolute or relative number of eosinophils in a blood or tissue sample from an individual. Another modality performs a step of detecting or determining the presence, absolute or relative concentration or absolute or relative number of eosinophils in a sample of blood or tissue from an individual before, during or after treatment.

[0094] The experimental data in this document report that the synuclein overexpression model in mammals with Parkinson's disease results in decreased eosinophils, which are restored to levels in non-transgenic mice through treatment with Compound 1, suggesting an immune modulation beneficial in this model of Parkinson's disease. This also suggests that determination of eosinophil levels in Parkinson's disease patients treated with Compound 1 may be a biomarker for the disease, including to determine the level of disease progression, stasis or regression, as well as the effectiveness of treatment ( see, for example, Figures 44A and 44B).

[0095] Another modality performs the step of detecting or determining the presence, absolute or relative concentration or absolute or relative number of eosinophils in a blood or tissue sample from an individual who has a diagnosis of Parkinson's disease before, during or after treatment. Another modality comprises determining the presence, absolute or relative concentration or absolute or relative number in a blood or tissue sample of an individual who has been diagnosed with Parkinson's disease before he is treated with a compound of the invention, such as as Compound 1 in order to obtain a baseline concentration or number. Another modality subsequently performs a step of detecting or determining eosinophil levels after treatment, in order to compare such levels with the baseline eosinophil concentration or number in order to monitor the effectiveness of the treatment. Comparison of such levels may show an increase or decrease in the number or concentration of eosinophils compared to baseline. Another embodiment of the invention comprises a step of monitoring disease progression or damage by comparing the number or concentration of eosinophils where, if the number is increased after treatment, there is improvement in disease progression. In another modality-

ity, improvement may comprise a 1-5% increase from baseline in the number or concentration of eosinophils in an individual's blood or tissue, a 5-10% increase; an increase of 11-15%; an increase of 16-20%; an increase of 21-25%; an increase of 26-30%; an increase of 31-35%; an increase of 36-40%; an increase of 41-45%; an increase of 46-50%; an increase of 51-55%; an increase of 56-60%; an increase of 61-65%, an increase of 66-70%; an increase of 71-75%; an increase of 76-80%; an increase of 81-85%; an increase of 86-90%; an increase of 91-95%; an increase of 96-100%; and increases of 1-1.5%x, 1.5-2x, 2-2.5%, 2.5-3Xx, 3-3.5%x, 3.5-4x, 4-4.5% , 4.5-5%, 5-5.5%, 5.5-6x, 6-6.5%, 6.5-7%, 7-7.5%, 7.5-8x, 8- 8.5x, 8.5-9x, 9-9.5x, 9.5-10x and over 10x.

[0096] Another embodiment of the invention includes diagnosing Parkinson's disease by determining the baseline number or concentration of eosinophils in the blood or tissue of an individual and comparing to the standard numbers or concentrations of eosinophils in a non-disease population who have normal eosinophil counts. It is known in the art that an eosinophil count is the number of eosinophils in the body. For adults, a normal eosinophil count is between 30 and 350, but can reach 500 cubic millimeters (mm?) in blood. (See Medical News Today, December 2018 available at: https://www.medicalnewstoday.com/articles/323868.php, which is hereby incorporated by reference in its entirety). A count of more than 500 mm? in the blood is considered eosinophilia. Lower-than-normal eosinophil counts occur in some diseases, such as alcoholism and cortisol overprotection. (Id.) One aspect of the invention detects or determines the numbers or concentrations of eosinophils in an individual suspected of having Parkinson's disease. If the individual's eosinophil numbers or concentrations are less than normal (eg, 30 mm? in blood), then the result can be used by a caregiver to determine the diagnosis of disease. The. Compounds

The methods of the invention further comprise administering to a subject the following compounds. In the groups, radicals or moieties defined in this "Compounds" section, the number of carbon atoms is often specified preceding the group, for example, C1-6 alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups which are described in this "Compounds" section, the last named group is the point of attachment to the radical, for example, "thioalkyl" means a monovalent radical of the formula HS-Alk-. Unless otherwise specified below, conventional definitions of terms prevail and conventional stable atom valences are assumed and obtained in all formulas and groups.

[0098] An embodiment of the invention also comprises administering to a subject the compounds of formula 1, wherein the N is

LA R° N R R 1 A is CH 2 , O or N-C 1+6 alkyl; R? is selected from eNHR!, NMeR*!; eNHR!?2, NMeR!?; eNHCH2-R*?; eNH-C3.6 cycloalkyl while optionally one carbon atom is replaced by a nitrogen atom, while the ring is optionally replaced by one or two residues selected from the group consisting of C1.6 alkyl, O-C1-6 alkyl, NHSO>-phenyl, NHCONH-phenyl, halogen, CN, SO>2-C1-6 alkyl, COO-C1-alkyl;

and a Co or 10-bicyclic ring, while one or two carbon atoms are replaced by nitrogen atoms and the ring system is linked via a nitrogen atom to the basic structure of formula 1 and while the ring system is optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, COO-C1-6 alkyl, C1-6 haloalkyl, O-C1-6 alkyl, NO>, halogen , CN, NHSO 2 -C 1-6 alkyl, methoxy-phenyl;

and a group selected from NHCH(pyridinyl J|CH 2 COO-C 1-6 alkyl, NHCH(CH 20 -C 1-6 -alkyl)-benzoimidazolyl optionally substituted by halogen or CN;

and/or 1-aminocyclopentyl optionally substituted by methyl-oxadiazole;

R1* is phenyl optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C1-6-alkylene-OH, C2- 6 alkenylene-OH, — C>6 — alkynylene-OH, CH2CON(C1-6-alkyl), CHaNHCONH-C3.6 cycloalkyl, CN, CO-pyridinyl, CONR!HIR1H2, COO-C1-6 alkyl, N( SO2-C1-6-alkyl(CHOCON(C1-1 alkyl)2) O-C1-6 alkyl, O-pyridinyl, SO2-C1.6 alkyl, SO2-C1-6-alkylen-OH, SO> 2-C3-6 cycloalkyl, SO>z-piperidinyl, SONH-C1-6 alkyl, SO2N(C1-6-alkyl), halogen, CN, CO-morpholinyl, CHa-pyridinyl or a heterocyclic ring optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, NHC1.6-alkyl and =O;

RH, C1-6 alkyl, Ca6 cycloalkyl, C1.6 haloalkyl, CH2CON(C1-6 alkyl)., CH2CO-azetindinyl, C1-6-alkylen-C1-6 cycloal-

chyla, CH>a-pyranyl, CH>-tetrahydrofuranyl, CH2-furanyl, C1-6-alkylen-OH or thiadiazolyl optionally substituted by C1-6 alkyl;

R112 H,C1.6 alkyl, SO2C1-6 alkyl;

or R111 and R11-2 together form a four-, five- or six-membered carbocyclic ring that optionally contains an N or O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group containing. syste in C1-6 alkyl, C14 alkylene-OH, OH, =O;

or

R1* is phenyl, wherein two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic alkyleneoxy ring optionally containing, independently of one another, one or two N, S or SO'; substituting a ring carbon atom, wherein the ring is optionally substituted by C 1-1 alkyl or =O;

R'!? is selected from

heteroaryl optionally substituted by one or two residues selected from the group consisting of C1 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ca.6 cycloalkyl, CH2COO-C1-6 alkyl, CONR121R1-22, COR123, COO-C1.6 alkyl, CONH>2, O-C1.6 alkyl, halogen, CN, SO2N(C1-s-alkyl)=- or heteroaryl optionally substituted by one or two residues selected from the group consisting of in C 1-6 alkyl;

o heteroaryl optionally substituted by a five- or six-membered non-aromatic carbocyclic ring which contains, independently of one another, two N, O, S or SO> replacing a ring carbon atom;

a Cs or 1o-bicyclic aromatic or non-aromatic ring, while one or two carbon atoms are replaced by N, O or S, each optionally substituted by one or two residues selected from the group consisting of N(C1 .6-alkyl)>, CONH-C1-6 alkyl, =O;

a non-aromatic heterocyclic ring optionally substituted by pyridinyl;

and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCO-C1-: alkyl,

R121 H, C1.6 alkyl, C1.6-alkylene-C3.6 cycloalkyl, C14 alkylene-phenyl, C1-4 alkylene-furanyl, C.6 cycloalkyl, C14 alkylene-O-C14 alkyl, C1.6 haloalkyl or one five- or six-membered non-aromatic carbocyclic ring optionally containing, independently of one another, one or two N, O, S or SO' replacing a ring carbon atom, optionally substituted by 4-cyclopropylmethyl-piperazinyl

R122 H,C16alkyl;

R'23 is a five- or six-membered non-aromatic carbocyclic ring which optionally contains, independently of one another, one or two N, O, S or SO' replacing a carbon atom of the ring;

R*3 is selected from phenyl, heteroaryl or indolyl, each optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, C1-6 cycloalkyl, O-C1-. 6 alkyl, O-C1-6 haloalkyl, phenyl, heteroaryl;

R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-heteroaryl, each optionally substituted by one, two or three selected residues. ioned from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, O-C 1.6 alkyl, O-C 1-6 haloalkyl, halogen;

Rº is H; C1.6 alkyl;

Rº is H; C1.6 alkyl;

or R? and Rº together form a CH2-CH> group.

[0099] Another embodiment of the present invention also comprises administering to an individual the compounds of formula 1 (above), wherein

A is CH2, O or N-C14 alkyl;

R? is selected from eNHR!, NMeR*!;

eNHR!?2, NMeR!?;

eNHCH2-R*?;

R 1 ** is phenyl optionally substituted by one or two residues selected from the group consisting of C 1 , alkyl, C 2,6 alkenyl, C 2,6 alkynyl, C 1,6 haloalkyl, C 1-6 alkylene-OH, C 2 -6 alkenylene-OH, — C>6 — alkynylene-OH, CH2CON(C1-6-alkyl), CHaANHCONH-C3+6 cycloalkyl, CN, CO-pyridinyl, CONR1IR112, COO-C1-6 alkyl, N (SO2-C1-6-alkyl(CHOCON(C1-1 alkyl)2) O-C1-6 alkyl, O-pyridinyl, SO2-C1.6 alkyl, SO2-C1-6-alkylen-OH, SO >2-C3-6 cycloalkyl, SO>z-piperidinyl, SONH-C1-6 alkyl, SO2N(C1-6-alkyl), halogen, CN, CO-morpholinyl, CH2-pyridinyl or a heterocyclic ring optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, NHC1-6 alkyl, =O;

RH, C1-6 alkyl, Ca cycloalkyl, C1-6 haloalkyl, CH2CON(C1-6 alkyl,);, CH2CO-azetinidinyl, C1.6-alkylen-C1-6 cycloalkyl, CH>-pyranyl, = CH >-tetrahydrofuranyl, =CH 2 -furanyl, C 1-6 -alkylen-OH or thiadiazolyl optionally substituted by C 1-6 alkyl;

R112 HH, C1.6 alkyl, SO2C1.6 alkyl;

or R!!! and R112 together form a four-, five- or six-membered carbocyclic ring that optionally contains an N or O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of C1- .6 alkyl, C14 alkylene-OH, OH, =O;

or

R1* is phenyl, wherein two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring which optionally contains, independently of one another, one or two N, S or SO' replacing a ring carbon atom , wherein the ring is optionally substituted by C 1-1 alkyl or =O;

R'!? is selected from

* — heteroaryl optionally substituted by one or two residues selected from the group consisting of C1 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ca.6 cycloalkyl, CH2 COO-C1-6 alkyl, CONR1-21R1- 22, COR123, COO-C1.6 alkyl, CONHâ2, O-C1.6 alkyl, halogen, CN, SO2N(C1-« alkyl)) or heteroaryl optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl;

o heteroaryl optionally substituted by a five- or six-membered non-aromatic carbocyclic ring which contains, independently of one another, two N, O, S or SO> replacing a ring carbon atom;

R121 H, C1.6 alkyl, C1.6-alkylene-C3.6 cycloalkyl, C14 alkylene-phenyl, C1-4 alkylene-furanyl, C.6 cycloalkyl, C14 alkylene-O-C14 alkyl, C1.6 haloalkyl or one five- or six-membered non-aromatic carbocyclic ring optionally containing, independently of one another, one or two N, O, S or SO' replacing a ring carbon atom, optionally substituted by 4-cyclopropylmethyl-piperazinyl

R122 H,C16alkyl;

R123 is a non-aromatic five- or six-membered carbocyclic ring optionally containing, independently of one another, one or two N, O, S or SO» replacing a carbon atom of the ring;

R'13 is selected from phenyl, heteroaryl or indolyl, each optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, C1-6 cycloalkyl, O-C1- 6 alkyl, O-C 1-6 haloalkyl, phenyl, heteroaryl; where in some cases R*? is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of C1.6 alkyl, C3.6 cycloalkyl, O- C 1-6 alkyl, O-C 1-6 haloalkyl, phenyl, pyrrolidinyl; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-thiophenyl, each optionally substituted with one, two or three residues selected from from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, O-C 1-6 alkyl, O-C 1-6 haloalkyl, halogen; Rº is H; Cia alkyl; Rº is H; C and alkyl; or R? and Rº together form a CH2-CH> group.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1 (above), wherein A is CH 2 , O or N-C 14 alkyl; R is selected from eNHR!, NMeR*!; R1** is phenyl optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, C>2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C1-6-alkylene-OH, C2 -6 alkenylene-OH, — C>6 — alkynylene-OH, CH2CON(C1-6-alkyl), CHIANHCONH-C3+6 cycloalkyl, CN, CO-pyridinyl, CONR1IR112, COO-C1-6 alkyl, N (SO2-C1-6-alkyl(CHOCON(C1-1 alkyl)2) O-C1-6 alkyl, O-pyridinyl, SO2-C1.6 alkyl, SO2-C1-6-alkylen-OH, SO >2-C3-6 cycloalkyl, SO>z-piperidinyl, SONH-C1-6 alkyl, SO2N(C1-6-alkyl), halogen, CN, CO-morpholinyl, CH2-pyridinyl or a heterocyclic ring optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, NHC1-6 alkyl, =O; RH, C1-6 alkyl, Ca6 cycloalkyl, C1.6 haloalkyl, CH2CON(C1-6 alkyl,)), CH2CO -azetindinyl, C1-6-alkylen-C3-6-cycloalkyl, CH>a-pyranyl, CH>-tetrahydrofuranyl, CH2-furanyl, C1-6-alkylen-OH or thiadiazolyl optionally substituted by C1-6 alk uila; R112 HH, C1.6 alkyl, SO2C1.6 alkyl; or R111 and R11-2 together form a four-, five- or six-membered carbocyclic ring that optionally contains an N or O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group containing. system in C 1.6 alkyl, C 1-4 alkylene-OH, OH, =O; or R** is phenyl, wherein two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring which optionally contains, independently of one another, one or two N, S or SO' replacing a carbon atom of the ring, wherein the ring is optionally substituted by C 1-1 alkyl or =O; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-thiophenyl, each optionally substituted by one, two or three residues selected from from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, O-C 1.6 alkyl, O-C 1-6 haloalkyl, halogen; Rº is H; Cia alkyl; Rº is H; Cia alkyl; or R? and Rº together form a CH2-CH> group.

[00101] Another embodiment of the present invention also comprises

aims to administer to an individual the compounds of formula 1, wherein

A is CH2, O or N-C14 alkyl;

R is selected from eNHR!?2, NMeR!?;

R'!? is selected from

heteroaryl optionally substituted by one or two residues selected from the group consisting of C1 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ca.6 cycloalkyl, CH2COO-C1-6 alkyl, CONR121R1-22, COR123, COO-C1.6 alkyl, CONH>2, O-C1.6 alkyl, halogen, CN, SO2N(C1-« alkyl)) or heteroaryl optionally substituted by one or two residues selected from the group consisting of C1 -6 alkyl;

o heteroaryl optionally substituted by a five- or six-membered non-aromatic carbocyclic ring which contains, independently of one another, two N, O, S or SO> replacing a ring carbon atom;

º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of N(C1-6-alkyl)-, CONH- C1-6 alkyl, =O;

º piperidinyl optionally substituted by pyridinyl;

and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCO-C1+ alkyl,

R121 H, C16 alkyl, C1,6-alkylene-C3a.6 cycloalkyl, C14 alkylene-phenyl, C1-4 alkylene-furanyl, C.6 cycloalkyl, C14 alkylene-O-C14 alkyl, C1.6 haloalkyl or a ring not five- or six-membered carbocyclic aromatic which optionally contains, independently of one another, one or two N, O, S or SO' replacing a ring carbon atom, optionally substituted by 4-cyclopropylmethyl-piperazinyl

R122 H,C16alkyl; R'23 is a five- or six-membered non-aromatic carbocyclic ring which optionally contains, independently of one another, one or two N, O, S or SO' replacing a carbon atom of the ring; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-thiophenyl, each optionally substituted by one, two or three residues selected from from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, O-C 1.6 alkyl, O-C 1-6 haloalkyl, halogen; Rº is H; Cia alkyl; Rº is H; C and alkyl; or R? and Rº together form a CH2-CH> group.

[00102] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1 (above), wherein A is CH2, O or N-C14 alkyl; R is selected from eNHR!?, NMeR'?; R'!? is selected from * — heteroaryl optionally substituted by one or two residues selected from the group consisting of C 1-6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C .6 cycloalkyl, CH2 COO-C 1-6 alkyl, CONR!21R1-22, COR123, COO-C1.6 alkyl, CONH>2, O-C1.6 alkyl, halogen, CN, SO2N(C1. alkyl)- or heteroaryl optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl; o heteroaryl optionally substituted by a five- or six-membered non-aromatic carbocyclic ring which contains, independently of one another, two N, O, S or SO> replacing a ring carbon atom; R121 H, C1.6 alkyl, C1.6-alkylene-C3.6 cycloalkyl, C14 alkylene-phenyl, C1-4 alkylene-furanyl, C.6 cycloalkyl, C14 alkylene-O-C14 alkyl, C1.6 haloalkyl or one five- or six-membered non-aromatic carbocyclic ring optionally containing, independently of one another, one or two N, O, S or SO' replacing a ring carbon atom, optionally substituted by 4-cyclopropylmethyl-piperazinyl R122 H, C16alkyl; R123 is a non-aromatic five- or six-membered carbocyclic ring optionally containing, independently of one another, one or two N, O, S or SO» replacing a carbon atom of the ring; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-thiophenyl, each optionally substituted by one, two or three residues selected from from the group consisting of C 1.6 alkyl, C 1.6 haloalkyl, O-C 1.6 alkyl, O-C 1-6 haloalkyl, halogen; Rº is H; Cia alkyl; Rº is H; C and alkyl; or R? and Rº together form a CH2-CH> group.

[00103] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or N-C14 alkyl; R? is selected from eNHCH2-R*3; R'3 is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of C1.6 alkyl, C3.6 cycloalkyl, O-C 1-6 alkyl, O-C 1-6 haloalkyl, phenyl, pyrrolidinyl; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-thiophenyl, each optionally substituted with one, two or three residues selected from from the group consisting of C 1.6 alkyl, C 1.6 haloalkyl, O-C 1-6 alkyl, O-C 1-6 haloalkyl, halogen; Rº is H; Cia alkyl; Rº is H; C and alkyl; or R? and Rº together form a CH2-CH> group.

[00104] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or N-C14 alkyl; R is selected from eNHR!!, NMeR*; eNHR!?, NMeR'?; eNHCH2-R*:3; eNH-C3.6 cycloalkyl while optionally one carbon atom is replaced by a nitrogen atom, while the ring is optionally replaced by one or two residues selected from the group consisting of C1.6 alkyl, O-C1-6 alkyl, NHSO>-phenyl, NHCONH-phenyl, halogen, CN, SO>2-C1-6 alkyl, COO-C1-alkyl; and a Cs or 10-bicyclic ring, while one or two carbon atoms are replaced by nitrogen atoms and the ring system is linked via a nitrogen atom to the basic structure of formula 1 and while the ring system is optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, COO-C1-6 alkyl, C1-6 haloalkyl, O-C1.6 alkyl, NO>, halogen , CN, NHSO>z-Cls alkyl, m-

methoxyphenyl;

and a group selected from NHCH(pyridinyl J|CH 2 COO-C 1-6 alkyl, NHCH(CH 20 -C 1-6 -alkyl)-benzoimidazolyl optionally substituted by CI;

and/or 1-aminocyclopentyl optionally substituted by methyl-oxadiazolyl;

R1* is phenyl optionally substituted by one or two residues selected from the group consisting of C1 alkyl, C1-6 haloalkyl, CH2CON(C1-6-alkyl)-, CHANHCONH-C3.6 cycloalkyl, CN , CONR-1--IR1-1-2, COO-C1-6 alkyl, O-C1-6 alkyl, SO2-C1-6 alkyl, SO2-C1-6-alkylen-OH, SO2-C3.6 cycloalkyl , SO>-piperidinyl, SO2NH-C1-6 alkyl, SO2N(C1-6 alkyl)>—, — halogen, CN, CO-morpholinyl, CHa-pyridinyl or a heterocyclic ring optionally substituted by one or two selected residues from the group consisting of C1-6 alkyl, NHC1-6 alkyl, =O;

RH, C1-6 alkyl, Ca cycloalkyl, C1-6 haloalkyl, CH2CON(C1-6 alkyl,)), CH2CO-azetindinyl, C1-6-alkylen-C3-6 cycloalkyl, CHa-pyranyl, CH>- tetrahydrofuranyl, CH2-furanyl, C1-6-alkylen-OH or thiadiazolyl optionally substituted by C1-6 alkyl;

R112 H,C1.6 alkyl, SO2C1-6 alkyl;

or R!!! and R112 together form a four-, five- or six-membered carbocyclic ring that optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH

R'!? is selected from

º heteroaryl optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, C3.6 cycloalkyl, CHXCOO-C1-6 alkyl, CONR1-21R1 22, COO-C1.6 alkyl, CONH >2, O-C1. alkyl, halogen, CN, CO-pyrrolidinyl, CO-

morpholinyl or heteroaryl optionally substituted by one or two residues selected from the group consisting of C 1-6 alkyl; º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of N(C1-6-alkyl)-, CONH- C1-6 alkyl, =O; º piperidinyl optionally substituted by pyridinyl; and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCO-C1-: alkyl, R121 H,C16 alkyl; R122 H,C16alkyl; R'13 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of C1-6 alkyl, Ca. 6 cycloalkyl, O-C1-6 alkyl, O-C1-6 haloalkyl; R? is selected from C1.5-alkylene-phenyl or C1-6-alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, O-C1 -.6 alkyl, O-C1-6 haloalkyl, halogen; or CH 2 -thiophenyl optionally substituted by one or two residues selected from the group consisting of halogen; Rº is H; Cia alkyl; Rº is H; C and alkyl; or R? and Rº together form a CH2-CH> group.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNHR!!, NMeR*;

eNHR!?2, NMeR!?;

eNHCH2-R*?;

eNH-cyclohexyl optionally substituted by one or two residues selected from the group consisting of C14 alkyl, NHSO;»-phenyl, NHCONH-phenyl, halogen;

eNH-pyrrolidinyl optionally substituted by one or two residues selected from the group consisting of SO>2-C1-4 alkyl, COO-C14 alkyl;

epiperidinyl optionally substituted by one or two residues selected from the group consisting of NHSO 2 -C 1 -alkyl, m-methoxyphenyl;

edihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl, or tetrahydro-isoquinolinyl optionally substituted by one or two residues selected from the group consisting of C 1-4 alkyl, COO-C 1-1 alkyl, C1-4 haloalkyl, O-C1-4 alkyl, NO>, halogen;

and a group selected from NHCH(pyridinyl JCH 2 XCOO-C 1-4 — alkyl, NHCH(CH 20 -C 1-4 — alkyl)-benzoimidazolyl optionally substituted by CI;

and/or 1-aminocyclopentyl optionally substituted by methyl-oxadiazolyl;

R1* is phenyl optionally substituted by one or two residues selected from the group consisting of C1 alkyl, C1-4 haloalkyl, CHXCON(C1-4 alkyl)o, CHANHCONH-C3.6 cycloalkyl, CN, CONR-1--IR1-1-2, COO-C1-1 alkyl, O-C1-1 alkyl, SO2-C144 alkyl, SO2-C1-1' alkylene-OH, SO2-C3.6 cycloalkyl, SO> -piperidinyl, SO2NH-C1-1 alkyl, SO2N(C1-14 alkyl)2o, halogen, CO-morpholinyl, CH>a-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl , pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of C1.1 alkyl, NHC1-4 alkyl, =O;

RH, C1-6 alkyl, Ca.6 cycloalkyl, Cia haloalkyl, CH2CON(C1-1 alkyl)., CH2CO-azetindinyl, C1-4 alkylen-Ca.6 cycloalkyl, CHa-pyranyl, CHa-tetrahydrofuranyl, CH 2 -furanyl, C 1-4 alkylen-OH or thiadiazolyl optionally substituted by C 1-1 alkyl;

R112 HH, Cisalkyl, SO2C1.1 alkyl;

or R111 and R11-2 together form a four-, five- or six-membered carbocyclic ring that optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH

R'!? is selected from

º pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of C1-n alkyl, Ca-6 cycloalkyl, CHXCOO-C1.4 alkyl, CONR! 2IR122, COO-C1.« alkyl, CONH>2, O-C1+4 alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of C1« alkyl;

º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of N(C1-4 alkyl)-, CONH-C1 -n alkyl, =O;

º piperidinyl optionally substituted by pyridinyl;

and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCO-C14 alkyl,

R121 H, Cisalkyl;

R122 HH, Cyaalkyl;

R'3 is selected from phenyl, pyrazolyl, isoxazolyl,

pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of C14 alkyl, Ca.6 cycloalkyl, O-C1-1 alkyl, O-C1-1 haloalkyl ; R? is selected from C1.5-alkylene-phenyl or C1-6-alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of C14 alkyl, C1-4 haloalkyl, O-C1-4 haloalkyl, halogen; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of halogen; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00106] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R is selected from eNHR!!, NMeR*; eNHR!?, NMeR'?; eNHCH2-R*:3; eNH-piperidinyl optionally substituted by pyridinyl; eNH-cyclohexyl optionally substituted by one or two residues selected from the group consisting of t-Bu, NHSO;-phenyl, NHCONH-phenyl, F; eNH-pyrrolidinyl optionally substituted by one or two residues selected from the group consisting of SO>Me, COO-t-Bu; epiperidinyl optionally substituted by one or two residues selected from the group consisting of NHSO 3 -n-Bu, m-methoxyphenyl;

edihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl optionally substituted by one or two residues selected from the group consisting of Me, COO-Me, CF3, OMe, NO; ,F,Br;

and a group selected from NHCH(pyridinyl)CHXxCOOMe, NHCH(CH2OMe)-benzoimidazolyl optionally substituted by CI;

and/or 1-aminocyclopentyl optionally substituted by methyl-oxadiazolyl;

R1* is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CHxCONMe2, CHANHCONH-cyclohexyl, CN, CONR1-IR1H12, COOMe, COOEt, OMe , SO2Me, SO2CH2CH2OH, SO2Et, SO>-cyclopropyl, SO>x-piperidinyl, SONHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH>2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted by one or two residues selected from the group consisting of Me, NHMe, =O;

R11 H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH2-i-Pr, CHa-t-Bu, CH(CH3)JCH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH>a -cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 O0H or thiadiazolyl optionally substituted by Me;

R'12 H, Me, Et, SO2Me, SO-Et or R111 and R11'2 together form a four-, five- or six-membered carbocyclic ring which optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH

R!? is selected from º pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR! 21R1-22, COOMe, COOEt, CONH>2, OMe, CI, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMe>, CONHMEe, =O; and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCOMe, R*2* HH, Me; R122 H, Me; R'3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF>2; R? is selected from CH2-phenyl or CHo-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, Cl, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; Re H; R° is H; or R? and Rº together form a CH2-CH> group.

[00107] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe;

R is selected from eNHR!!

eNHR!?,

R1* is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF3, CH2CONMe>, CHaNHCONH-cyclohexyl, CN, CONR1-IR1-12, CoOOoMe, COOEt, OMe, SOxMe, SO>CHxCH2OH, SO2Et, SO>x-cyclopropyl, SO>z-piperidinyl, SO2NHEt, SO2NMEEt, F, CI, CO-morpholinyl, CHa-pyridinyl or imidazolidinyl, piperidinyl, oxazine-niyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted by one or two residues selected from the group consisting of Me, NHMe, =O;

RH, Me, Et, t-Bu, i-Pr, cyclopropyl, CH2-i-Pr, CH2-t-Bu, CH(CH3)JCH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH>a-cyclopropyl, CHa-cyclobutyl, CH2-pyranyl, CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me;

R'12 H, Me, Et, SO2Me, SO-Et or R111 and R11'2 together form a four-, five- or six-membered carbocyclic ring which optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH

R'!? is selected from

º pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR!21R1-22, COOMe , COOEt, CONH>2, OMe, CI, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, iso-

xazolyl, oxadiazolyl, each optionally substituted Me; º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMes», CONHMEe, =O; and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCOMe, R*2* HH, Me; R122 H, Me; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et R&H; RºéH.

[00108] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from and NHR*, NMeR*!; and NHR!?2?, NMeR!?; eNHCH2-R*3; RH is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF3, CH2CONMe>, CHaNHCONH-cyclohexyl, CN, CONR!-R1-12, COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO>x-cyclopropyl, SO>z-piperidinyl, SO2NHEt, SO2NMEEt, F, CI, CO-morpholinyl, CHa-pyridinyl or imidazolidinyl, piperidinyl, oxazine-nyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted by one or two residues selected from the group consisting of Me,

NHMe, =O;

R++1 H, Me, Et, Pr, Bu, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz-cyclobutyl, CH> -pyranyl, =CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me;

R112 —H,Me, Et, SO2Me, SO2Et, or R11 and R1-12 together form a four, five, or six-membered carbocyclic ring that optionally contains an O replacing a ring carbon atom , optionally substituted by one or two residues selected from the group consisting of CH2OH

R1? is selected from epyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR1-21R1- 22, COOMe, COOEt, CONH>2, OMe, CI, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me;

ebenzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMe', CO-NHMe, =O;

+ 4,5-dihydro-naphtho[2,1-d]thiazole optionally — substituted by NHCOMe,

R121 H, Me;

R1.22 H, Me;

R'3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group containing

sis on Me, Et, Pr, cyclopentyl, OMe, OCHF>2; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00109] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNHR!!, NMeR*; RH is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CHxCONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1H12, COOMe, COOEt, OMe, SO2Me , SO2CH2CH2OH, SO2Et, SO>-cyclopropyl, SO>x-piperidinyl, SONHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH>2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMEe, =O; R11 H, Me, Et, Bu, Pr, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz-cyclobutyl, CH>- pyranyl, =CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me; R'12 H, Me, Et, SO2Me, SO-Et or R111 and R11'2 together form a four-, five- or six-membered carbocyclic ring which optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00110] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R is selected from eNHR!!, NMeR*; RH is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CHxCONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1H12, COOMe, COOEt, OMe, SO2Me , SO2CH2CH2OH, SO2Et, SO>-cyclopropyl, SO>x-piperidinyl, SONHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH>2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMEe, =O; RR! H, Me, Et, Bu, Pr, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-

cyclopropyl, CHaz-cyclobutyl, CH>-pyranyl, =CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me; R112 H, Me, Et, SO2Me, SO-2Et or R!!! and R112 together form a four-, five- or six-membered carbocyclic ring that optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2OH; R? is as defined in Table 1 shown below; ReH; RºéH.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNHR!!, NMeR*; RH is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CHxCONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1H12, COOMe, COOEt, OMe, SO2Me , SO2CH2CH2OH, SO2Et, SO>-cyclopropyl, SO>x-piperidinyl, SONHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH>2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMEe, =O; and R1-1! and R1+12 together form a four-, five- or six-membered carbocyclic ring that optionally contains an O replacing a ring carbon atom, optionally substituted by one or two residues selected from the group consisting of CH2O0H; R? is as defined in Table 1 shown below; ReH; RºéH.

[00112] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNHR!!, NMeR*; R** is phenyl optionally substituted by one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CHxCONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1H12, COOMe, COOEt, OMe , F, CI; RR! H, Me, Et, Bu, Pr, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz-cyclobutyl, CH>-pyranyl, = CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me; R112 H, Me, Et, SO2Me, SO-2Et R? is as defined in Table 1 shown below; R° is H; RºéH.

[00113] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R is selected from and NHR!1, NMeR!; RH is phenyl optionally substituted by one or two residues selected from the group consisting of SO>2MEe,

SO2CH2CH2O0H, SO2Et, SO>-cyclopropyl, SO>-piperidinyl, SO2NHEt, SO2NMEEt; R1 H, Me, Et, Bu, Pr, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz-cyclobutyl, CH>- pyranyl, =CH>-tetrahydrofuranyl, CH>-furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me; R112 —H,Me, Et, SO2Me, SO2Et R? is as defined in Table 1 shown below; ReH; Rº is H.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R is selected from eNHR!, NMeR*!; RH is phenyl optionally substituted by a residue selected from the group consisting of Me, Et, t.Bu, CF3, CHCONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1:2, Coo-Me, COOEt, OMe , SO2Me, SO2CH2CH2O0H, SO2Et, SO>z-cyclopropyl, SO>»-piperidinyl, SONHEt, SO2NMEeEt, F, Cl, and additionally with a residue selected from the group consisting of CO-morpholinyl, CHa-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; R11 H, Me, Et, Bu, Pr, cyclopropyl, CH2-Pr, CH2-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz-cyclobutyl, CH>- pyranyl, = CH>-tetrahydrofuranyl,

CH2 -furanyl, CH2CH2O0H or thiadiazolyl optionally substituted by Me; R112 H, Me, Et, SO2Me, SO-2Et R? is as defined in Table 1 shown below; R° is H; RºéH.

[00115] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R is selected from eNHR!?2, NMeR!?; R'!? is selected from º pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CHXCOOEt, CONR! 2R122, COOMe, COOEt, CONH,, OMEe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; º benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMes», CONHMEe, =O; and —4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCOMe, R121 H, Me; R122 H, Me; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br,

Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00116] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNHR!?2, NMeR!?; R'!? is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, n-Pr, i-Pr, Bu , cyclopropyl, CH2 COOEt, CONR1-2'R122, COOMe, COOEt, CONH7, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; R121 H, Me; R122 H, Me; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00117] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe;

R is selected from eNHCH2-R*?; R'3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted by one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF>2; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, Cl, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; Re H; R° is H; or R? and Rº together form a CH2-CH> group.

[00118] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH2, O or NMe; R? is selected from eNH-piperidinyl optionally substituted by pyridinyl; and NH-cyclohexyl optionally substituted by one or two residues selected from the group consisting of t-Bu, NHSO;-phenyl, NHCONH-phenyl, F; and NH-pyrrolidinyl optionally substituted by one or two residues selected from the group consisting of SO>Me, COO-t-Bu; and piperidinyl optionally substituted by one or two residues selected from the group consisting of NHSO 3 -n-Bu, m-methoxyphenyl; and dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl optionally substituted by one or two residues selected from the group consisting of Me, COO-Me, CF3, OMe, NO ;, F, Br; and a group selected from NHCH(pyridinyl)CHXxCOOMe, NHCH(CH2OMe)-benzoimidazolyl optionally substituted by CI; and or 1-aminocyclopentyl optionally substituted by Methyl-Oxadiazolyl; R? is selected from CH2-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, Cl, Br, Et; or CH>-thiophenyl optionally substituted by one or two residues selected from the group consisting of Cl, Br; ReH; R° is H; or R? and Rº together form a CH2-CH> group.

[00119] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH>2, O or NMe, R' is selected from NHR12, NMeR12; R? is as defined in Table 1 shown below; Rº is H; Re, and R'2 is selected from e pyridinyl optionally substituted by one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, cyclopropyl, CONR121R122, COOMe , COOEt, CONH>2, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; and pyrrolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, COO-Me, COOEt; and pyrazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, cyclo-

propyl, COOEt, CO-pyrrolidinyl; and isoxazolyl optionally substituted by one or two residues selected from the group consisting of t-Bu, COOEt; and thiazolyl optionally substituted by one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CH2COOEt, CONR-1-21R1-22; and thiadiazolyl optionally substituted by one or two residues selected from the group consisting of COOEt; and benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMe', CO-NHMe, =O; and 4,5-dihydro-naphtho[2,1-d]thiazole optionally substituted by NHCOMe, and R''* is HouMe; R'2? isHouMe.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is CH>2, O or NMe, R' is selected from NHR12, NMeR12; R? is as defined in Table 1 shown below; Rº is AND RK is He R' ? is selected from epyridinyl optionally substituted by one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR!-21R1-22, COOMe, COOEt, CONH>2, OMe, Cl, Br; epyrrolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, COO-Me, COOEt; epyrazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, cyclo-

propyl, COOEt, CO-pyrrolidinyl; eisoxazolyl optionally substituted by one or two residues selected from the group consisting of t-Bu, COOEt; ethiazolyl optionally substituted by one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR121R1-22; ethiadiazolyl optionally substituted by one or two residues selected from the group consisting of COOEt; ebenzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMe>z, CO-NHMe, =O; and R'?* is HouMe; R122? isHouMe.

Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein and A is CH'O or NMe, R' is selected from NHR12, NMeR12; R? is as defined in Table 1 shown below; Rº is H; Rº is H; R1? is pyridinyl optionally substituted by one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR121R122, COOMe, COOEt, CONH>2, OMe, Cl, Br; R' 2! is Hou Me and R' 2? is H or Me.

and A is CH, O or NMe, R'? is selected from NHR!2, NMeR!2; R? is as defined in Table 1 shown below; Rº is H; Rº is H; R1? is pyrrolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; R1-2* is H or Me and R12? is H or Me.

and A is CH, O or NMe, R'? is selected from NHR!2, NMeR*-2; R? is as defined in Table 1 shown below.

xo; Rº is H; R is H; RE2 is pyrazolyl optionally substituted by one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; R4 21 is H or Me and RI22 is H or Me.

and A is CH, O or NMe, R'? is selected from NHR!2, NMeR!2; R? is as defined in Table 1 shown below; Rº is H; Rº is H; R 2 is isoxazolyl optionally substituted by one or two residues selected from the group consisting of t-Bu, COOE; R*?* is H or Me and R2? is H or Me.

and A is CH»O or NMe, R' is selected from NHR12, NMeR*-2; R? is as defined in Table 1 shown below; Rº is H; Rº is H; RI? is thiazolyl optionally substituted by one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR121R1-22: ; R421 is Hou Me and R12? is H or Me.

and A is CH»O or NMe, R' is selected from NHR12, NMeR*-2; R? is as defined in Table 1 shown below; Rº is H; Rº is H; R1? is thiadiazolyl optionally substituted by one or two residues selected from the group consisting of COOEt; R12! is it H or Me and R1 2? is H or Me.

and A is CH, O or NMe, R'? is selected from NHR!2, NMeR!2; R? is as defined in Table 1 shown below; Rº is H; Rº is H; R 2 is benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted by one or two residues selected from the group consisting of NMe2, CONHMEe, =O; A! 2 is H or Me and R12? is H or Me.

[00122] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein all groups are as defined above, except that R 1° is selected from and phenyl optionally substituted by OCHF >2; and pyrazolyl optionally substituted by Me or Et; and isoxazolyl optionally substituted by Pr; and pyrimidinyl optionally substituted by two OMe; and indolyl; * oxadiazolyl optionally substituted by cyclopentyl.

[00123] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein all groups are as defined above, except that A is CH.

[00124] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein all groups are as defined above, except that A is O.

[00125] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein all groups are as defined above, except that A is NMe.

[00126] Another embodiment of the present invention are compounds of formula 1, wherein A is CH2, O or NMe; R' is selected from . O x v o OI is Pa Sa, ú PC a po FT = OE neN ; and ne ; CH, ; A | é — Õ É : No ZH = N=0 x x o x A N C te, N bi 2 LE O N HC Ne, HC >N Nut , , , , ,

HC v E ( and o O [= [= Q oR "on, Ts 55 o O, O, O, O, O, O.

À À À À À À x x x, x x x , , , , , ,

OH NH x CS h úÚ = O Os

N “ N NO O, O À À À À N x not X CH, X, NeN , , , , ,

X N N. É ” O. ENO N x CH, Oct. Ô i so NATION N N | N N ALL “AND , , , , CH. 0º o o A vã í N. N. nc N. R N N N | " % x x Z , , , , No. x, He q € s, Y Ds À PP O ' vÓTÓÔ *v x X xXx , , , , , “ o Ô N o AN so OA,

N N Nx x X x , , , , , ,

| F in the knot

EQ

N DN N X x X Orc , , , ,

LOVE

N nO e | [Ca " | A x À N SO N N rn PY % VOO ne He et, X L , , , , ,

F =N No v nº O x No N FF F F x , , , , ,

Y N. Hs CH. E UCA, Oos (PO xx , , , , nÔ 7 NN== AX | N = vw Nx 7 ne" PACS ' > toa N o nv À F x CH xx , , , , , a = NX 7 4 N ox À No É X x E&, , , , , x

N

Ú Á . - No x He g “<Q R “Z Y ; o N Ne NN OO Ds O teho o GIVES To o=s P ne» o, Ss , , , ,

% É N. o O x 4 <<] No h N % TH, N o neo ne o Et a N SN CH, bs L O o , , , , “, x

N N o “4 o “x” EA N—CH, D N NE / / O N ne ne ne , , , , x H H N x N x—N CH. o o Ne : NO No o— = = , , , , He x Pp NAN, H H o — x N x N — o o No DL OL Px e A Von — = 2 ne x ne , , , , CH, x Mx,

SS HN )=N / x Pp o Ss X—N SA = —C! P NAS " He NAN — / : xo o CH, X | , , , == (> x

N o N A )=n He x xo ON SA o o NO Oo =x 9 CH, AA CH, “cn, , , , , x PN CH, o = n 2 * os s NE n d io Z x N x N 1 ? KZ a O OO o CH, O W NE NG , , , ,

Q and QN and

N N "Hs"

N N x ú N No. O o NS HC” ne “O h O Hen HE-N J CH, CH, , , , , o Q e x Ler yu N A o x N X—N “ Hs o

N NO CH, o o o À o HN CH, / , , ,

H H H X—N X—N X—N o V P 11 P o— o o— F MeO , , ,

N NO "x"x

H N N N X—N ú ! N “v N y o CH, = —N o— 1 AS Ss Cc! CH; N es , , , , , H,C—N Xx FAN EN )=n v SS ) “o “O

N He N N N o x x x , , , , = Ts EN nNÔSN nes N ne CH, Ss N > N Re N oS o

V Nsy x" x x" x" x , , , , ,

H,C—N der “And o xD NOT x o [ON Pr Pé

N o x" x" E x - On x / 3 / N O He, N HC N x Ace x N "ven, 7 N 1 BA 7 N N N o N o N = o = o

HC HC CH, ne a, Aa X

HE NO NO NO NO NO

O OS OR = o eH, K q X N CC N a rá N N — N—CH, XY “OS — o o ne > HC

F

F He A O x AX x x N ÕO N ne N o N o N N—CH o = o A o j x bo SCORES, CH,

o what

N

N x Y x À N N o N V N o CH, , , , Nº t Ho | Scr, — and Es x o NA Ha x ER Y 1 | N. NW N N N. o VT and H, , , , CH, Ho retro, - rá Hs N N—CH, A K N Ç CH, x x N ) N— h o N o N

NON fo) = o , , , ,

H AZ o. A o | Des X % V N o N o o” NO | , , , CH,

HC x o o. CH, À N N * * ROS if N o y " HCÉ x , , , A o N He CH. rá Ne x nos H,C—N b N À N—CH, CH, fo) o He Cc , , , o o

OH o x OA x 2H, 3 N v N x n N N À v 1 CH, CH, CH,

HC HC o He” Ae HA , , ,

o o o CH. ú N * No “N

N A N V N A CH, CH, CH, HC CH. o o AC 3 HC ne , , , A o o N ne x Hs x q N N v NA AS N. À N. À OH CH, CH, o

HC F F , , , oH Q

CH "NA X No

N V N V CH, CH, o o

À V CH, CH, , , o E Q and R X “en x Nu CH H = — ú NO XE o N ' N :

N RW NE NX A n No NN ç = / CH, o CH, "” He HC , , , , NO NES, CH. / LA en, O, ax N x, NNNNN un N “o, x N x A : you us

N q / He/O if o is O o is o " >" , , , , CH,

H H HO O, x A, x=N xN N =

N x | 7 AA FR Pe FR N = | N N í CH, No =" o— =" bo— Ne CH, Br MeO , , , , x CH,

ISO N N N LL XxX x x nen Px Px Ps er HC >N HC ON HC N , , , ,

oo O oxxxx SO WS of O " À SS x CH, CH, CH, CH, Oo Oo Oo Oo xxxxh CS h SS h. CS h SS CH, CH, CH, CH, NA, x, = pn NN (ON = N x = N x " y RN NZ A No ax N CH, H Í À J

Q EH

NX = CH, o CH N ( H NE NO XxeN n " x = CH, » o xX—NN — o— NEN — = He . R? is selected from xx E q * HC. fo o. F CI Cc !F Cl Br * x * xxx a. cr F and c F CH, ox Br: Ds R° is H; R° is H; or R' and R° together form a CH2-CH> group.

[00127] Another embodiment of the present invention are compounds of formula 1, wherein A is as defined above; RR is |; Re H; and R? is as defined in Table 1 shown below; and R' is selected from 2H

N A X o x NO HS ú x q x À SN CH, Ny d. Y N—N Y À F. Lo A NN TF h neN x h N. x

N N—CH, 385, b ça, Õ L o: At all po

W CH, right O & = CH, x N No RD Do O A Y x

N

N NO V N Net Wo x X k

HC cH. io NH oH o re = O CX 4 os ot "mer, Ss, os57 = uv Ob N o x Y x A Y x x x x x CH, X

FS o" no

A HC N O. = À N x x v no k " EN x o x x

NA à hoo and the HAND the N.

DSO

5. & N / N = nv n À OA x X x He o ú

NO I u

OQ O o NA xo Ss He Ns hoo Á Nes À No ja TS & TÁ, HC ) o CH, CH, OH, , , , , x “ 4 No already oo 1d N— CH Ot Of Vim o Nº, right , , , , “x nu o N x NH CH, o Xx—N ns o pn N No o— Hé / > / , , , , Q and QN A

N N "Hs"

N N / x N x o ne o o h TT Hen HE-N o CH, CH , , , , o Q EH x e uy N ? o Y N x=N X, Hs o h o o o [oa o HAN CH, / , , ,

H H H x—N xXx N xXx N o 1 P 11 P o o / o — F MeO , , ,

N ne H x LON AA “Ss À N / e

No—TV on CC! CH, N o , , , , H,C—N FAN OF N = N = | "the year

R NO NO

N N N N x x x x , , , , H,C—N EN NS nos = N Ss N " = N ve “o v IT" “O

N N N N x x x x , , , ,

CH x HC, A: DD

N

N N N x E. x XY N o N fo] N o

A CH, , , , , cu ne x of “CH, He CH, N He N—CH, N x N x Í N—CH, N. SM o N. oo 1 DD ne , , , , CH, F - ne A e AN x NN % À t Y OS N o N oo , , , , A o O xv "A ) ixv | x XN 1 N o N oh YN o CH, , , , ,

nN Ho Que De ho N nos NO x YY N. o N o N o , , , , chH, Ho seas CH o A 3 NN—CH, NN— SO” N. o OS o , , , , 4 or C o P the x Y He. HE—N N o N o nv N—CH, À ( A x X , , , , x f and o x o no.

CH NH “ NS N ê Y ã N—cn, —N eu, N ba, CH, o He He a a Ae , , , , Q o CH, o ú Node x x 2 Hs N. DN JN N N o CH. N. YN ) x 3 CH, CH, À n Ff HC " o Ae" Hs AH ne ne , , , , ooo CH, OH Cs ú NAS to aa > ? ne FF CH, , , , , Ns, Ns, x A NE Ns oo À ê YYN

À NÓ À N It's me, o meo o o o Hey N

À À bs bs - 6 O , , , , ,

o o o o X X 9 h nv N N ss N *% v CH, CH, EH, ú 4, o o o o o x x x x WS WS À " CH, CH, CH, CH,

[00128] "Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is as defined above; Rº is H; Rº is H; and R? it is as defined in Table 1 shown below; and R' is selected from nO X N. A 4 oo N ne N x 4 N UN Oo=S=, a "a nO % L nO Ned & F Hs If eH, x NC % voxxh Qdo v / NN o , "Cl% q CH; TN X x cH, He CH, N. Ç( oe 7 Nena, ne N N v ob” b ol s = N N O. N N

À À N À À x x X x x o x oH = HN .. e) o =s

N

N 1 À NON À x CH, x Zé x o

CH. ZA 0º He o NODE = x if N N h Nov

À y y Y No x x X , , , , x N x “x, N o x N N O ( À

AT THE- : ; / | > q N—CH, D SN CH 3 GRANDSONS / No NH, He, , , , x, xn NNX—NH o CH, o Xx—N aa o pç N No o— HC G o , , , , o CH o ENY xx CH, h / q N x—NX o —N He oo H,CN HEN o / “A CH, , , , , q Fe o HN x en X—NH % in oo X—N oo Es o < / ÓN oo HN CH, / F , , , , H —NH XxX NH x N » x—N ox—N À N oo Hs oo— o— MeO Cc! CH, , , , ,

CH FAN NO in “x” x v | dy Oo o —)

N

N K ne n n Ú N o x x x , , , , ,

cH, He. xa ne er A x L WA Í bh x Hex OH, A MAS ú o N NA To O ú CH, A , , , , A eH, N C. x, $ He, A / — CH, NN He N—CH , NV x N—CH, % N o DN o fo) He, , , ,

À A À ' o x ú NS ATO X N o x N o Ss hn N o 4 , , , , in o Or ba AA is 2) XxX N N N Ç CH. NNX x ne o , , , , GH, Ho repros - ox N—CH, x N xx N nen SO” N o SO” WS N—CH, o , , , , Q oH A oox Po N HC x À N * x 2H, NN " t N—CH, x N N. À CH, CH, CH, o He Á Ct ne aa ne " , , , , oooox Hs SN x nO x êN NNV dh N xn CH, Hs eH CH, no He o 7 mos, ET, no ne , , , , ox CH. o N He x NO o OH N N x no OS A CH, N V N OH CH, cn, 9 b" ne FF e , , , ,

o o x Hs x Hs Ro o d x h Ss “ N x N eH, N V N À o o CH, CH.

L A K CH, CH, o Q o o x x x x NS N h Y h N A Y CH, CH, CH, CH, o o x x kh Nao Y CH, CH, ; :

[00129] "Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is as defined above; Rº is H; Rº is H; and R? it is as defined in Table 1 shown below; R' is selected from x À N. XxX, o XxX N “ Í x í Á N tv, N gd Nes, He" He Neon, ne

HC x x x.

ER A OL RO AA O TT so A no No DD x ne He HC. Y N., | Í as x—N H o= = o X—N = VS N - SNL ne k ne CH, S x o o HN da Ao E X CH. = SS On” o V N RENA" O = “eH, k o NZ 0H,

x, / XN o No ne dx Ss = * Ss > ox Ss x N DZ N/A ec, CH, Êo AZ , , , , cH, eH “xy He cH, o number % 4 x = 7 Cs À NS HE N > “s NS CH, Hc “OD EEN N AO 3 ) PA xe” x , , , , , CH.

MK xx & O N ne A | N jo FX Not N Õ SAN & N VN —= > VN ne HC — o , , , , x CS o / x N / xo 7 N x) N “SN 7 a & O) NN—CH, Q b WA DR - O HE = o CH, — o , , , , qexx P u N =x SA x—hox 2 Ss.

N XY h (x COD J n and A A ) Fl e | He Br ne , , , , CH, o E o. ace v A o x — “o, x, — “om, He. % ú = MA / MA x | 7 O N N. = NE o Ú CH, He He NX CH, , , , , tos xN VW ? o x—N ” x N node Y FR o — Do N He—nNSN — = o— 2N O AN Br Meo N=N HE UN , , , ,

NA x—N xeN N= x = N. He N > 0 — R No

AN AN N HC "N HC "N x CH, , , , , Yo q AN x N

N À x N N° y of NA “ = CH, ? = x ) << / N. == ho YY N N | NE hp J right, , , , CH, x N No H ? xXN o x Di [= [> is o — 7X o— N — = NE ' ' ts X X , . , , , ne NH, x O EC ne oo (O - dn N o on, eo S 557 Ds TN o" o O, O, O, N N nv x x X x x CH, , , , , , , ,

OH the Ú N OB IS 3 YEAR 02nd ne OS.

N N = x N HN. x N N A ? X À x EN x o x , , , , , en - qn À A “E . NO O. >

N = / y O, Y A X k x ne o , , , , x N . IT'S

O Q O ) = o” already ns. ho (the Le + E LO Hey/o SW nen? meo bu, Ps & , , , ,

x x “N x x N o o N o WS NH, ne , , , , x H x Is X—N yu o eo o XN y Ss À / NV ZA o— / He (o) , , , , q e q N N x

Y “ Hs N / vn X—N xoo “TO o nen H,C—N BO ( A LON v = CH, CH, , , , , o cH N ' Q xx 2H, —H x CH, À ox NHN o XN oo 2H, o / ÓN oo HN fe / F , , , , —N

H H H NO X—N X—N xXx N x | 7 1 N o P o N > o— o o— MeO cl CH, , , , , “x and N rr. HE-N N = = “o | “the is

À “O N. If neo ó N N N o x x xo , , , , , - õÕ l ne se O es b: ” “o o Ne !

N N x x x x x , , , , ,

x Na He, & O

N x o x v x NOS N o N o N o CH, , , , , É es E cH, x N x ú x Hex CH, N He N—CH, À — o HC , , , ,

FCH, Õ

F a E A N A x Y x Y N ÕO SO SO N fo) & N fe) , , , , NO He. o Q * x x : “D) x x N. o h o N. N N o CH, , , , , That Bs | Xeon n oH A : A x CH, X ú ú ÇA “SO” “OS” N o o N o , , , , and in the neton, — AD o. h x N—CH, À TC) x À x x SO N o N o N o , , , ,

CC

HC A o x A XcH, nen N ne x N ne bL Neca N—cH, b N o x o He , , , ,

o i o o q x 4 Y “ ço x emo N and dk v R N N L 3 CH. N A CH, : CH, HC c & a Rem Eras o o CH. xxa À N N. À N À CH, CH, Cc Oo Fe and He , , R [) x ú NON x no xq CH, N N. LV À N No en e, oo He ne FE nº oox LL CH, CH . À o or x No x in h 4 x DNA N À N NS CH, kh o o ? í í Hen and c, CH, CH, Hs nº, N je WA x À | AA Q o 4 : Hc. o NM % N x ty À % N N 1 O) CH, f ' 4) o o o o o o o x x x x k CS WS RS RA, Ra CH, CH, CH, CH, CH, o “N

NV CH,

[00130] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is as defined above; Rº is H; Rº is H; and R? it is as defined in Table 1 shown below; and R' is selected from

2H | N N. xx (0 N HG ho Q to N x, $-. ozs=ão — N ea | dN PS No. po Ne N ZE cH, No = , , , , , xx E Fã CC / À o NO o NN = oe, o. N e. o N Ss vs=0 so NS yvv À CH, WN XXX x , , , , , , ss oH N-, es Ss CH, O po xo JS

D A SS oe" = AN N ob o NNN no N = x XXX e X NA , , , , , , =N o nÔ H,N. E Ê A ne o AS o É . 5. Kb. v hn No HN À NNN À ? À À xo “x X x , , , , , xxx à x He NN o CV E O PP O ( / W —NS—N CH, N—CH, N NOM / o NH, É , , , yeah, x

X À K H H N o à x—N x N poSos bi De

N ne NA o Il , , , , , O, Ss o CH. o o CH, N N h x 4 x N / LS dh x CH, X—N A vn FP o “TO o o HEN HC-N o = “a “Ha nN , , , , ,

o x Hs À o H H d x—N xt x—N o o o Hs O S/ ON o o o—CH, / F MeO , , , , x x x=N No Di. “r 7x | o % N o N ua o— ' —N. the 1 ne Cc! CH N , , , , , CH, HE-N FAN pos N Y = xo He, Fo RW o 9 A N x CH, N N. o o xo” xo x E, , , , , , CH, HC. xa Dea a N (hx HC b N ne No x | N—CH, NATO sn o > > o He , , , , PH F x or IDA x NO Ao Rom Ao DR NA o NATO LU LU o , , , , No. o. o O — | ú ox OO x ' Que À x À N o N À o & NS 2 , , , , Ho cH, Ho x CH.cn reset, AND NO is bw n N—CH, x NA xx “> a N > N. oo , , , , xo AAN n xe, NH,CN N—CH, dk N te & N—CH, CH, N. o > o ne e , , , ,

o [o] [) 9 x EX NO S nv % CS n ' & ' & & CH, C- C- fe] "e Hs Re Hs "Re Hs Oo oxx N / ox ão À À N ne x en, bh e CH, NE À N : om && o A" o He HC HC E oo OH ox nv x O x 2H h 1 hyh ' CH, CH, CH, O o í E CH, CH, o fe] oox no. xxx N. RN TO NRN

DD Y N N LN V o CH, CH, CH, E. o 9 o o x x x x WS Sa h % h % CH, CH, CH, CH, o x h Y e

[00131] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein A is as defined above; Rº is H; Rº is H; and R? it is as defined in Table 1 shown below; R' is selected from ú No x x p x L / / N 8 N A, No Pa —/ ga Ox gd “es nes He Nem He SN

He x Y To JA * NEMENSAN No N À o 2 (> (ds A No No = X He He , , , , , x

HC H “o No x—N” o: — NAS Pp XN = o AL OA EÊ Pa =/N/ ne x He , , , , CH, x

SS CN x Pp Y=N A NEAR o FO» N Qi E =x 6 N HE Z>N V Re SN oÊ NT CH, k | AA CH, , , , , is AM

N HN P o N = xs den & Ss > o N Ss XxX N. Ns o E/SN CH, ú “cn, CH, Êo No , , , , CH, HC CH, eH Xx E oo TT x ) À Ch xk UN O Ns NS CH, rá HEAN NNO " “ON xx , , , , ,

NA X N x A x N No. no x | Pi O NCH, N O

NO NES N = > = o NS He He — o , , , , X; À o o x O x x =v 7 N OO N He AA N x o SA) FX N—CH. W OH, N o) N DN 7 NX º No jo — > N NAAS CÊ NA ne = o CH, =/ | , , , , , ,

the Wai x. the o. E NS xl o NE ENS CC Es) NA ú " FR / AN — NM N No OD DO o y ne B/ ne ne H CH, Á, “No 7H HC ox = H x—N Lo = (Os N/A x—N' o LL x / í o FR N/A NE Z ne NWH, =/ o = o— nen NZ CH, Br MeO es

NA — N —N x = x x x = Na = = HePNZ | 2 = > NE Z

AN AN He >N ne PN He N xe ts ETA o N na x = “o o x 2 N O) x = o x = x ) 7 A nO h/s AE * =/ NZ RZ » , , ' , , ,

H X—N o Ns =/ Table 1: R? is defined as one of the groups shown below in definitions 1 to 4: x x E 1 From to ó AN x A!

XÁ Í a a LA Z x x x x * x Definition 1 Dos Tea LS LS LS Br or F à Phe o Br x x x x x en RR cro ,; Cc ; , Hs ; Br, xf; Ls | x, x, F.

[00132] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein the compounds of formula 1 are present in the form of individual optical isomers, mixtures of the individual enantiomers or racemates, for example, in the form of the enantiomerically pure compounds.

[00133] Another embodiment of the present invention also comprises administering to a subject the compounds of formula 1, wherein the compounds of formula 1 are present in the form of the acid addition salts thereof with pharmacologically acceptable acids, as well as optionally in the form of solvates and/or hydrates. B. Cocrystals and Salts

[00110] "Additional embodiments of the present invention also comprise administering to an individual the co-crystals of the compounds of formula 2 (below). In general, for groups comprising two or more subgroups in this "Cocrystals and Salts" section, the first named subgroup is the point of attachment to the radical, for example, the substituent "C1-3-alkyl-aryl" means an aryl group that is attached to a C1-3-alkyl- group, the latter of which is attached to the nucleus or to the group to which the substituent is attached.

O.

Rd G Us ND *(HX), RR 2 where

R' is C1.6 alkyl, C1.6 haloalkyl, O-C1.6 haloalkyl, halogen;

m is 1.20u3; and in some cases 1 or 2;

R?? and R?? are each independently selected from H, C1.6 alkyl, C1.6 alkenyl, C1-6 alkynyl, Ca. cycloalkyl, COO-C1-6 alkyl, O-C1-6 alkyl, CONR2? R2P2, halogen;

R2p* is H; C1-6 alkyl, Cos-alkyl-C1-6-cycloalkyl, C1-6 haloalkyl;

R2?? is H; C1.6 alkyl;

or R2nd! and R?p?? together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom

Rº is H; C1.6 alkyl;

X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p-toluenesulfonate; and in some cases chloride or dibenzoyltartrate j is 0.0,5,1,1,50uU2; and in some cases 1| or 2;

with a cocrystal former selected from the group consisting of orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3- acid hydroxy-2-naphthoic acid, mucic acid (galactaric), pamoic acid (embonic), stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, 1-lysine, 1-proline, D-valine, L -arginine, glycine, in some cases ascorbic acid, mucic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, 1-lysine, 1-proline.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R' is H; C1.6 alkyl, C1.6 alkenyl, C1.6 alkynyl, Ca. cycloalkyl, O-C1-6 alkyl, CONR221R222: R'2* is H; C1.6 alkyl, C1.6 haloalkyl; R?2? is H; C1.6 alkyl; R? is H; C1.6 alkyl, C1.6 alkenyl, C1.6 alkynyl, Ca.6 cycloalkyl, COO-C1-6 alkyl, O-C1.6 alkyl, CONR2P-1R2P?2, halogen; R2p* is H; C1-6 alkyl, Cos-alkyl-C1-6-cycloalkyl, C1-6 haloalkyl; R2?? is H; C1.6 alkyl; or R??! and R2'2 together are a Cza.s-alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

[00112] Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R&quot; is H; C1.6 alkyl, C1-6 alkynyl, C1-6 cycloalkyl, O-C1-6 alkyl, CONR'221R22'; R°* is cCisalkyl; R222 is H; R* is H; C1.6 alkyl, O-C1.6 alkyl, CONR??1R2>?; R°??** is Cr1.6 alkyl, Cos-alkyl-Ca.e-cycloalkyl, C1.6 halo-

alkyl; R2?? is H; C1.6 alkyl; or R2nd! and R2?? together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R' is H; C1.1 alkyl, C1-4 alkynyl, C1-6 cycloalkyl, O-C1-alkyl, CONR'221R22'; R?°** is Cia alkyl; R22? is R?º is H; C1.1 alkyl, O-C14 alkyl, CONR2?:1R2:2; R2'* is C14 alkyl, C1-6 alkyl-C1-6-cycloalkyl, C1-4 haloalkyl; R2?p? is H; Cia alkyl; or R2-! and R2?? together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R'* is H; Cisalkyl, R2; is H; CONR22IR22?2; R2p* is C14 alkyl, Co1-alkyl-C1-6-cycloalkyl, C1-4 haloalkyl; R2?? is H; Cia alkyl;

or R2nd! and R2?? together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the cocrystals of compounds of formula 2, wherein R' is C1.6 alkyl, C1.6 haloalkyl, O-C1-6 haloalkyl, halogen; m is 1 or ?2; R?º* is H; Cisalkyl; R2? is H; CONR22IR22?2; R2p* is C14 alkyl, Co1-alkyl-C1-6-cycloalkyl, C1-4 haloalkyl; R2?? is H; Cia alkyl; or R??! and R2'2 together are a Cza,s-alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom R6 is H; C1.6 alkyl; X is an anion selected from the group consisting of chloride or dibenzoyltartrate; j is 1 or 2 .

Another aspect of the present invention also comprises administering to a subject the co-crystals of the compounds of formula 2, wherein R' is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R?P-1 is C1.1 alkyl; in some cases Methyl, Ethyl, Propyl;

R2?? is C1.4 alkyl; in some cases Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R' is H; Ci, alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R'p-* is Co.1-alkyl-C.6-cycloalkyl; R2?? is H; C1.4 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of the compounds of formula 2, wherein R' is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22IR22?2; R'-* is C1a haloalkyl; R2'2 is H; C14 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R2'1 and R2'?' together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2, wherein R', m, R&%, R°, Rà, X and j are as defined above and the cocrystal former is selected from the group consisting of ascorbic acid, mucic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, 1-lysine, 1-proline or hydrates or hydrochlorides thereof.

Another aspect of the present invention also comprises administering to a subject the co-crystals of the compounds of formula 2a, wherein R', R°', R', X and j are as defined above O. Soy *(HX) RR 2a.

Another aspect of the present invention also comprises administering to a subject the co-crystals of compounds of formula 2a, wherein R'* is H; Chrys alkyl; in some cases Methyl, Ethyl, Propyl; R2 is H; CONR'2-1R2b:2: R2'* is C1.4 alkyl; in some cases Methyl, Ethyl, Propyl; R2?P? is C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of the compounds of formula 2a, wherein R' is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R2'* is Co.1-C3-alkyl-and-cycloalkyl; R2?? is H; C1.4 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

[00124] Another aspect of the present invention also comprises administering to an individual the co-crystals of the compounds of formula

2a, where R' is H; Ci, alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R'-* is C1a haloalkyl; R2?? is H; C1.4 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the co-crystals of the compounds of formula 2a, wherein R2'1 and R2'?' together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

[00126] The free bases of compounds of formula 2 (j = 0) are often amorphous and are used for a cocrystal manufacturing process, however salts of compounds of formula 2 are employed in some cases for a cocrystal manufacturing process. Thus, another aspect of the invention are salts of compounds of formula 2, wherein R', m, R$, R°, R° are as defined for the above cocrystals and X is an anion selected from the group consisting of in chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p-toluenesulfonate; in some cases chloride or dibenzoyltartrate j is 0, 0.5, 1, 1.5 or 2; in some cases 1 or 2.

[00127] Another aspect of the present invention also comprises administering to an individual the cocrystals of compounds of formula 2, wherein R', m, R2, R°', R' are as defined for the above cocrystals and X is an anion selected from from the group consisting of chloride or dibenzoyltartrate;

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2, wherein R', m, R2°, Rº', R6 are as defined for the above salts and X is chloride and j is 2.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2, wherein R', m, R2°, R°', R6 are as defined for the above salts and X is dibenzoyltartrate and j is 1.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R', R 2', R', X and j are as defined above O. If AY) a *(H) RR 2a .

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R' is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R?P-1 is C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2?P? is C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the salts of the compounds of formula 2a, wherein

R? is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22IR22?2; R'p-* is Co.1-alkyl-C.6-cycloalkyl; R2'2 is H; C14 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R' is H; C1.1 alkyl; in some cases Methyl, Ethyl, Propyl; R2? is H; CONR22-1R2b:2; R2'* is C1.4 haloalkyl; R2?? is H; C1.4 alkyl; in some cases H, Methyl, Ethyl, Propyl; and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R2'-1 and R2'? together are a C3-6 alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom and the remaining residues are as defined above.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R', m, R2°, R°', R6 are as defined for the above salts and X is chloride and j is 2.

Another aspect of the present invention also comprises administering to a subject the salts of compounds of formula 2a, wherein R', m, R2°, R°', R6 are as defined for the above salts and X is dibenzoyltartrate and j is 1. Another aspect of the invention are salts of compounds of formula 2a, wherein R', m, R2', R2', R6 are as defined for the above salts and X is (S)-(S)-(+)-2, 3-dibenzoyl tartrate and j is 1. c. Formulations

[00137] "Additional embodiments of the present invention also comprise administering to a subject a pharmaceutical composition containing formula 3 compounds

SS RR d =

IA OD *(HX), 3 where R' is H; C1.6 alkyl, Co-1-alkyl-C1-6-cycloalkyl, C1-6 haloalkyl; R? is H; C and alkyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate;

[00138] An embodiment of the present invention also comprises administering to a subject a pharmaceutical composition containing compounds of formula 3 wherein R' is H; C1-4 alkyl; R? is H; C1-6 alkyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate;

An embodiment of the present invention also comprises administering to a subject a pharmaceutical composition containing compounds of formula 3 wherein R' is H; Methyl, Ethyl, Propyl, Butyl;

R? is H; Methyl, Ethyl, Propyl, Butyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate, such as chloride; j is 1 or 2, in some cases 2.

[00140] An embodiment of the present invention also comprises administering to a subject a pharmaceutical composition containing compounds of formula 3 wherein R' is H; Methyl, Ethyl, Propyl, Butyl; R? is H; Methyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate, such as chloride; j is 1 or 2, in some cases 2.

An embodiment of the present invention also comprises administering to a subject a pharmaceutical composition containing compounds of formula 3 wherein R' is H; Methyl; R? is H; Methyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate, such as chloride; j is 1 or 2, in some cases 2.

An embodiment of the present invention also comprises administering to a subject a pharmaceutical composition which contains compounds described in Table 2 as a hydrochloride. A further embodiment of the present invention also comprises administering to a subject a pharmaceutical composition which contains compounds described in Table 2 as a dihydrochloride. TABLE 2

2 a OP o O OD 3 & meo cr CX DAL dLDA4 a 1 DSR AD % x e AA -” FT Us AQ. and the

OA A CO 3 a

OS 7 NC

E and "oe | Do, TE Âo A Ono 3

The A "the LES |

Another objective of the present invention is to administer to an individual a pharmaceutical dosage form of the compounds described above, wherein the dosage is an orally administrable dosage form.

[00144] Another objective of the present invention is to administer to an individual a pharmaceutical dosage form of the compounds described above, which is in the form of a tablet, capsule, granules, powder or granules.

[00145] Another objective of the present invention is to administer to an individual the pharmaceutical dosage forms described above for use as a medicine.

[00146] Another objective of the present invention is the use of the above pharmaceutical dosage forms for the preparation of a medicine for the treatment of a disease or neurodegenerative condition selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia , Huntington's disease, amyotrophic lateral sclerosis, participating sclerosis, glaucoma, myotonic dystrophy, vascular dementia, and progressive supranuclear palsy.

[00147] Another object of the present invention is a process for the treatment and/or prevention of a disease or condition selected from a neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Hunting's disease. ton, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia and progressive supranuclear palsy, characterized by the fact that an effective amount of the pharmaceutical dosage form defined above is administered orally to an individual or patient once, twice, three times or several times a day. d. Dosage Forms/Ingredients

Ready-to-use/intake solid pharmaceutical compositions made from a compound of formula 3 comprise powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, troches and lozenges. In detail: * The capsule formulations according to the invention comprise the intermediate powder of a compound of formula 3, an intermediate mixture comprising the intermediate powder, granules or granules obtained by means of conventional granulation via the wet route, dry or hot or hot extrusion or spray drying of a suitable intermediate mixture filled with conventional capsules, for example hard gelatin capsules or HPMC.

* The above capsule formulations may also include the powdered intermediate of a formula 3 compound in a compressed form.

* Capsule formulations according to the invention comprise the compound of formula 3 suspended or diluted in a liquid or mixture of liquids.

* The tablet formulations according to the invention comprise these tablets obtained by compression.

are direct from a suitable final blend or compressed granules or granules obtained by conventional granulation via wet, dry or hot granulation or hot melt extrusion or spray drying of a suitable intermediate mixture.

[00149] Another object of the present invention is a dosage form in which a pH adjusting agent or buffer is added to improve the stability of the active ingredient. The pH adjusting/buffering agent can be a basic amino acid, which has an amino group and alkaline characteristics (isoelectric point, pl: 7.59-10.76) such as, for example, L-arginine , 1-lysine or L-histidine. A buffering agent within the meaning of the present invention is L-arginine. L-arginine has a particularly suitable stabilizing effect in the compositions of the present invention, for example, by suppressing chemical degradation of compounds of formula 3.

[00150] Thus, in one embodiment, the present invention is directed to a pharmaceutical composition (e.g., a solid oral dosage form, particularly a tablet) which comprises a compound of formula 3 and L-arginine to stabilize the composition, particularly against chemical degradation; as well as one or more pharmaceutical excipients.

[00151] - Suitably, the pharmaceutical excipients used in the present invention are conventional materials such as cellulose and derivatives thereof, D-mannitol, corn starch, pregelatinized starch as a filler material, copovidone as a binder, crospovidone as a disintegrant , magnesium stearate as a lubricant, colloidal anhydrous silica as a glidant, hypromelose as a film coating agent, polyethylene glycol as a plasticizer, titanium dioxide, red/yellow iron oxide as a pigment, and talc, etc.

[00152] In detail, pharmaceutical excipients can be a first and a second diluent, a binder, a disintegrant and a lubricant; an additional disintegrant and an additional slider are another option.

* Suitable diluents for a pharmaceutical composition according to the invention are powdered cellulose, microcrystalline cellulose, lactose in various crystalline modifications, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, erythritol, dihydrate of dibasic cellulose, erythritol, hydroxypropyl cellulose with low degree of substitution, mannitol, starch or modified starch (for example, pregelatinized or partially hydrolyzed) or xylitol. Among these diluents, mannitol and microcrystalline cellulose are used in some cases.

* Diluents that are used as the second diluent are the aforementioned diluents, mannitol and microcrystalline cellulose.

* Suitable lubricants for a pharmaceutical composition according to the invention are talc, polyethylene glycol, calcium behenate, calcium stearate, sodium stearyl fumarate, hydrogenated castor oil or magnesium stearate. The lubricant, in some cases, is magnesium stearate.

* Suitable binders for a pharmaceutical composition according to the invention are copovidone (copolymerizates of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, hydroxypropyl-hydroxypropyl stearic-palmityl acid (L-HPC), copovidone and pregelatinized starch being used in some formulations. The aforementioned pregelatinized starch and L-HPC binders show additional diluent and disintegrant properties and can also be used as the second diluent or the disintegrant.

* Suitable disintegrants for a pharmaceutical composition according to the present invention are corn starch, crospovidone, potassium polacrylin, croscarmellose sodium, low substitution degree hydroxypropylcellulose (L-HPC) or pregelatinized starch; such as croscarmellose sodium.

* As an optional glidant, colloidal silicon dioxide can be used.

[00153] “An exemplary composition according to the present invention comprises mannitol as a diluent, microcrystalline cellulose as a diluent with additional disintegrating properties, copovidone, croscarmellose sodium as a disintegrant and magnesium stearate as a lubricant.

Typical pharmaceutical compositions comprise (% by weight) 10 to 50% of active ingredient 20 to 88% of diluent 1, to 50% of diluent 2, 1 to 5% of binder, 1 to 15% of disintegrant and 0.1 to 5% lubricant.

[00155] Pharmaceutical compositions according to some modalities comprise (% by weight) 50% of active ingredient to 75% of diluent 1, 5 to 30% of diluent 2, 2 to 30% of binder 1 to 12% of disintegrant and 0.1 to 3% lubricant

[00156] Pharmaceutical compositions according to some modalities comprise (% by weight)

10 to 90% active ingredient to 70% thinner 1, 5 to 30% thinner 2, 0 to 30% binder 1 to 12% disintegrant and 0.1 to 3% lubricant

[00157] Pharmaceutical compositions according to some modalities comprise (% by weight) 50% of active ingredient to 75% of diluent 1.5 to 30% of diluent 2, 2 to 30% of binder 0.5-20% of buffering agent, 1 to 12% of disintegrant and 0.1 to 3% of lubricant

[00158] Pharmaceutical compositions according to some modalities comprise (% by weight) to 70% of active ingredient 20 to 75% of diluent 1, 5 to 30% of diluent 2, 2 to 30% of binder 0.5 to 20 % buffering agent, 1 to 12% disintegrant and 0.1 to 3% lubricant

[00159] “Pharmaceutical compositions that contain 10 to 90% of active ingredient, such as 30 to 70% of active ingredient (% by weight), are used in some cases.

[00160] A tablet formulation according to the invention may be uncoated or coated, for example film coated, using suitable coatings known to not negatively affect the dissolution properties of the final formulation. For example, tablets can be provided with a sealing layer to protect against the environment of the patient and clinical staff, as well as for protection from moisture, when dissolving a high molecular weight polymer such as polyvinylpyrrolidone or hydroxypropyl methylcellulose, together with plasticizers, lubricants and pigments optionally and surfactants in water or an organic solvent such as acetone, and spraying this mixture onto the tablet cores within a coating equipment such as a coater pot or a fluid bed coater with a wurster device.

[00161] In addition, agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, film-forming polymers such as hydroxypropylcellulose, ethylcellulose, and polymeric methacrylates can be applied to tablets, provided that the coating has no substantial effect on the disintegration/dissolution of the dosage form and that the stability of the coated dosage form is not affected.

[00162] After the dosage form is film coated, a sugar coating can be applied over the sealed pharmaceutical dosage form. The sugar coating can comprise sucrose, dextrose, sorbitol and so on or mixtures thereof. If desired, colorants or opacifiers can be added to the sugar solution.

The solid formulations of the present invention tend to be hygroscopic. They can be packaged using PVC blisters, PVDC blisters or a moisture-proof packaging material such as aluminum foil blisters, alu/alu blisters, clear or opaque polymer blisters with pouch, polypropylene tubes , glass bottles and HDPE bottles optionally having a child resistant element or can be tamper proof. The primary packaging material can comprise a desiccant, such as a molecular sieve or silica gel, to improve the chemical stability of the API. Opaque packaging such as colored blister materials, tubes, brown glass vials or the like can be used to prolong the life of the API by reducing photodegradation. and. Dosages

A dosage range of the compound of formula 3 is generally between 100 and 1000 mg, in particular between 200 and 900 mg, 300 and 900 mg or 350 and 850 mg or 390 and 810 mg. It is possible to administer one or two tablets where, in some cases, two tablets for a daily oral dose of 100, 200, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800 , 850, 900 mg and in some cases 350, 400 450, 750, 800, 850 are employed.

[00165] The dosage range can be reached by one tablet or by two tablets; in some cases, two tablets are administered, each containing half the dosage.

[00166] The application of the active ingredient can occur up to three times a day, such as once or twice a day. Particular dosage intensities are 400 mg or 800 mg. f. Terms Used and Definitions

Terms not specifically defined in this document shall be given the meanings that would be given to them by those skilled in the art in light of the invention and context. As used in the specification, however, unless otherwise specified, the following terms have the indicated meaning and the following conventions are associated with them.

[00168] The term "about" means 5% plus or minus the specified value. Thus, about 100 minutes can also be understood as between 95 and 105 minutes.

[00169] In the case where a compound of the present invention is represented in the form of a chemical name and, as a formula, in the case of any discrepancy, the formula shall prevail. An asterisk can be used in subformulas to indicate the bond that is connected to the core molecule, as defined.

[00170] Unless specifically indicated, throughout the descriptive report and in the appended claims, a given formula or chemical name shall encompass tautomers and all stereomers, optical and geometric isomers (for example, enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof, as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers or mixtures of any of the above forms, where such isomers and enantiomers exist, as well as salts, including salts pharmaceutically acceptable compounds thereof, and solvates thereof such as, for example, hydrates, including solvates of the free compounds or solvates of a salt of the compound.

[00171] The term "substituted", as used herein, means that any one or more hydrogens in the designated atom is replaced by a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and that the replacement results in a stable compound.

The term "optionally substituted" means, within the scope of the invention, the aforementioned group optionally substituted by a lower molecular group. Examples of chemically significant lower molecular groups are groups consisting of 1 to 200 atoms. Of interest are groups that have no negative effect on the pharmacological efficacy of the compounds. For example, the groups can comprise: * Straight or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups.

* Aromatic or non-aromatic ring systems which consist of carbon atoms and optionally heteroatoms which, in turn, can be substituted by functional groups.

* Various aromatic or non-aromatic ring systems which consist of carbon atoms and optionally heteroatoms which can be linked through one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.

The compounds described herein may exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of salts may be useful in the preparation and purification of the subject compound. Basic addition salts can also be formed and be pharmaceutically acceptable. For a more complete description of the preparation and selection of salts see Pharmaceutical Salts: Properties, Selection and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt", as used herein, represents salts or zwitterionic forms of the compounds described herein which are soluble or dispersible in water or oil and therapeutically acceptable as defined herein. Salts can be prepared during the final isolation and purification of the compounds or by separately reacting the appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphor, camphor sulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulphate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, iodate, 2-hydroxyethanesulphonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulphonate, methanesulphonate, naphthylenesulphonate, nicota- lenesulphonate, 2-naphthate , pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate ) and undecanoate. In addition, basic groups in the compounds described in this document can be quaternized with methyl, ethyl, propyl, butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids which may be employed to form therapeutically acceptable addition salts are inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, and organic acids such as oxalic, maleic, succinic and citric. Salts can also be formed by coordinating the compounds with an alkali or alkaline earth metal ion. Therefore, the present invention considers the sodium, potassium, magnesium and calcium salts of the compounds described in this document and so on.

[00175] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or an organic amine primary, secondary or tertiary. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine , tributylamine, N,N-dimethylaniline, — N-methylpiperidine, — N-methylmorpholine, — dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,P-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[00176] While it may be possible for the compounds of the present invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations comprising one or more of certain compounds described herein or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, together with one or more pharmaceutically acceptable carriers. acceptable and optionally one or more other therapeutic ingredients. The vehicle(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. The proper formulation depends on the chosen route of administration. Any of the well known techniques, vehicles and excipients can be used as appropriate and understood in the art; for example, in Remington's Pharmaceutical Sciences. The pharmaceutical compositions described herein may be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, tableting, levigating, emulsifying, encapsulating, entrapping or compression.

[00177] "Heterocyclic rings" ("het") include saturated or unsaturated heterocyclic rings of five, six or seven elements or heterobicyclic rings of 5 to 10 elements which may contain one, two or three heteroatoms, selected from oxygen, sulfur and nitrogen; the ring may be attached to the molecule through a carbon atom or, if present, a nitrogen atom. The following are examples of five-, six-, or seven-membered, saturated or unsaturated heterocyclic rings: N-O. N' o Ss N N N

DOLDLONOUDOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO-----

SO Ko

[00178] Unless otherwise stated, a heterocyclic ring may be provided with a keto group. Examples include: o o [e] o [o] N WO We o Ss -s No nÁÃ, N NO NO Q Ly (so, Ls o

[00179] Examples of 5- to 10-membered heterobicyclic rings are pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine, N N S

N N N N OD US OR CP N N

[00180] Although the term heterocyclic rings includes aromatic heterocyclic groups, the term heterocyclic aromatic groups ("hetaryl") denotes heterocyclic aromatic groups of five or six elements or bicyclic hetaryl rings of 5 to 10 elements that may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, which contain enough conjugated double bonds to form an aromatic system. The ring can be attached to the molecule through a carbon atom or, if present, through a nitrogen atom. The following are examples of five- or six-membered heterocyclic aromatic groups:

[00181] Examples of bicyclic hetaryl rings of 5 to 10 elements include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pterididine , pyrimidopyrimidine.

[00182] The term "halogen", as used herein, means a halogen substituent selected from fluorine, chlorine, bromine or iodine.

[00183] By the term "C 1-6 alkyl" (including those that are part of other groups) is meant branched and unbranched alkyl groups having 1 to 6 carbon atoms and by the term "C1+4 alkyl" is meant - gives branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are present in some cases. Examples thereof include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopropyl, neopentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. can also optionally be used for the aforementioned groups. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, etc.

[00184] By the term "C1.6-alkylene" (including those that are part of other groups) is meant branched and unbranched alkylene groups having 1 to 6 carbon atoms and by the term "C1-« alkylene-

in" is understood both branched and unbranched alkylene groups having 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are present in some cases. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene , 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene 1,3-dimethylpropylene or hexylene. As stated, the definitions propylene, butylene, pentylene and hexylene also include all possible isomeric forms of the relevant groups with the same carbon number. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1 ,1-dimethylethylene, 1,2-dimethylethylene.

[00185] The term "C2. alkenyl (including those that are part of other groups) indicates branched and unbranched alkenyl groups having 2 to 6 carbon atoms and the term "C2.4 alkenyl" indicates branched and unbranched alkenyl groups branched with 2 to 4 carbon atoms, provided they have at least one double bond. In some cases, alkenyl groups with 2 to 4 carbon atoms are employed. Examples include: ethenyl or vinyl, propenyl, butenyl , pentenyl or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propernyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2-and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.

[00186] By the term "C2. alkenylene" (including those that are part of other groups) is meant branched and unbranched alkenylene groups having 2 to 6 carbon atoms and by the term "C2.4-alkenylene" is meant groups branched and unbranched alkylene having 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are present in some cases. Examples in-

include: ethenylene, propenylene, 1-methylethylene, butenylene, 1-methylpropenylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1, 3-dimethylpropenylene or hexenylene. Unless otherwise stated, the definitions propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the respective groups with the same carbon number. Thus, for example, propenyl also includes 1-methylethylene and butenylene includes 11-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

[00187] By the term "C2.6 alkynyl" (including those that are part of other groups) is meant branched and unbranched alkynyl groups having 2 to 6 carbon atoms and by the term "C>2.4-alkynyl" is meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms are available, provided they have at least one triple bond. Alkynyl groups with 2 to 4 carbon atoms are present in some cases. Examples include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless otherwise stated, the definitions propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the respective groups. thus, for example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2-and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

[00188] By the term "C2. alkynylene" (including those that are part of other groups) is meant branched and unbranched alkynylene groups having 2 to 6 carbon atoms and by the term "C2.4-alkynylene" is meant groups branched and unbranched alkylene having 2 to 4 carbon atoms. Alkynylene groups with 2 to 4 carbon atoms are present in some cases. Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene ,

1,3-dimethylpropynylene or hexinylene. Unless otherwise stated, the definitions propynylene, butynylene, pentynylene and hexynylene include all possible isomeric forms of the respective groups with the same carbon number. Thus, for example, propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

[00189] The term "Cz.s-cycloalkyl" (including those that are part of other groups), when used herein, means cyclic alkyl groups having 3 to 8 carbon atoms where, in some cases, such groups are cyclic alkyl groups having 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[00190] By the term "C1.6 haloalkyl" (including those that are part of other groups) is meant branched and unbranched alkyl groups having 1 to 6 carbon atoms in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, such as fluorine and chlorine, eg fluorine. By the term "C1.4 haloalkyl" is meant correspondingly branched and unbranched alkyl groups having 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced analogously to that specified above. C14 haloalkyl is present in some cases. Examples include: CH2F, CHF>2, CF3.

[00191] The term "Cr1.r-alguila", where n is an integer from 2 to an, individually or in combination with another radical, indicates an acyclic, saturated, branched or linear hydrocarbon radical with 1 an C atoms. For example, the term C1-+5 alkyl encompasses the radicals H3C-, H3C-CH2-, H30-CH2-CH2-, H30-CH(CHs3)-, H3C-CH2-CH2-CH2-, H3C -CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H30-CH2-CH2-CH(CH3)- , H;C-CH>2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, Ha3C-C

(CH3)2-CH2-, H3GC-CH(CH3)-CH(CH3)-and H3C-CH2-CH(CH2CH3)-.

[00192] The term"Cir-haloalkyl", where n is an integer from 2 to n, individually or in combination with another radical, indicates an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms , in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, such as fluorine and chlorine, for example, fluorine Examples include: CH2F, CHF>2, CF3.

[00193] The term "Cryr-alkylene", where n is an integer from 2 to n, individually or in combination with another radical, indicates a divalent acyclic, linear or branched alkyl radical containing from 1 to n atoms of carbon. For example, the term C1-a alkylene includes -CH2-, -CH2-CH>2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3) -, -CH(CH3a)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH>-, -CH2-CH2-CH(CH3)-, — -CH(CH3)-CH2 -CH2-, — -CH2-CH(CH3)-CH>-, -CH2-C(CH3)2-, -C(CH3)-CH>-, -CH(CH3)-CH(CHs3)-, -CH2-CH(CH2CH3)-, — -CH — (CH2CH3)-CH2-, — -CH(CH2CH2CHs3)-, -CH(CH(CH3)).-and -C(CH3)(CH2CH;3)- .

[00194] The term "C>.r-alkenyl" is used for a group as defined in the definition for "C1-n-alkyl" having at least two carbon atoms, if at least two such carbon atoms of said group are linked together through a double bond.

[00195] The term "C>.r-alkynyl" is used for a group as defined in the definition for "C1-n-alkyl" having at least two carbon atoms, if at least two such carbon atoms of said group are linked together through a triple bond.

[00196] The term "Cz-r-cycloalkyl", where n is an integer from 4 to an, individually or in combination with another radical, indicates a cyclic, saturated, unbranched hydrocarbon radical with 3 an atoms of C. For example, the term C3-;cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[00197] It should be noted that, as used in this document and the appended claims, the singular forms "a, a", and "o, a" include plural references, unless the context clearly indicate otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "peptide" includes reference to one or more peptides and equivalents thereof, e.g., polypeptides, known to those skilled in the art. in technique, and so on.

[00198] By "an individual who is suffering from or at risk of suffering from cognitive impairment associated with aging" is meant an individual who has exceeded more than 50% of their predicted life expectancy, such as more than 60%, by For example, more than 70%, such as more than 75%, 80%, 85%, 90%, 95% or up to 99% of the expected life expectancy. The age of the individual will depend on the species in question. Thus, this percentage is based on the expected life expectancy of the species in question. For example, in human beings, such an individual is 50 years or older, for example, 60 years or more, 70 years or more, 80 years or more, 90 years or more and, in general, is not older than 100 years old, such as 90 years old, that is, ages between about 50 and 100, for example, 50... 55... 60... 65)... 70... 75... 80...85...90...95....100 years of age or older or any age between 50 and 100 who is suffering from an age-associated condition, as described below, for example , cognitive damage associated with the natural aging process; an individual who is about 50 years of age or older, for example, 60 years or older, 70 years or older, 80 years or older, 90 years or older and generally not older than 100 years ie aged between 50 and 100, for example, 50... 55... 60... 65)... 70... 75...

80... 85... 90... 95... 100 years of age, who has not yet started to show symptoms of a condition associated with aging, eg cognitive impairment; an individual of any age who is suffering from cognitive impairment due to an age-associated disease, as also described below, and an individual of any age who has been diagnosed with an age-associated disease which is usually accompanied by cognitive impairment, where the individual has not yet begun to show symptoms of cognitive impairment. Corresponding ages for non-human subjects are known and are intended to apply in this document.

[00199] “As summarized elsewhere, in some cases the individual is a mammal. Mammalian species that can be treated with the present methods include canines and felines; horses; cattle; sheep; etc., and primates, including humans. The methods, compositions and reagents can also be applied to animal models, including small mammals, for example, murine, lakemorphs, etc., for example, in experimental investigations.

[00200] — As used herein and described above, "treatment" refers to any (i) prevention of the disease or disorder or (ii) reduction or elimination of symptoms of the disease or disorder. Treatment can be carried out prophylactically (before disease onset) or therapeutically (after disease onset). The effect can be prophylactic in terms of total or partial prevention of a disease or symptom thereof and/or it can be therapeutic in terms of partial or complete cure of a disease and/or adverse effect attributable to the disease. Thus, the term "treatment", as used herein, encompasses any treatment of an aging-related disease or disorder in a mammal and includes: (a) preventing the disease from occurring in an individual who may be predisposed to the disease, but has not yet been diagnosed with ten-

of the same; (b) inhibit the disease, that is, stop its development; or (c) alleviating the disease, that is, causing regression of the disease. Treatment can result in a variety of different physical manifestations, eg modulation of gene expression, tissue or organ rejuvenation, etc. The therapeutic agent can be administered before, during or after the onset of illness. Treatment of ongoing disease, where the treatment stabilizes or reduces the patient's undesirable clinical symptoms, is of particular interest. Such treatment can be carried out before complete loss of function in the affected tissues. Therapy can be given during the symptomatic stage of the disease and, in some cases, after the symptomatic stage of the disease.

[00201] In some modalities, the condition treated is an impairment associated with aging of an individual's cognitive capacity. By cognitive ability or "cognition" is understood mental processes that include attention and concentration, learning of complex tasks and concepts, memory (acquisition, retention and retrieval of new information in the short and/or long term), information processing (dealing with information collected by the five senses), spatial vision function (visual perception, deep perception, use of mental images, copying drawings, building objects or shapes), production and understanding of language, verbal fluency (word search), problem solving, decision making and executive functions (planning and prioritization). By "cognitive decline" is meant a progressive decrease in one or more of these abilities, for example, a decline in memory, language, thinking, judgment, etc. By "impairment of cognitive ability" and "cognitive impairment" is meant a reduction in cognitive ability in relation to a healthy individual, eg healthy individuals of the same age or in relation to the individual's ability at an earlier time. , for example, 2 weeks, 1 month, 2 months, 3 months, 6 months, | year, 2 years, 5 years or 10 years or more. By "cognitive impairment associated with aging" is meant impairment of cognitive ability that is normally associated with aging including, for example, cognitive impairment associated with the natural aging process, for example, mild cognitive impairment (MC1. ); and cognitive impairment associated with an aging-associated disorder, that is, a disorder that is seen with increasing frequency with advancing senescence, eg, a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease , frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy, ataxia, associated frailty, and so on.

g. combinations

The compounds of general formula 1 can be used individually or in combination with other active substances of formula 1 according to the invention. The compounds of general formula 1 can also be optionally combined with other pharmacologically active substances. These include R2-adrenoceptor agonists (short and long acting), anticholinergics (short and long acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated glucocorticoidemimetics, PDE3 inhibitors, PDEA inhibitors, PDE7 inhibitors, LTDA antagonists, EGFR inhibitors, dopamine agonists, PAF antagonists, lipoxin A4 derivatives, FPRL1 modulators, LTB4 receptor antagonists (BLT1, BLT2), histamine receptor antagonists H1, histamine H4 receptor antagonists, dual histamine H1/H3 receptor antagonists, Pl3-kinase inhibitors, non-receptor tyrosine kinase inhibitors such as, for example,

plo, LYN, LOCK, SYK, ZAP-70, FYN, BTK or ITK, MAP kinase inhibitors such as, for example, p38, ERK1, ERK2, JNK1, JNK-2, JNK3 or SAP, signaling pathway inhibitors to NF-xB such as, for example, IKK2 kinase inhibitors, iNOS inhibitors, MRPA4 inhibitors, leukotriene biosynthesis inhibitors such as, for example, 5-lipoxygenase (5-LO) inhibitors, cPLA inhibitors ?2, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DP1 receptor modulators, thromboxane receptor antagonists, additional CCR3 antagonists, CCRA antagonists, antagonists of CCR1 antagonists, CCR5 antagonists, CCRG6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR3 antagonists, CXCRA4 antagonists, CXCR2 antagonists, CXCR1 antagonists, CXCR5 antagonists , CXCR6 antagonists, CX3CR3 antagonists, antagonist neurokinin (NK1, NK2) receptor modulators, sphingosine 1-phosphate inhibitors, sphingosine phosphatolyase 1 inhibitors, adenosine receptor modulators such as, for example, A2a agonists, purinergic receptor modulators such as, for example, P2X7 inhibitors, histone deacetylase (HDAC) activators, bradykinin antagonists (BK1, BK2), TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, converting enzyme inhibitors of interleukin 1 beta (ICE), Toll-like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonists, ENaC inhibitors, melanocortin receptor modulators (MC1R, MC2R, MC3R, MC4R, MC5R), CGRP antagonists, endothelin antagonists, TNFa antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti- CD46, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL antibodies -4, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/1L-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, anti-airway swelling compounds , cough suppressant compounds, VEGF inhibitors, but also combinations of two or three active substances.

[00203] In some embodiments, the other active substances are betamimetics, anticholinergics, corticosteroids, PDEA4 inhibitors, LTDA antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists and SYK inhibitors, but also combinations of two or three active substances ie: * —“Betamimetics with corticosteroids, PDEZA inhibitors, CRTH2 inhibitors or LTDA antagonists, * Anticholinergics with betaimetics, corticosteroids, PDEA inhibitors, CRTH2 inhibitors or LTDA antagonists, * Corticosteroids with PDEA4 inhibitors, CRTH?2 inhibitors or LTD4 antagonists * PDE4 inhibitors with CRTH2 inhibitors or LTDA antagonists.

* CRTH2 inhibitors with LTDA antagonists.

[00204] “In these modalities, the compounds that make up the combination are co-administered to an individual. The terms "co-administration" and "in combination with" include the administration of two or more therapeutic agents simultaneously, concomitantly or sequentially, with no specific time limits. In one modality, agents are present in the individual's cell or body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or in unit dosage form. in other mo-

Furthermore, the therapeutic agents are in separate compositions or unit dosage forms.

In certain embodiments, a first agent may be administered prior to (eg, minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks before), concomitantly with or subsequent to (eg, 5 minutes, 15 minutes , 30 minutes, 45 minutes), 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after) administration of a second therapeutic agent. "Concurrent administration" of a known therapeutic drug with a pharmaceutical composition of the present invention means administering the compound and the second agent at a time when both the known drug and the composition of the present invention will have a therapeutic effect. .

Such concomitant administration may involve simultaneous administration (i.e., at the same time), prior to or subsequent to the drug in relation to administration of an individual compound.

The routes of administration of the two agents can vary, where representative routes of administration are described in more detail below.

Those skilled in the art will have no difficulty in determining the appropriate timing, sequence, and dosages of administration for particular drugs and compounds of the present invention.

In some embodiments, the compounds (e.g., a target compound and at least one additional compound) are administered to the subject within twenty-four hours of each other, such as within 12 hours of each other, within 6 hours of each other. each other, within 3 hours of each other or within 1 hour of each other.

In certain embodiments, compounds are administered within 1 hour of each other.

In from-

In all embodiments, the compounds are administered substantially simultaneously. By substantially simultaneous administration is meant that the compounds are administered to the individual within about 10 minutes or less of each other, such as 5 minutes or less or 1 minute or less of each other.

[00205] An "add-on diagnostic" or "additional diagnostic device" means an in vitro diagnostic device or an imaging tool that provides essential information for the safe and effective use of a corresponding therapeutic product. of an in vitro complementary diagnostic device with a specific therapeutic product is stipulated in the instructions for use on the label of the device and corresponding therapeutic product, as well as on the label of any generic equivalents and biosimilar equivalents of the therapeutic product.

[00206] The complementary diagnostic test can be in several ways including, by way of example and not by way of limitation: screening test of family genetic patterns and conditions of difficult diagnosis; prognostic tests that predict the future course of a disease; therapeutic testing to indicate a patient's response to a prescribed therapy; monitoring tests that assess the efficacy and appropriate dosage of a prescribed therapy; and recurrence tests that assess a patient's risk of disease recurrence. See Agarwal A. et al., Pharmgenomics Pers Med. 8: 99-110 (2015), which is hereby incorporated by reference in its entirety. H. dosage forms

Preparations suitable for administering the compounds of formula 1 and the cocrystal or salt forms of formulas 2 and 2a include, for example, tablets, capsules, suppositories, solutions and powders, etc. The content of the pharmaceutically active compound(s) should be in the range of 0.05 to 90% by weight, such as 0.1 to 50% by weight of the composition as a whole. Suitable tablets can be obtained, for example, by mixing the active substance(s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents to delay release such as carboxymethylcellulose, cellulose acetate phthalate or acetate polyvinyl. Tablets can also comprise multiple layers.

[00208] “Consequently, coated tablets can be prepared by coating cores produced analogously to tablets with substances commonly used for tablet coatings, for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core can also consist of several layers. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the aforementioned excipients for the tablets.

[00209] - Syrups or elixirs containing the active substances or combinations thereof according to the invention may furthermore contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, for example such a flavoring like vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[00210] Solutions are prepared in the usual way, for example,

with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants whereas, if water is used as a diluent, for example, organic solvents can optionally be used as solubilizers or dissolution aids and the solutions can be transferred to injection vials, ampoules or infusion vials.

[00211] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers, such as lactose or sorbitol, and packaging them in gelatine capsules.

[00212] — Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

[00213] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), vegetable oils (eg peanut or sesame oil), mono or polyhydric alcohols. onals (eg ethanol or glycerol), carriers such as, for example, natural mineral powders (eg kaolin, clay, talc, chalk), synthetic mineral powders (eg silicic acid and highly dispersed silicates), sugars ( for example cane sugar, lactose and glucose), emulsifiers (eg lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate ).

[00214] For oral use, tablets may obviously contain, in addition to the specified carriers, additives such as sodium citrate.

Indium, calcium carbonate and dicalcium phosphate, together with various additional substances such as starch, for example, potato starch, gelatin and so on. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used to make the tablets. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or colorants, in addition to the aforementioned excipients.

For administering the compounds of formula 1 or the cocrystal or salt forms of formulas 2 and 2a, pharmaceutical preparations or formulations which are suitable for inhalation may be employed. Inhalable preparations include inhalable powders, metered dose aerosols containing propellant or propellant-free inhalable solutions. Within the scope of the present invention, the term propellant-free inhalable solutions also includes ready-to-use sterile inhalable or concentrated solutions. The formulations that can be used within the scope of the present invention are described in greater detail in the following part of the descriptive report.

Inhalable powders which can be used according to the invention may contain a compound of formula 1 or a cocrystal or salt form of formulas 2 and 2a, alone or in admixture with suitable physiologically acceptable excipients.

[00217] If active substances of the compounds of formula 1 or of the cocrystal or salt forms of formulas 2 and 2a are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders accordingly with the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol) , salts (eg sodium chloride, calcium carbonate) or mis-

of these excipients. In some cases, mono- or disaccharides are used, such as lactose or glucose, for example, in the form of its hydrates, for example, lactose, such as lactose monohydrate.

[00218] Within the scope of inhalable powders according to the invention, excipients have a maximum average particle size of up to 250 µm, such as between 10 and 150 µm, and including between 15 and 80 µm. Sometimes it may seem appropriate to add finer excipient fractions with an average particle size of up to 1 to 9 µm to the aforementioned excipient. These finer excipients are also selected from the group of possible excipients listed above. Finally, in order to prepare the inhalable powders according to the invention, the micronized active substance of the compounds of the formula 1 or the cocrystal or salt forms of the formulas 2 and 2a, such as with an average particle size of 0.5 to 10 µm, including 1 to µm, is added to the excipient mixture. Processes for the production of inhalable powders according to the invention by means of milling and micronization and finally mixing the ingredients together are known from the state of the art.

Inhalable powders according to the invention can be administered using inhalers known from the state of the art.

Inhalation aerosols containing propellant gas according to the invention may contain a compound of formula 1 or a cocrystal or salt form of formula 2 and 2a dissolved in the propellant gas or in dispersed form. The compounds of formula 1 or the cocrystal or salt forms of formulas 2 and 2a may be contained in separate formulations or in a common formulation in which they are both dissolved, both dispersed or, in each case, only one component is dissolved and the other is dispersed. Gases pro-

Pellets which can be used to prepare inhalation aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above propellant gases can be used individually or mixed. In some cases, propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

[00221] Inhalation aerosols activated by propellants may also contain other ingredients, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH regulators. All these ingredients are known in the art.

The aforementioned propellant-actuated inhalation aerosols according to the invention can be administered using inhalers known in the art (MDIs = metered dose inhalers).

[00223] Furthermore, the active substances of the compounds of the formula 1 or of the cocrystal or salt forms of the formulas 2 and 2a according to the invention can be administered in the form of inhalable solutions and suspensions free of propellants. The solvent used can be an aqueous or alcoholic one, such as an ethanolic solution. The solvent can be water itself or a mixture of water and ethanol. The relative proportion of ethanol compared to water is not limited, but the maximum is in some cases up to 70 percent by volume, such as up to 60 percent by volume and including up to 30 percent by volume . The remainder of the volume is made up of water. Solutions or suspensions containing a compound of formula 1 or a cocrystal or salt form of formulas 2 and 2a are adjusted to a pH of 2 to 7, such as 2 to 5, using suitable acids. The pH can be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, etc. In some cases, inorganic acids are hydrochloric and sulfuric acids. It is also possible to use acids that have already formed an acid addition salt with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are used in some cases. If desired, mixtures of the above acids can be used, particularly in the case of acids that have properties other than their acidifying qualities, for example, as flavourings, antioxidants or complex-forming agents such as citric acid or ascorbic acid, for example. According to the invention, in some cases, hydrochloric acid is used to adjust the pH.

[00224] If desired, the addition of edetic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complex-forming agent, can be omitted in these formulations. Other embodiments may contain this compound or these compounds. In one embodiment, the content, based on sodium edetate, is less than 100 mg/100 ml, such as less than 50 mg/100 ml, and including less than 20 mg/100 ml. Inhalable solutions in which the sodium edetate content is 0 to 10 mg/100 ml are used in some cases. Co-solvents and/or other excipients may be added to propellant-free inhalable solutions, such as those containing hydroxyl groups or other polar groups, for example alcohols - particularly isopropyl alcohol, glycols - particularly propylene glycol, polyethylene glycol, polypropylene glycol , glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives, in this context, indicate any pharmacologically acceptable substance that is not an active substance, but which can be formulated with the active substance or substances in a physiologically suitable solvent in order to improve the qualitative properties of the formulation of the active substance. In some embodiments, these substances have no pharmacological effect or, in relation to the desired therapy, no appreciable or at least undesirable pharmacological effect. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that secure or extend the shelf life of the finished pharmaceutical formulation, flavors, vitamins and/or other additives known in the art. Additives also include pharmacologically acceptable salts, such as sodium chloride, as isotonic agents.

[00225] In some embodiments, excipients include antioxidants such as ascorbic acid, for example, as long as it has not already been used to adjust pH, vitamin A, vitamin E, tocopherols, and similar vitamins and provitamins that occur in the Human Body.

[00226] Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are those that are known in the art, particularly acetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate, in the concentration known from the prior art. The aforementioned preservatives may be present in concentrations of up to 50 mg/100 ml, such as between 5 and mg/100 ml.

[00227] In some embodiments, the formulations contain, in addition to the solvent water and the compounds of formula 1 or the co-crystal or salt forms of formulas 2 and 2a, only benzalkonium chloride and sodium edetate. In one modality, no sodium edetate is present.

[00228] The dosage of the compounds according to the invention is, of course, highly dependent on the method of administration and on the illness being treated. When administered by inhalation, the compounds of formula 1, the cocrystal or salt forms of formulas 2 and 2a are characterized by high potency, even at doses in the µg range. Compounds of formula 1 or the cocrystal or salt forms of formulas 2 and 2a can also be used effectively above the µg range. The dosage can then be in the gram range, for example.

[00229] In another aspect, the present invention relates to the aforementioned pharmaceutical formulations, such as those which are characterized by containing a compound of formula 1 or a cocrystal or salt form of formulas 2 and 2a, particularly the formulas - aforementioned pharmaceuticals which can be administered by inhalation.

[00230] The following examples of formulations illustrate the present invention without restricting its scope: i. Examples of Pharmaceutical Formulations A) Tablets per tablet active substance 1, 2 or 2a 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

[00231] The finely ground active substance, lactose and part of the corn starch are mixed. The mixture is sieved and then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, remaining cornstarch and magnesium stearate are sieved and blended together. The mixture is compressed into tablets of the proper shape and size. B) Tablets per tablet active substance 1, 2 or 2a 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

[00232] The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and worked with the remaining corn starch and water to form a granulate which is dry and sifted. Sodium carboxymethyl starch and magnesium stearate are added and mixed and the mixture is compressed to form tablets of suitable size. C) Active substance 1, 2 or 2 ampoule solution 50 mg sodium chloride 50 mg water for injection 5 ml

[00233] The active substance is dissolved in water on its own

PH or optionally at a pH of 5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions to ampoules which are then sterilized and thermally sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. D) Metered dose aerosol active substance 1, 2 or 2a 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and TG134a: TG227 2:1 ad. 100

[00234] The suspension is transferred to a conventional aerosol container with metering valve. Preferably, 50 ul of suspension is released on each trigger. The active substance can also be released in higher doses if desired (eg 0.02 % by weight). E) Solutions (in mg/100ml) active substance 1, 2 or 2a 333.3 mg benzalkonium chloride 10.0 mg EDTA 50.0 mg HCI (1N) adpH2.4

[00235] This solution can be prepared in the usual way. F) Inhalable powder active substance 1, 2 or 2a 1249 lactose monohydrate ad 25 mg

[00236] The inhalable powder is prepared in the usual way by mixing the individual ingredients. . Indications

Methods are provided to improve cognition or other symptoms of cognitive illness by treating an individual/patient diagnosed with an illness associated with cognition.

Aspects of the methods include modulation of CCR3, for example, with a CCR3 modulating agent, sufficient to treat the patient for cognition-associated disease.

The methods include treating the cognition-associated disorder with an orally administrable and bioavailable composition, including a formula 1 compound composition, a cocrystal or salt of formula 2 or 2a, or a formula 3 formulation, described above. .

As summarized above and described in more detail below, a variety of injuries associated with aging, for example, diseases associated with cognitive development, can be treated through the embodiments of the invention.

In some cases, the target condition is a cognition-associated pathological condition that is associated with neurodegeneration, for example, as evidenced by neural damage, such as one of more than reduced neurodegeneration, for example, as manifested by reduced cell numbers positive for BrdU or EdU, positive cells for Ki67 and positive cells for Dex when compared to non-diseased tissues.

The composition that modulates CCR3 can be administered to a patient/individual diagnosed with a disease associated with cognition, such as (by way of example and not limitation): mild cognitive impairment (MCI); Alzheimer's disease; Parkinson's disease; frontotemporal dementia (FTD); Huntington's disease; amyotrophic lateral sclerosis (ALS); multiple sclerosis (MS); glaucoma; myotonic dystrophy; insanity; progressive supranuclear palsy (PSP); ataxia; atrophy of multiple systems; and fragility; which are described further below.

The methods of the invention may further comprise monitoring improvement in neurodegenerative disease progression by measuring cognitive or physical improvement.

[00238] Methods are provided to improve motor coordination, function or other symptoms of motor disorders through the treatment of an individual/patient diagnosed with motor disorders. Aspects of the methods include modulating CCR3, for example, with a CCR3 modulating agent, sufficient to treat the patient with a motor disorder. The methods include treating the motor disorder with an orally administrable and bioavailable composition, including a formula 1 compound composition, a cocrystal or salt of formula 2 or 2a, or a formula 3 formulation described above. As summarized above and described in more detail below, a variety of damage associated with aging, for example, motor disorders, can be treated through the embodiments of the invention. In some cases, the target condition is a motor disorder that is associated with neurodegeneration, for example, as evidenced by neural damage, such as reduced neurodegeneration, for example, as manifested by the reduced number of BrdU-positive cells or EdU, Ki67 positive cells and Dcx positive cells when compared to non-diseased tissues. The composition that modulates CCR3 can be administered to a patient/individual diagnosed with a motor disorder, such as (by way of example and not limitation): Parkinson's disease; Parkinsonism; dementia with Lewy bodies; ataxia; dystonia; cervical dystonia; Korea; Huntington's disease, multiple systems atrophy; spasticity; progressive supranuclear palsy; tardive dyskinesia; Tourette's syndrome; and trembling; which are also described below. The methods of the invention may further comprise monitoring improvement in the progression of a neurodegenerative disease by measuring cognitive or physical improvement. Mild Cognitive Damage (M.C.l.)

[00239] This is a modest disruption of cognition that manifests as problems with memory or other mental functions, such as planning, following instructions or making decisions that have worsened over time, whereas general mental function and daily activities do not are harmed. Thus, although significant neuronal death does not typically occur, neurons in the aging brain are vulnerable to age-related sublethal changes in structure, synaptic integrity, and molecular processing at the synapse, which impair cognitive function. Individuals who suffer from or are at risk of developing an aging-associated cognitive impairment who will benefit from treatment with the target compounds of the invention, for example by the methods described herein, also include individuals of any age who suffer from an impairment. cognitive due to a disorder associated with aging; and individuals of any age who have been diagnosed with an aging-associated disorder that is often accompanied by cognitive impairment, where the individual has not yet begun to experience symptoms of cognitive impairment. Examples of such aging-associated disorders include, without limitation, those listed below. Alzheimer's disease

[00240] Alzheimer's disease is characterized by a progressive and inexorable loss of cognitive function associated with an excessive number of senile plaques in the cerebral cortex and subcortical gray matter, in addition to excessive B-amyloid and neurofibrillary tangles which consist of tau protein. The common form affects people >60 years and its incidence increases with advancing age. It is responsible for over 65% of dementias in the elderly.

[00241] The caused of Alzheimer's disease is not known. The disease runs in families in about 15 to 20% of cases. The cases of-

sporadic nominates remaining have some genetic associations. The disease has an autosomal dominant genetic pattern, in most cases of early onset and in some cases of late onset, however, with variable penetration at the end of life. Environmental factors are the focus of active investigation.

[00242] Over the course of the disease, synapses and finally neurons are lost within the cerebral cortex, hippocampus and subcortical structures (including selective cell loss in the basal nucleus of Meynert), locus coeruleus and nucleus raphae dorsalis. Glucose use and cerebral perfusion are reduced in some areas of the brain (parietal lobe and temporal cortices in early-stage disease, prefrontal cortex in advanced-stage disease). Neurotic or senile plaques (composed of neurites, astrocytes, glial cells surrounding an amyloid nucleus) and neurofibrillary tangles (composed of paired helical filaments) play a role in the pathogenesis of Alzheimer's disease. Senile plaques and neurofibrillary tangles occur with normal aging but are much more prevalent in people with Alzheimer's disease. Parkinson's disease

[00243] Parkinson's disease (PD) is an idiopathic, slowly progressive degenerative disorder of the CNS, characterized by slow and diminished movement (bradykinesia), muscle rigidity, resting tremor (dystonia), muscle freezing and postural instability. Originally considered primarily a motor disorder, PD is now recognized to cause depression and emotional changes as well. PD can also affect cognition, behavior, sleep, autonomic function and sensory function. The most common cognitive impairments include impairment of attention and concentration, working memory, executive function, language production, and spatial vision function. A feature of PD are symptoms related to reduced motor function that usually precede those related to cognitive impairment, which aids in the diagnosis of the disease.

[00244] In primary Parkinson's disease, the pigmented neurons of the substantia nigra, locus coeruleus, and other groups of brainstem dopaminergic cells degenerate. The cause is not known. The loss of neurons in the substantia nigra, which project to the caudate nucleus and putame, results in depletion of the neurotransmitter dopamine in these areas. Onset usually occurs after age 40 years, with increasing incidence in older age groups.

[00245] Parkinson's disease has recently been diagnosed in about 60,000 Americans each year and currently affects approximately one million Americans. Although PD itself is not fatal, its complications are the fourteenth leading cause of death in the United States. Currently, PD cannot be cured and treatment is usually prescribed to control symptoms, with surgery later prescribed in severe cases.

[00246] Treatment options for PD include administration of pharmaceuticals to help manage motor impairments. These options augment or replace the neurotransmitter dopamine, of which PD patients have low brain concentrations. Such medications include: carbidopa/levodopa (which creates more dopamine in the brain); apomorphine, pramipexolol, ropinirole and rotingotine (dopamine agonists); selegiline and rasagiline (MAO-B inhibitors that prevent dopamine breakdown); entacapone and tolcapone (Catechol-O-methyltransferase [COMT] inhibitors that deliver more levodopa to the brain); benztropine and trihexyphenidyl (anticholinergics); and amantadine (controls tremor and stiffness). Exercise/physiotherapy is also commonly prescribed to help maintain physical and mental function.

[00247] Current treatment options, however, treat the symptoms.

but of PD, are not curative and fail to prevent disease progression. Furthermore, current medications tend to lose effectiveness in advanced PD. The most prescribed drug, levodopa, usually results in adverse effects within 5 to 10 years of starting medication. These adverse effects can be severe and can result in motor fluctuations and unpredictable swings in motor control between doses, as well as seizures/spasms (dyskinesia) that are difficult to manage and are as disabling as the symptoms of the PD itself. Thus, there is still a need for new therapies with new mechanisms of action that can be administered together or in combination with current PD medications.

Parkinsonism

[00248] Secondary parkinsonism (also known as atypical Parkinson's disease or Parkinson's addiction) results from loss of or interference with the action of dopamine in the basal ganglia due to other idiopathic degenerative diseases, drugs, or exogenous toxins. The most common cause of secondary parkinsonism is ingestion of antipsychotic drugs or reserpine, which produce parkinsonism by blocking dopamine receptors. Less common causes include carbon monoxide or manganese poisoning, hydrocephalus, structural lesions (tumors, infarcts that affect the midbrain or basal ganglia), subdural hematoma, and degenerative disorders, including nigrostriatal degeneration. Certain disorders such as Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD) and Lewy Body Dementia (DLB) may exhibit symptoms of parkinsonism before the necessary cardinal symptoms specific diagnosis can be verified, and, therefore, can be labeled as "Parkinsonism".

PD Progression Assessment

[00249] Several rating scales have been used to assess the progression of PD. The most widely used scales include the Unified Parkinson's Disease Rating Scale (UPDRS, which was introduced in 1987) (J. Rehabil Res. Dev., 2012 49 (8): 1269-76) and the Hoehn scale and Yahr (Nerrology, 1967 17(5): 427-42). Additional scales include the updated Movement Disorder Society (MDS) UPDRS scale (MDS-UPDRS) as well as the Schwab and England Activities of Daily Living (ADL) scale.

[00250] The UPDRS scale assesses 31 items that contributed to three subscales: (1) mentation, behavior and mood; (2) activities of daily living; and (3) motor examination. The Hoehn and Yahr scale classifies PD into five stages with distinct substages: O -no signs of disease; 1 - symptoms on one side only; 1.5 - symptoms on one side, but also involving neck and spine; 2 - symptoms on both sides without balance damage; 2.5 - mild symptoms on both sides, with recovery when the "pull" test is performed; 3 - balance damage with mild to moderate disease; 4 - severe disability, but ability to walk or stand without assistance; and 5 -need a wheelchair or bedridden without assistance. The Schwab and England scale ranks the PD at various percentages (100% - completely independent to 10% - fully dependent). Frontotemporal dementia

[00251] Frontotemporal dementia (FTD) is a condition resulting from the progressive deterioration of the frontal lobe of the brain. Over time, degeneration can progress to the temporal lobe. Losing only Alzheimer's disease (AD) in prevalence, FTD accounts for % of pre-senile dementia cases. Symptoms are classified into three groups based on frontal and temporal lobe functions.

ral affected:

[00252] Behavioral variant FTD (bvFTD), with symptoms including lethargy and spontaneity on the one hand and disinhibition on the other; non-fluent progressive aphasia (PNFA), in which a break in speech fluency is observed due to difficulties in articulation, phonological and/or syntactic errors, but the comprehension of the words is preserved; and semantic dementia (DS), in which patients remain fluent with normal phonology and syntax but have increasing difficulty naming and understanding words. Other cognitive symptoms common to all patients with FTD include impaired executive function and the ability to focus. Other cognitive abilities, including perception, spatial abilities, memory and practice normally remain intact. FTD can be diagnosed by observing atrophy of the frontal and/or anterior temporal lobe on structural MRI scans.

[00253] There are several forms of FTD, any of which can be treated or prevented using the present methods and compositions. For example, one form of frontotemporal dementia is Semantic Dementia (SD). DS is characterized by a loss of semantic memory in both the verbal and non-verbal domains. Patients with DS usually complain of difficulty in finding words. Clinical signs include fluent aphasia, anomie, impaired understanding of word meanings, and associative visual agnosia (the inability to match images or related objects semantically). As the disease progresses, behavioral and personality changes are often seen, similar to those seen in frontotemporal dementia, although cases of 'pure' semantic dementia with few late behavioral symptoms have been described. Structural MRI imaging shows a characteristic pattern of atrophy in the temporal lobes (predominantly).

left), with lower involvement greater than superior and atrophy of the anterior temporal lobe greater than the posterior.

[00254] As another example, another form of frontotemporal dementia is Pick's disease (PiD, also PwD). A defining feature of the disease is the accumulation of tau proteins in neurons, accumulating in spherical, silver-stained aggregations known as "Pick bodies." Symptoms include loss of speech (aphasia) and dementia. Patients with orbitofrontal dysfunction can become aggressive and socially inappropriate.

[00255] They may steal or demonstrate obsessive or repetitive stereotyped behaviors. Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or diminished spontaneity. Patients may demonstrate an absence of self-monitoring, abnormal self-awareness, and an inability to appreciate meaning.

[00256] Patients with loss of gray matter in the posterolateral bilateral orbitofrontal cortex and right anterior insula may demonstrate changes in eating behaviors such as pathological gluttony. Patients with more focal gray matter loss in the anterolateral orbitofrontal cortex may develop hyperphagia. Although some of the symptoms may initially be relieved, the disease progresses and patients usually die within two to ten years. Huntington's Disease

[00257] Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities; loss of intellectual or cognitive functioning; and movement abnormalities (motor disorders). The classic signs of HD involve the development of chorea - involuntary, fast, irresponsible movements.

gular and abrupt that can affect the face, arms, legs or trunk - as well as cognitive decline, including the gradual loss of thought processing and acquired intellectual capacities. There may be memory damage, abstract thinking and judgment; inappropriate perceptions of time, place, or identity (disorientation); increased agitation; and personality changes (personality disintegration). Although symptoms typically become evident during the fourth or fifth decade of life, the age of onset is variable and ranges from infancy to late adulthood (eg, 70 or 80 years).

[00258] AHD is transmitted within families as an autosomal dominant trait. The disorder occurs as the result of abnormally long sequences or "repeats" of instructions encoded within a gene on chromosome 4 (4p16.3). The progressive loss of nervous system function associated with HD results from the loss of neurons in certain areas of the brain, including the basal ganglia and cerebral cortex. Amyotrophic lateral sclerosis

[00259] Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurological disease that attacks motor neurons. Muscle weakness and atrophy and signs of anterior horn cell dysfunction are first noticed more frequently in the hands and less frequently in the feet. The starting location is random and the progression is asymmetric. Cramps are common and can precede weakness. Rarely does a patient survive 30 years; 50% die within 3 years of onset, 20% live 5 years and % live 10 years.

[00260] — Diagnostic aspects include onset during mid to late adult life and progressive generalized motor involvement without sensory changes. Nerve conduction velocities are normal until the end of the disease. Recent studies have documented the presentation of cognitive impairments, as well as particularly a reduction in immediate verbal memory, visual memory, language and executive function.

[00261] “A decrease in cell body area, number of synapses and total synaptic length has been reported even in the normal looking neurons of patients with ALS. It has been suggested that when the plasticity of the active zone reaches its limit, a continual loss of synapses can lead to functional damage. Promoting the formation or loss of new synapses or preventing synapses from maintaining neuronal function in these patients. Multiple sclerosis

[00262] Multiple sclerosis (MS) is characterized by various symptoms and signs of CNS dysfunction, with remissions and recurrent exacerbations. The most common symptoms present are paresthesia in one or more extremities, on the trunk or on one side of the face; weakness or clumsiness of a leg or hand; visual disturbances, for example, partial blindness and pain in one eye (retrobulbar optic neuritis), darkness of vision, or scotomas. Common cognitive impairments include memory impairment (acquisition, retention and retrieval of new information), attention and concentration (particularly divided attention), information processing, executive functions, visuospatial functions, and verbal fluency. Common initial symptoms are ocular paralysis resulting in double vision (diplopia), transient weakness of one or more extremities, mild stiffness or unusual fatigability of a limb, minor gait disturbances, difficulty in bladder control, dizziness, and emotional disturbances. light; all indicating dispersed CNS involvement and usually occur months or years before the disease is recognized. Excessive heat can accentuate symptoms and signs.

[00263] The course is highly varied, unpredictable and, in most patients, sender. At first, months or years of remission can separate episodes, especially when the disease starts with retrobulbar optic neuritis. However, some patients have frequent attacks and are rapidly incapacitated; for some, the course can be rapidly progressive. Glaucoma

[00264] Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs). Evidence supports the existence of compartmentalized degeneration programs in synapses and dendrites, including in RGCs. Recent evidence also indicates a correlation between cognitive impairment in the elderly and glaucoma (Yochim BP et al. Prevalence of Cognitive Impairment, Depression and Anxiety Symptoms Among Older Adults with Glaucoma. J. Glaucoma. 2012; 21(4) : 250-254). myotonic dystrophy

[00265] Myotonic dystrophy (MD) is an autosomal dominant multisystem disorder characterized by dystrophic muscle weakness and myotonia. The molecular defect is an expanded trinucleotide repeat (CTG) in the 3' untranslated region of the myotonin protein kinase gene on chromosome 19qg. Symptoms can occur at any age and the range of clinical severity is wide. Myotonia is prominent in the muscles of the hands and ptosis is common even in mild cases. In severe cases, marked peripheral muscle weakness occurs, usually with cataracts, premature baldness, hatchet facies, cardiac arrhythmias, testicular atrophy, and endocrine abnormalities (eg, diabetes mellitus). Mental retardation is common in severe congenital forms, whereas an aging-related decline in frontal and temporal cognitive functions, particularly in language and executive functions, is observed in the milder adult forms of the disorder. Severely affected people die in their 50s. Insanity

[00266] Dementia describes a class of disorders that have symptoms that affect thinking and social skills severe enough to interfere with daily functioning. Other cases of dementia, in addition to the dementia seen in advanced stages of the aging-associated disorders discussed above, include vascular dementia and dementia with Lewy bodies, described below.

[00267] In vascular dementia or "dementia with multiple infarcts", cognitive damage is caused by problems in the blood supply to the brain, typically through a series of minor strokes or sometimes a major stroke preceded or followed by other smaller strokes. Vascular lesions can be the result of diffuse cerebrovascular disease, such as small vessel disease or focal lesions, or both. Patients suffering from vascular dementia have cognitive impairment, either acute or subacute after an acute cerebrovascular event, after which a progressive cognitive decline is observed. Cognitive damage is similar to that seen in Alzheimer's, including damage to language, memory, complex visual processing, or executive function, although the related changes in the brain are not due to AD pathology but to chronic reduced blood flow in AD. brain, eventually resulting in dementia. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging can be used to confirm the diagnosis of multiple infarct dementia in conjunction with assessments that involve mental state examination. Dementia with Lewy Bodies

[00268] Lewy body dementia (DLB), also known under a variety of other names, including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and Lewy-type senile dementia , is a type of dementia anatomically characterized by the presence of Lewy bodies (clusters of alpha-synuclein and ubiquitin proteins) in neurons, detectable in brain histology after death. Its main feature is cognitive decline, particularly in executive functioning. Attention and short-term memory will increase and decrease.

[00269] —Persistent or recurrent visual hallucinations, with vivid and detailed images, are often an early diagnostic symptom. DLB is often confused in its early stages with Alzheimer's and/or vascular dementia, although where Alzheimer's usually starts gradually, DLB usually has a rapid or acute onset. DLB symptoms also include motor symptoms similar to those of Parkinson's disease. DLB is distinguished from the dementia that sometimes occurs in Parkinson's disease by the length of time the dementia symptoms appear relative to the Parkinson's symptoms. Parkinson's disease with dementia (PDD) would be the diagnosis when the onset of dementia is more than a year after the onset of Parkinson's disease. DLB is diagnosed when cognitive symptoms begin at the same time or within a year of Parkinson's symptoms.

[00270] The treatment of DLB is a complex process and requires a multifaceted approach. (Neurology, 2017, 89: 1-13). Typical therapies for parkinsonism, such as dopaminergic and anticholinergic drugs, can exacerbate symptoms of cognition and behavior. Optimal treatment usually uses both: pharmacological approaches (exercise, cognitive training, and mentoring training.

by caregivers) and non-pharmacological. For cognitive symptoms, acetylcholinesterase inhibitors can be administered (eg, rivastigmine, donepezil) as well as the NMDA receptor antagonist memantine. For neuropsychiatric symptoms, acetylcholinesterase inhibitors can improve apathy and hallucinations. Antipsychotics, unfortunately, increase the risk of mortality in patients with DLB. Motor symptoms are less responsive to dopaminergic treatments in patients with DLB and may exacerbate the risk of psychosis. Levodopa can be used, but only at low threshold doses, so there is a distinct need in the field for new agents to treat DLB.

Progressive Supranuclear Palsy

[00271] Progressive supranuclear palsy (PSP) is a brain disorder that causes serious and progressive problems in gait control and balance, in addition to complex eye movements and thinking problems. One of the classic signs of the disease is the inability to aim the eyes properly, which occurs due to damage to the area of the brain that coordinates eye movements. Some individuals describe this effect as a blur. Affected individuals usually show changes in mood and behavior, including depression and apathy, as well as mild progressive dementia. The long name of the disorder indicates that the disease starts slowly and continues to worsen (progressively) and causes weakness (paralysis), damaging certain parts of the brain above pea-sized structures called nuclei, which control eye movement. (supranuclear). PSP was first described as a distinct disorder in 1964 when three scientists published a paper that distinguished the condition from Parkinson's disease. It is sometimes called Steele-Richardson-Olszewski syndrome, reflecting the names with-

combinations of the scientists who defined the disorder. Although PSP gets progressively worse, no one dies from PSP itself. ataxia

[00272] People with ataxia have coordination problems as parts of the nervous system that control movement and balance are affected. Ataxia can affect the fingers, hands, arms, legs, body, speech and eye movements. The word ataxia is often used to describe a symptom of incoordination that may be associated with infections, injuries, other diseases or degenerative changes in the central nervous system. Ataxia is also used to indicate a group of specific degenerative diseases of the nervous system called hereditary and sporadic ataxias, which are the main emphases of the National Ataxia Foundation's. Multiple Systems Atrophy

[00273] Multiple systems atrophy (MSA) is a degenerative neurological disorder. MSA is associated with degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance, and other autonomic functions of the body, such as bladder control or blood pressure regulation.

[00274] The caused MSA is unknown and no specific risk factors have been identified. About 55% of cases occur in men, with a typical age from onset in the late 50s to early 60s. MSA usually has some of the same symptoms as Parkinson's. However, patients with MSA generally show minimal, if any, responses to the dopamine medications used in Parkinson's disease. dystonia

[00275] —Adystonia is a condition that involves sustained involuntary muscle contractions. Such contractions can exhibit movement.

twisted and repetitive movements. This disorder can affect the entire body or specific parts of the body, called generalized dystonia or focal dystonia (respectively). Cervical dystonia can cause intermittent or lasting contractions of the neck muscles. There is no cure for dystonia. Current therapies include carbido-pa-levodopa, trihexyphenidyl, benztropine, tetrabenazine, diazepam, clonazepam, baclofen, physical therapy, speech therapy, stretching, massage, and invasive surgery. Fragility

[00276] Frailty Syndrome ("Fragility") is a geriatric syndrome characterized by functional and physical decline, including decreased mobility, muscle weakness, physical sluggishness, low endurance, low physical activity, malnutrition and involuntary loss of Weight. This decline is often accompanied as a consequence of diseases such as cognitive dysfunction and cancer. However, frailty can occur even without illness. Individuals who suffer from frailty are at increased risk of a negative prognosis due to fractures, accidental falls, disability, comorbidity and premature mortality. (C. Buigues, et al. Effect of a Prebiotic Formulation on Frailty Syndrome: A Randomized, Double-Blind Clinical Trial, Int. J. Mol. Sci. 2016, 17, 932). In addition, individuals suffering from frailty have an increased incidence of higher healthcare costs. (Id.)

[00277] Common frailty symptoms can be determined by certain types of tests. For example, unintentional weight loss involves a loss of at least 10 pounds or more than 5% of body weight in the past year; muscle weakness can be determined by reduced grip strength by 20% more than baseline (adjusted for gender and BMI); physical slowness can be based on the time needed to walk a distance of 15 feet; low resistance can be determined by the individual's self-report of exhaustion; and low physical activity can be measured using a standardized questionnaire (Z. Palace et al., The Fragilty Syndrome, Today's Geriatric Medicine 7(1), 18 (2014)).

[00278] In some embodiments, the present methods and compositions are useful for slowing the progression of cognitive, motor, or other age-related impairment associated with aging. In other words, the individual's cognitive, motor or other abilities will decrease more slowly after treatment using the described methods than before or in the absence of treatment using the described methods. In some cases, treatment methods measure the progression of decline in cognitive, motor, or other age-related ability after treatment and determine that the progression of decline is slowed. In some cases, the determination is made by comparison with a reference, for example, the rate of decline in the individual before treatment, for example, as determined by the measurement of cognitive, motor or other skills related to the age before of two or more time points prior to administration of the present blood product.

[00279] The present methods and compositions are also useful in stabilizing the cognitive, motor or other abilities of an individual, for example, an individual suffering from cognitive decline associated with aging or an individual at risk of suffering from cognitive decline associated with aging . For example, the individual may demonstrate some cognitive impairment associated with aging and the progression of cognitive impairment observed before treatment with the methods described will be stopped after treatment by the methods described. As another example, the individual may be at risk of developing an aging-associated cognitive decline (for example, the individual may be 50 years or older or may have been diagnosed with an aging-associated disorder) and the individual's cognitive abilities are suboptimal. - tangentially unaltered, that is, no cognitive decline can be detected after treatment using the described methods compared to before treatment with the described methods.

[00280] The present methods and compositions are also useful in reducing cognitive, motor, or other age-related impairment in an individual who is suffering from an aging-associated impairment. In other words, the affected capacity is improved in the individual after treatment by means of the present methods. For example, the cognitive ability in the individual is increased, for example, by 2 times or more, 5 times or more, 10 times or more, 15 times or more, 20 times or more, 20 times, 30 times or more or 40 times or more, including 50 times or more, 60 times or more, 70 times or more, 80 times or more, 90 times or more, or 100 years or more after treatment with the present methods in relation to ha - cognitive ability observed in the individual before treatment using the present methods.

[00281] In some cases, treatment by the present methods and compositions restores cognitive, motor or other capacity in the individual who is suffering from cognitive or motor decline associated with aging, for example, to its level when the individual was approximately 40 years old or younger. In other words, cognitive or motor damage is nullified. k. Methods of Diagnosis and Monitoring for the Improvement of Diseases Associated with Neurodegeneration

[00264] Those of skill in the art will recognize that, among the variety of methods for diagnosing and monitoring disease progression and improvement in disease associated with neurodegeneration, the following types of assessments can be used individually or in combination with individuals who are suffering from a neurodegenerative disease. The following types of methods are presented as examples and are not limited to the cited methods. Those skilled in the art will recognize that other methods of monitoring the disease will be useful in the practice of the invention. These methods are also contemplated by the methods of the invention. i. general cognition

The methods of the invention further comprise methods of monitoring the effect of a drug or treatment on an individual for the treatment of cognitive impairment and/or age-related dementia, the method comprising comparing cognitive function before and after treatment . Those skilled in the art recognize that there are well known methods of assessing cognitive function. For example, and without limitation, the method may comprise assessing cognitive function based on medical history, family history, physical and neurological examinations by clinicians specializing in dementia and cognitive function, laboratory examinations, and neuropsychological assessment. Additional modalities considered by the invention include: assessment of consciousness, such as the use of the Glasgow Coma Scale (EMV); mental state examination, including abbreviated mental test score (AMTS) or mini mental state examination (MMSE) (Folstein et al., J. Psychiatr. Res 1975; 12: 1289-198); global assessment of superior functions; estimation of intracranial pressure, such as by funduscopy.

[00266] In one modality, examinations of the peripheral nervous system can be used to assess cognitive function, including any of the following: smell, visual fields and acuity, eye movements and pupils (sympathetic and parasympathetic), sensory function of the face, strength of the muscles of the face and shoulder girdle, hearing, pa-

barking, pharyngeal movement and reflex, tongue movements, which can be tested individually (eg, visual acuity can be tested by a Snellen chart; a reflex hammer used to test reflexes, including masseter, biceps, and triceps tendon, knee tendon, ankle and plantar flexion (ie, Babinski's sign); muscle strength often on the 1-5 MRC scale; muscle tone and signs of stiffness. ii. Multiple Sclerosis

[00267] In addition to monitoring the improvement of symptoms associated with cognition, the progression or improvement of neurodegeneration associated with multiple sclerosis (MS) can be monitored using methods well known to those skilled in the art. By way of example and not by way of limitation, monitoring can be performed using techniques such as: monitoring the cerebrospinal fluid (CSF); magnetic resonance (MR) to detect lesions and development of demyelinating plaques; evoked potential studies; and gait monitoring.

[00268] The analysis of the CSF can be performed, for example, through a lumbar puncture to obtain the pressure, appearance and content of the CSF. Normal values generally vary as follows: pressure (70 to 180 mm H2); appearance is clear and colorless; total protein (15 to 60 mg/100 ml); IgG is 3 to 12% of the total protein; glucose is 50 to 80 mg/100 ml; cell count is 0 to 5 white blood cells and no red blood cells; chloride (110 to 125 mEq/L). Abnormal results may indicate the presence or progression of MS.

[00269] MRI is another technique that can be performed to monitor the progression and improvement of the disease. Typical criteria for monitoring MS with MRI include the appearance of irregular areas of abnormal white matter in the cerebral hemisphere and paraventricular areas, lesions present in the cerebellum and/or brainstem, as well as in the cervical or thoracic regions of the spinal cord. spinal.

[00270] Evoked potentials can be used to monitor the progression and improvement of MS in individuals. Evoked potentials measure the latency of electrical impulses, such as in Visual Evoked Response (VER), Brainstem Auditory Evoked Responses (BAER) and Somatosensory Evoked Responses (SSER). Abnormal responses help to indicate that there is a decrease in conduction speed in the central sensory pathways.

[00271] Gait monitoring can also be used to monitor disease progression and improvement in individuals with MS. MS is often accompanied by impaired mobility and abnormal gait due, in part, to fatigue. Monitoring can be carried out, for example, with the use of mobile monitoring devices used by individuals (Moon, Y,, et al., Monitoring gait in multiple sclerosis with novel wearable motion sensors, PLOS One, 12 ( 2): e0171346 (2017)). iii. Huntington's Disease

[00272] In addition to monitoring the improvement of symptoms associated with cognition, the progression or improvement of neurodegeneration associated with Huntington's disease (HD) can be monitored using methods well known to those skilled in the art. By way of example and not as a limitation, monitoring can be performed using techniques such as: motor function; behavior; functional assessment; and imaging.

[00273] Examples of motor functions that can be monitored as an indication of disease progression or improvement include chorea and dystonia, stiffness, bradykinesia, oculomotor dysfunction, and changes in gait/balance. Methods to perform monitoring of these metrics are well known to those skilled in the art.

ca (see Tang C, et al., Monitoring Huntington's disease progression through preclinical and early stages, Neurodegener Dis Manag 2 (4): 421-35 (2012)).

[00274] The psychiatric effects of HD present opportunities to monitor the progression and improvement of the disease. For example, psychiatric diagnoses can be performed to determine if the individual is suffering from depression, irritability, agitation, anxiety, apathy, and psychosis with paranoia (/d.)

[00275] Functional assessment can also be used to monitor the progression or improvement of the disease. Total functional scoring techniques have been reported (/d.) and often decrease by one point per year in some HD groups.

[00276] MRI or PET can also be used to monitor the progression or improvement of the disease. For example, there is a loss of striatal projection neurons in HD and the increase in the number of these neurons can be monitored in individuals. Techniques for determining neuronal changes in individuals with HD include Dopamine D receptor binding imaging. (1d.) iv. ALS

[00277] In addition to monitoring the improvement of symptoms associated with cognition, the progression or improvement of neurodegeneration associated with Amyotrophic Lateral Sclerosis (ALS) can be monitored using techniques well known to those skilled in the art. By way of example and not as a limitation, monitoring can be carried out through techniques such as: functional assessment; determination of muscle strength; measurement of respiratory function; measurement of lower motor neuron (LMN) loss; and measurement of upper motor neuron dysfunction (UMN).

[00278] Functional assessment can be performed using a functional scale well known to those skilled in the art, such as the ALS Functional Rating Scale (ALSFRS-R), which assesses symptoms related to bulbar, limb, and respiratory function. - ratory. The rate of change is useful to predict survival as well as disease progression or improvement. Another measure includes the Combined Function and Survival Assessment (CAFS), which ranks the clinical outcomes of individuals by combining survival time with change in ALSFRS-R. (Simon N.G. et al., Quantifying Disease Progression in Amyotrophic Lateral Sclerosis, Ann Neurol 76:643-57 (2014)).

[00279] Muscle strength can be tested and quantified through the use of the Manual Muscle Testing (MMT) composite score. This involves mean measurements obtained from various muscle groups using the Medical Research Council (MRC) Muscle Strength Rating Scale (/d.) Portable dynamometry (HHD) can also be used, among other techniques (/d. ).

[00280] Respiratory function can be determined using portable spirometric units used to obtain the forced vital capacity (FVC) at baseline to predict disease progression or improvement. In addition, maximal inspiratory pressure, nasal inspiratory aspiration pressure (SNIP) and FVC pressure can be determined and used to monitor disease progression/improvement. (Id.)

[00281] The loss of lower motor neurons is another metric that can be used to monitor disease progression or improvement in ALS. The Neurophysiological Index can be determined by measuring composite muscle action potentials (CMAPs) in motor nerve conduction studies, whose parameters include CMAP amplitude and F wave frequency. (/(d. and de Carvalho M) , et al., Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve 23: 344-352, (2000).) A smaller number of motor neuron units (MUNE) can also be estimated. number of residual motor axons that supply a muscle by estimating the contribution of individual motor units to maximal CMAP response and is used to determine disease progression or improvement (Simon NG,, et al., Supra Additional techniques for determining LMN loss include testing nerve excitability, electrical impedance myography, and use of muscle ultrasound to detect changes in muscle thickness. (Id.)

[00282] Upper motor neuron dysfunction is another metric that can be used to monitor disease progression or improvement in ALS. Techniques to determine dysfunction include performing MRI or PET scans of the brain and spinal cord, transcranial magnetic stimulation; and determination of the levels of biomarkers in the cerebrospinal fluid (CSF). v. Glaucoma

[00283] In addition to monitoring the improvement of symptoms associated with cognition, the progression or improvement of glaucoma-associated neurodegeneration can be monitored using methods well known to those skilled in the art. As an example and not as an imitation, monitoring can be carried out through techniques such as: determination of intraocular pressure; evaluation of the optic disc or optic nerve head for damage; visual field test for loss of peripheral vision; and optical disc and retinal imaging for topographic analysis. saw. Progressive Supranuclear Palsy (PSP)

[00284] In addition to monitoring the improvement of symptoms associated with cognition, the progression or improvement of neurodegeneration associated with Progressive Supranuclear Palsy (PSP) can be monitored using methods well known to those skilled in the art. By way of example and not as a limitation, monitoring can be performed using techniques such as: functional assessment (activities of daily living or ADL); motor assessment; determination of psychiatric symptoms; and volumetric and functional magnetic resonance imaging (MRI).

[00285] An individual's level of function in terms of independence, partial dependence on others, or complete dependence may be useful in determining disease progression or improvement (see Duff, K. et al., Functional Impairment in Progressive Supranuclear Palsy, Neurology 80: 380-84, (2013)). The Progressive Supranuclear Palsy Rating Scale (PSPRS) is a rating scale comprising twenty-eight metrics in six categories: daily activities (by history); behavior; bulbar, ocular motor, limb motor and gait/midline. The result is a score that ranges from 0 to 100. Six items are rated from 0 to 2 and twenty-two items from 0 to 4 for a possible total of 100. PSPRS scores are measured practices and robust predictors of patient survival. They are also sensitive to disease progression and useful in monitoring disease progression or improvement. (Golbe LI, et al., A Clinical Rating Scale for Progressive Supranuclear Palsy, Brain 130:1552-65, (2007)).

[00286] The ADL section of the UPDRS (Unified Parkinson's Disease Rating Scale) can also be used to quantify functional activity in individuals with PSP (Duff K. et al., Supra). Likewise, the Schwab & England Activities Daily Living Score (SE-ADL) can be used to assess independence. (/d.) In addition, the motor function sections of the UPDRS are useful as a reliable measure to assess disease progression in patients with PSP. The motor section can contain, for example, 27 di-

to quantify motor function in patients with PSP. Examples of these include rest tremors, stiffness, tapping fingers, posture and gait). The progression or improvement of an individual's disease can also be assessed by performing a baseline neuropsychological assessment completed by trained medical personnel, the assessment using the Neuropsychiatric Inventory (NPI) to determine the frequency and severity of behavioral abnormalities (eg, delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, and abnormal motor behavior). (ld.)

[00287] Functional MRI (fMRI) can also be employed to monitor disease progression and improvement. MRI is a technique that uses magnetic resonance imaging to measure changes in brain activity in certain regions of the brain, usually based on blood flow to those regions. Blood flow is considered to be correlated with activation of the brain region. Patients with neurodegenerative disorders such as PSP may undergo physical or mental testing before or during an MRI scanner. As an example and not as a limitation, the tests can be a well-established force control paradigm, in which patients are asked to produce force with the hand most affected by PSP and the maximum voluntary contraction (MVC) it is measured by fMRI immediately after performing the test. Burciu, R.G. et al., Distinct Patterns of Brain Activity in Progressive Supranuclear Palsy and Parkinson's Disease, Mov. Disorder (9): 1248-58 (2015)).

[00288] AMRI is a technique in which MRI scanners determine volume differences in regional brain volume. This can be done, for example, by contrasting different disorders or determining differences in volume in a region of the brain.

bral in a patient over time. Volumetric magnetic resonance imaging can be used to determine disease progression or improvement in neurodegenerative disorders such as PSP. The technology is well known to those skilled in the art. (Messina D. et al., Patterns of Brain Atrophy in Parkinson's Disease, Progressive Supranuclear Palsy and Multiple System Atrophy, Parkinsonism and Related Disorders, 17(3): 172-76 (2011)). Examples of brain regions that can be measured include, but are not limited to, intracranial volume, cerebral cortex, cerebellar cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, lateral ventricles, third ventricle, fourth ventricle, and cerebrostem. brazil vii. neurogenesis

[00289] Non-invasive techniques to assess neurogenesis have been reported (Tamura Y. et al., J. Neurosci. (2016) 36(31): 8123-31). Positron emission tomography (PET) used with the tracer, ['S?F]IFLT, in combination with the BBB transporter inhibitor probenecid, allows tracer accumulation in neurogenic regions of the brain. Such an image allows an assessment of neurogenesis in patients undergoing treatment for a neurodegenerative disease. viii. Parkinson's Disease and Motor Function

[00290] Several rating scales have been used to assess the progression of PD. The most used scales include the Unified Parkinson's Disease Rating Scale (UPDRS, which was introduced in 1987) (J. Rehabil. Res. Dev., 2012 49 (8): 1269-76) and the Hoehn scale and Yahr (Neurology, 1967 17(5): 427-42). Additional scales include the updated Society Disorder Movement (MDS) UPDRS scale (MDS-UPDRS) as well as the Schwab and En- gland Activities of Daily Living (ADL) scale.

[00291] The UPDRS scale assesses 31 items that contributed to three subscales: (1) mentation, behavior and mood; (2) activities of daily living; and (3) motor examination. The Hoehn and Yahr scale classifies PD into five stages with distinct substages: O - no signs of disease; 1 - symptoms on one side only; 1,5 - symptoms on one side, but also involving the neck and spine; 2 - symptoms on both sides without balance damage; 2.5 - mild symptoms on both sides, with recovery when the traction test is performed; 3 - balance damage with mild to moderate disease; 4 - severe disability, but ability to walk or stand without assistance; and 5 - need a wheelchair or bedridden without assistance. The Schwab and England scale classifies the PD at various percentages (100% - fully independent 10% - fully dependent).

[00292] General motor function can be assessed using widely used scales, including the General Motor Function Scale (GMF). This tests three components: dependency, pain and insecurity. (Aberg A.C. et al. (2003) Disabil. Rehabil. May 6, 2003; 25(9): 462-72). Motor function can also be assessed using home monitoring or portable sensors. For example: gait (speed of locomotion, variability, leg stiffness) can be detected with an accelerometer; posture (trunk leaning) by a gyroscope; the movement of the legs by an accelerometer; the movement of the hands by an accelerometer and gyroscope; tremor (amplitude, frequency, duration, asymmetry) by an accelerometer; falling by an accelerometer; the frozen march by an accelerometer; dyskinesia by an accelerometer, gyroscope and inertial sensors; bradykinesia (duration and frequency) by an accelerometer plus gyroscope; and aphasia (tuning) using a microphone. (Pastorino M. et al., Journal of Physics: Conference Series 450 (2013) 012055).

1. Reagents, Devices and Kits

[00282] “Reagents, devices and kits are also provided for the practice of one or more of the methods described above. The present reagents, devices and kits thereof can vary widely. Reagents and devices of interest include those recited in connection with methods of administering the compounds for formula 1 to the subject.

[00283] In addition to the above components, these kits will also include instructions for practicing the present methods. Such instructions may be present in the kits in a variety of forms, one or more of which may be present in the kit. One way in which such instructions can be present is as information printed on a suitable medium or substrate, for example, a piece or pieces of paper on which the information is printed, in the kit packaging, in a booklet informative, etc. Yet another medium would be a computer readable medium, eg floppy disk, CD, portable flash drive, etc., on which the information has been written. Yet another medium that may be present is a website address that can be used via the internet to access information on a remote website. Any convenient medium can be present in the kits. VII. Examples

[00284] The following examples are provided by way of illustration and not limitation. The. Pharmaceutical Preparation

[00285] Pharmaceutical compositions that are administered to individuals who have a cognitive or neurodegenerative disorder that are composed of the compounds, co-crystals and salts described above can be synthesized, manufactured and formulated using the examples described in United States Patent Application Publication United Nos. 2013/0266646, 2016/0081998, United States Patent Nos. 8,278,302, 8,653,075, RE 45323, 8,742,115, 9,233,950 and

8,680,280, which are hereby incorporated herein by reference in their entirety. Furthermore, pharmaceutical compositions can be prepared as described in the examples below:

1. Tablet formulation - wet granulation

[00286] Copovidone is dissolved in ethanol at room temperature to produce a granulation liquid. An active antagonistic ingredient of CCR3, lactose and part of the crospovidone are mixed in a suitable blender to produce a premix. The premix is moistened with the granulating liquid and subsequently granulated. The wet granulate is optionally sieved through a sieve with a mesh size of 1.6 to 3.0 mm. The granules are dried at 45°C in a suitable dryer to a residual moisture content corresponding to 1 to 3% loss on drying. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm. The granules are mixed with part of the crospovidone and microcrystalline cellulose in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following composition for tablets can be obtained:

2. Tablet formulation - melt granulation

[00287] A CCR3 antagonist active ingredient, lactose, part mcc, polyethylene glycol, lactose and part crospovidone are mixed in a suitable blender to produce a premix. The premix is heated in a high-shear mixer and then granulated. The hot granules are cooled to room temperature and sieved through a sieve with a mesh size of 1.0 mm. The granules are mixed with part of the crospovidone and microcrystalline cellulose in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following composition for tablets can be obtained: pe io ie A

3. Tablet formulation - hot melt granulation

[00288] A CCR3 antagonist active ingredient, mannitol, polyethylene glycol and part of the crospovidone are mixed in a suitable mixer to produce a premix. The premix is heated in a high-shear mixer and then granulated. The hot granulate is cooled to room temperature and sieved through a sieve with a mesh size of 1.0 mm. The granulate is mixed with part of the crospovidone and mannitol in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following composition can be obtained:

4. Tablet formulation - hot melt extrusion

[00289] A CCR3 antagonist active ingredient and stearic-palmitic acid are mixed in a suitable blender to produce a premix. The premix is extruded in a twin screw extruder and subsequently granulated. The granulate is sieved through a sieve with a mesh size of 1.0 mm. The granules are mixed with mannitol and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following tablet composition can be obtained: Eseaao cemaothesus — fire — the

5. Tablet formulation - hot melt extrusion

[00290] A CCR3 antagonist active ingredient and stearic-palmitic acid are mixed in a suitable mixer to produce a premix. The premix is extruded into a twin screw extruder and subsequently granulated. The granulate is sieved through a sieve with a mesh size of 1.0 mm. The granules are directly filled into hard capsules. The following capsule composition can be obtained: your action

6. Tablet formulation - roller compaction

[00291] A CCR3 antagonist active ingredient, part of mannitol and crospovidone and magnesium stearate are mixed in a suitable blender to produce a premix. The premix is compacted with a roller compactor and subsequently granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granules are mixed with part of mannitol and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following composition for tablets can be obtained:

7. Tablet formulation - roller compaction

[00292] A CCR3 antagonist active ingredient and magnesium stearate are mixed in a suitable blender to produce a premix. The premix is compacted with a roller compactor and subsequently granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granules are mixed with mannitol and croscarmellose sodium in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following tablet composition can be obtained: mgltablet %ltablet Active ingredient 114,200 [666 | Magnesium Stearate 1,800 Total (granulate) 116,000 Magnesium Stearate 2,500

8. Tablet formulation - roller compaction

[00293] A CCR3 antagonist active ingredient and magnesium stearate are mixed in a suitable blender to produce a premix. The premix is compacted with a roller compactor and subsequently granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granules are mixed with microcrystalline cellulose and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after passing through a 1.0 mm sieve for disposal. Subsequently, the final blend is produced by final blending in a suitable blender and compressed into tablets. The following tablet composition can be obtained: mgltablet %ltablet

Active ingredient 114,200 [s6.6 | Magnesium Stearate 1,800 Total (granulate) 116,000 Magnesium Stearate 2,500

9. Formulation of coated tablets

[00294] “Tablet cores according to the aforementioned formulations can be used to produce film-coated tablets. Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at room temperature to produce a coating suspension. The tablet cores are coated with the coating suspension at a weight gain of about 3% to produce film-coated tablets. The following film coating composition can be obtained: pass — be e bw Purified water (volatile component) Fo Ee

RR b. Drug Formulation and Administration

[00295] The experimental product of the invention (Compound 1) was in accordance with the following chemical structure: Broad Bean)

OX

NO (HC), cr COMPOUND 1

[00296] Those of skill in the art would recognize that the compounds, co-crystals, salts and formulations described above in the sections above could also be used in these examples.

Compound 1 was available as 100 mg, 200 mg and 400 mg film-coated tablets with a biconvex, round or oval shape and an opaque red color. The tablets were produced by a dry granulation process and contained microcrystalline cellulose, hydrogen phosphate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide and iron oxide yellow as inactive ingredients. The placebo tablets corresponding to the experimental product were produced by a direct compression process and contained the same inactive ingredients. ç. Pre-Clinical Examples

1. Materials and Methods (a) Subcutaneous osmotic pump implantation

[00298] Alzet minipumps were filled, primed and numbered by mouse ID the day before implantation to allow priming at 37°C and to allow blindness of treatment. The pumps were implanted in the back, slightly posterior to the scapulae and slightly lateral to the midline. Mice were anesthetized with 3% to 5% isoflurane using a vaporizer and regulator in an induction chamber, then moved to the procedure area and equipped with a cone to maintain anesthesia in 1 to 3% isoflurane. An ophthalmic ointment was applied to the eyes to prevent drying. The mice were injected with 5 mg/kg meloxicam subcutaneously. The skin was removed from the incision area using small sharp scissors and the area was cleaned with alternating applications of 70% isopropanol and betadine. A 0.5 to 1 cm incision was made and a hemostat was inserted to spread the subcutaneous tissue to create a pouch for the pump. The bomb was inserted into the pouch and the wound closed with staples. All surgical tools were autoclaved before the first use on the day of surgery. Subsequently, the instruments were sterilized with a glass bead sterilizer between the animals. The mice were placed in a clean recovery cage placed partially on top of a heating pad until complete recovery and walking. The mice were tested for anesthesia induction by the toe pinch method and breath monitoring. The mice were monitored postoperatively every 15 minutes until recovery. The mice were given a second dose of meloxicam the following day. If signs of infection were observed, the mice received 5 mg/kg of Baytril subcutaneously per day until the infection disappeared.

(b) Open Field Test

[00299] The Open Field is used to assess general locomotor activity and exploratory behavior in a new environment. Mice are taken to the experimental room for at least minutes for acclimatization to experimental room conditions (poor lighting) before testing. The test arena consists of a 50 cm x 50 cm square arena. The mice are placed in the center of an arena and tracked for 15 minutes. The time spent in the peripheral and central zones is analyzed, along with the breeding behavior. 70% ethanol is used to clean all surfaces between runs. (c) Labyrinth in Y

[00300] A large Y-maze test assesses short-term memory of the familiarity of a specific context. The mice are taken to the experimental room for at least 30 minutes of acclimatization to the conditions of the experimental room (poor lighting) before the test. For the initial training test, the mouse is placed at the end of one arm of a large Y-maze called the “initial arm” (arm length: 15 inches). The third arm of the maze is blocked, allowing the mouse to explore two of the three arms freely ("starting arm" and "familiar arm") for 5 minutes. Each arm contains space clues. One hour later, the mouse is placed back in the maze in the “initial arm” and is allowed to explore the three arms with the third arm unlocked (“new arm”). Movements in and out of each arm are tracked using automated tracking software (CleverSys). The test is carried out in low light and the apparatus is cleaned with 70% ethanol between tests. (d) Barnes Labyrinth

[00301] A modified Barnes Labyrinth was used to assess spatial/episodic work such as learning and memory. The Barnes Maze Apparatus consists of a circular platform 122 cm in diameter with 40 escape holes, each 5 cm in diameter, placed along three rings of varying distances from the center of the platform. An exhaust box is attached to one of the holes and all holes are left uncovered. Bright lights and a fan are trained in the maze to provide static.

adverse modules to encourage escape. Visual cues are placed on all four sides of the maze. The mice are given a series of 4 or 5 tests with intervals between tests of approximately 10 minutes and the maximum duration of each test is 90 or 120 seconds. For each test, mice are placed in the center of the maze. After 10 seconds, the mice can explore and the t-test terminates if the mouse finds and enters an escape box before the end of the test. Mice that cannot find the escape box are taken to it and allowed inside and given 30 seconds to stay before being returned to their cage. Training takes place over 4 days. Data that is logged and analyzed includes velocity, escape latency, and distance moved.

[00302] The mice are divided into groups of 4 to 5 mice each, with balanced treatment groups. For example, mice in Group 1 are run in 4 trials, then mice in Group 2 are run in 4 trials, and so on until all groups complete the trial. 70% ethanol is used to clean the arenas between tests. (e) Rotarod

[00303] The mice were trained in rotarod during 3 tests of up to 100 seconds each, being the rotarod a test of motor coordination. Success or failure was recorded in the last test, with success defined by a latency that drops to >90 seconds. A binomial test was performed to compare success rates between control and compound-treated mice. (f) Labyrinth in T

[00304] The Water Maze was filled with water at least 24 hours before the test to allow it to reach room temperature. The water was tinted with white latex paint to make the animals visible for tracking and allow the use of a hidden platform. Two distinct visual cues were placed at the end of both T-arms of the T-maze insertion. On day 1, animals received 4 tests each with a visible platform and a 30-minute interval between tests. Animals were given 60 seconds to reach the platform. If they didn't reach the platform in that time, they would be guided to it and left to stand for 5 seconds before being removed from the tank. The target arm was changed after every third mouse and both treatment groups had an equal number of arms on the right and left sides. After each test, mice were placed in an empty cage with blue pillows and allowed to dry under a red light bulb before being placed back in their cage. Day 2 is the test day, in which the animals undergo the same test of 4 tests each and a 30-minute interval between tests, but with a hidden platform. Animals were scored for given or wrong choice and for latency to reach the platform and a binomial test was performed to compare success rates between control and compound-treated mice. All tests were recorded using TopScan. (g) Protein quantification

[00305] CCL11 protein levels were measured from mouse plasma by zzzzz sandwich ELISA. Plasma was diluted 1:10 for assay. (CCL11 Mouse Kit/Eotaxin Duo Kit, R&D Systems, Minneapolis, MN).

Human CCL11 from human plasma was measured by a SomaLogic aptamer-based assay (SOMAscan from SomaLogic, Inc., Boulder, CO). (Gold L, et al. (2010) Aptamer-Based Multiplexed Proteomic Technology for Biomarker Discovery. PLOS ONE 5 (12): e15004.

[00307] Circulating mouse plasma cytokine panels were analyzed by Luminex. Luminex Assay Service performed by Eve Technologies (Calgary, Alberta, Canada).

(h) MRNA quantification

[00308] Instantly frozen hemibrains were dissected in the cortex, hippocampus, striatum and thalamus. The cortex was divided into three homogeneous parts and one part was used for RNA isolation. RNA was isolated using the Prolink RNA Mini Kit (Thermo Fisher Scientific ft 12183025). cDNA was prepared using the Tagman RT Kit (Thermo Fisher Sci tt N8080234). qPCR was performed in a Quant Studio 6 using custom Tagman Multiplex Primers for IL-1beta and GAPDH. All samples were run together on a single plate and analyzed for ddCT against its endogenous control first and then against the control group.

(i) HPLC/MS quantification of Compound 1

Compound levels were measured by MS/MS by Quintara (Hayward, CA).

(]) Flow Analysis Eosinophil Count

[00310] 200 ul of whole blood was collected during perfusion and sent to the Charles River Clinical Pathology Services (Shrewsbury, MA) for hematological analysis of the eosinophil count by FACS (fluorescence activated cell classifier).

Change in Eosinophil Form (ESC)

[00311] ESC determines the shape change of human eosinophils activated by human eotaxin-1 (PreProTech, Rocky Hill, New Jersey) compared to native eosinophils. The change is detected as the change in direct scatter measured by FACS (fluorescence activated cell classifier). The direct dispersion

t population mean of autofluorescence (eosinophils) for each sample was determined together with the mean of each set of sample triplicates. Methods for determining ESC have been described above and are known in the art. Internalization of CCR3 receptor

The CCR3 receptor internalization assay is based on FACS and uses human Eotaxin-1 (PreProTech, Rocky Hill, New Jersey) and an APC-labeled anti-human CCR3 antibody (R&D Systems, Minneapolis, Minnesota) or I9G2A antibody of isotype control to monitor CCR3 receptor internalization in human eosinophils induced by human eotaxin-1 compared to naive eosinophils. The median APC fluorescent intensity units for each sample were determined along with the mean of each set of sample triplicates. Methods of monitoring CCR3 receptor internalization have been previously described and are known in the art. (k) Histology

[00313] The mice were removed the day after the end of the behavior tests. Anesthesia was induced during 2,2,2-tribromoethanol and mice were subsequently perfused with 0.9% saline solution transcardially. The brains were dissected and cut sagittal in two equal parts. One half was snap frozen for later use on dry ice and the other half was fixed in 4% paraformaldehyde in PBS for use in immunohistochemistry. After two days of fixation, the hemibrains were transferred to 30% sucrose in PBS solution and changed after two days. Hemibrains were sectioned at 30 µm in a microtome at -22°C. Brain sections were stored in cryoprotectant medium at -20 ºC until needed for staining. Blocking was performed in appropriate serum free-floating sections.

Added to 10% serum in 0.5% PBST. Primary antibodies were incubated overnight at 4°C. For light microscopy, the following antibodies were used at the indicated concentrations: DCX, 1:200, Santa Cruz BioTech, CD68, 1:1000. ALD Serotech. Secondary biotinylated antibodies were applied the following day at a concentration of 1:300. Visualization of staining was obtained by reaction with the ABC kit (Vector) and diaminobenzidine (Sigma). Dehydration of the mounted slides was achieved using immersions in ethanol and xylene. Images were acquired on a Leica light microscope at 5x magnification.

[00314] For fluorescent microscopy, the following antibodies were used at the indicated concentrations: GFAP, 1:500, DAKO; Iba1, 1:1000, Wako; and BrdU, 1:500, AbCam. Antigen retrieval protocol was required for BrdU (2N HCl, 37C, 30 min) before blockade. Appropriate fluorescent secondary antibodies were applied the following day at a concentration of 1:300 for one hour at room temperature. Prolong Gold mounting medium was used to laminate the slides. Images were acquired under an optical microscope at 5x magnification.

2. Experimental groups First experimental group (see Figures 1-2): Two-month or 18-month-old C57BI/6 mice were dosed with IgG antibody control by IP injection or Compound 1 subcutaneously via an osmotic pump Alzet for 2 or 4 weeks. During the last week of treatment, mice underwent behavioral testing prior to perfusion on the last day of treatment. All mice received, for 5 consecutive days, an injection of BrdU at 150 mg/kg IP immediately before starting treatment. Drug Formulation. Control mouse IgG2A clone 54447

(MABO0O6, R&D Systems) was administered at 50 ug/kg in sterile saline. Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). Solutions were prepared fresh weekly and stored at 4°C. Treatment Groups: * Treatment Group 1, Young Controls: Young C57BL/6 mice (n = 18), aged 1 to 2 months, received 5 injections of control IgG by intraperitoneal (IP) injection, one injection each 3 days over a 14 day period. * Treatment Group 2, Elderly Controls: Elderly C57BL/6 mice (n = 18), 18 months of age, received 5 injections of control IgG by IP injection, one injection every 3 days for one 14 day period. * Treatment Group 3, Compound 1 (dose 1) in the elderly: C57BL/6 elderly mice (n = 16), aged 18 months, received infusion of — 50 mg/ml of Compound 1 via the Alzet minipump, model 2001 (1 uL/h), for two weeks with a replacement. * Treatment Group 4, Compound 1 (dose 2) in the elderly: elderly C57BL/6 mice (n = 16), aged 18 months, received infusion of — 50 mg/ml of Compound 1 through the Alzet minipump, model 2002 (0.5 uL/h), for two weeks. * Treatment Group 5, Compound 1 (dose 2) in the elderly: elderly C57BL/6 mice (n = 16), aged 18 months, received infusion of — 50 mg/ml of Compound 1 through the Alzet minipump, model 2002 (0.5 uL/h), for four weeks with one replacement.

Four-week subcutaneous dosing of Compound 1 in 18-month-old mice increased the number of doublecortin-positive cells in the hippocampus, an indicator of neurogenesis (see Figure 1A). A higher dosage of Compound 1 for 2 weeks led to a trend towards an increase in BrdU-positive cells in the hippocampus, a marker for cell proliferation (see Figure 1B). Low or high infusion of Compound 1 over 2 or 4 weeks led to an improvement in the suggested Y-maze, a memory test (see Figure 2 reporting percentage of time normalized to total interaction time and number of visits (similar effects were also observed when evaluating the total time spent). Comparisons are made with control groups (treatment groups 1 and 2) that were treated with IgG antibody without compound, and dosage and behavior were performed in parallel.

Thus, the administration of Compound 1 increased the number of positive cells for Dcx and BrdU, which indicates that Compound 1 increased neurogenesis and cell survival, respectively. Compound 1 was able to improve memory (cognition), as evidenced by performance on the Y-maze test. Second Experimental Group (See Figures 3-6):

[00317] “Three-month or 16.5-month-old C57BI/6 mice were dosed with vehicle control or Compound 1 subcutaneously via an Alzet osmotic pump for 4 weeks. During the last week of treatment, mice underwent behavioral testing prior to perfusion on the last day of treatment. All mice received, for 5 consecutive days, an injection of BrdU at 150 mg/kg IP immediately before starting treatment. Drug Formulation. Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. The solutions were prepared fresh weekly and stored at 4ºC. Treatment Groups:

* Treatment Group 1, Young Controls: Young C57BL/6 mice (n = 19), 3 months old, received vehicle infusion through the Alzet minipump, model 2002 (0.5 uL/h), du- for four weeks with a replacement.

* Treatment Group 2, Elderly Controls: Elderly C57BL/6 mice (n = 19), aged 16 months, received vehicle infusion through the Alzet minipump, model 2002 (0.5 uL/h), du- for four weeks with a replacement.

* Treatment Group 3, Compound 1 (dose 2) in elderly: elderly C57BL/6 mice (n = 19), aged 16 months, received infusion of — 50 mg/ml of Compound 1 via the Alzet minipump , model 2002 (0.5 uL/h), for four weeks with a replacement.

Four-week subcutaneous dosing of Compound 1 in 16.5-month-old mice improved cognitive performance in the suggested Y-maze test for memory (see Figure 3). The 4-week dosing of Compound 1 also tended to improve performance in the Barnes maze, a test for hippocampal-dependent spatial memory (see Figure 4). Trends to improve memory were also observed in the analysis of mean latency for tests on day 4, as well as in the difference between latencies for tests 13 and 16. The four-week dosage of Compound 1 also significantly increased the number of BrdU-positive cells in the hippocampus, an indicator of neurogenesis (see Figure 5). therefore, Compound 1 was able to improve cell survival and improve memory (cognition), as evidenced by the results obtained using the Y-maze and Barnes' maze tests.

Cerebrospinal Fluid Levels of Compound in Mice

[00319] Cerebrospinal fluid (CSF) from both the 2-month-old “young” and the 16.5-month-old “elderly” groups was collected and Compound 1 levels were determined by mass spectroscopy . Figure 6 shows the levels of the compound of the invention that were detected in mouse CSF for the young and old groups (both below 10 nM). These CSF levels do not approach the Ki for the compound in mice (124 nM, determined by binding to the cell lineage receptor) and therefore do not cross the blood-brain barrier (BBB) at significant concentrations. For comparison, the levels of the compound of the invention that were measured in the plasma of young (2 months old) and old (18 month old) mice perfused for 2 and 4 weeks, respectively, at 0.5 uL/h of 50 mg µg/mL of solution were significantly higher (352 + 31 nM and 355 + 43 NM, respectively; values are mean + sem), further indicating that the compound of the invention fails to cross the BBB in significant amounts.

[00320] These data show that Compound 1 does not act directly on the CNS and therefore acts peripherally. Furthermore, what crosses the BBB is insufficient in concentration to be effective. Furthermore, there is no difference in BBB penetration between young and old mice, indicating that the effects that Compound 1 exhibits on cognition and neurodegeneration are not due to differences in BBB between the two groups. Composite Tissue Distribution Levels

[00321] The distribution of Compound 1 in mouse tissues was determined after oral administration of which it was [°C]-radiolabeled with ("Marked Compound") in male pigmented C57BL/6JOlaHsd mice (Harlan Labs, BV). The labeled compound was administered at 10 mg/kg body weight, corresponding to 17 µmol/kg. One animal was sacrificed after 1, 24 and 168 hours after administration. Blood, plasma and eye radioactivity concentrations were measured using liquid scintillation counting (LSC). Tissue and organ concentrations were determined by whole body autoradiography (QWBA) technique. Preparation of sections from whole-body animals was performed according to known techniques (see S. Ullberg, et al., Autoradiography in Pharmacology in: The Int. Encyclopedia of Pharmacology, J. Cohen (Ed.), 1 ( 78): 221-39 (1971)), using a Reichert-Jung CRYO MACROCUT crystal microtome or a LEICA CM 3600° CRYO MACROCUT.

[00322] The following sections were taken at different levels through the incorporated animal and the whole body sections selected at levels from 5 to 7, in order to allow quantitative assessment of radioactivity: adrenal glands; blood; bone marrow; brain; eye (lenses); epididymis; fat (white and brown); Harderian gland; heart; kidneys; liver; lung; muscle; hypophysis; pancreas; prostate, spinal cord; salivary gland of the spleen; skin; testicle; thyroid; thymus; uveal tract. Two sections were taken from each level chosen per animal and the sections lyophilized in a microtome at - at -25 ºC for a minimum period of 48 hours.

Figure 7 shows a plot of values reporting the area under the curve (AUC) for all three time points and quantifies the exposure of each tissue to the labeled POI after compound administration. Figure 7 shows that Compound 1 does not cross the blood-brain barrier (BBB) to significant levels.

[00324] Again, these results show that, as Compound 1 cannot cross the BBB at appreciable levels, it acts peripherally. Thus, the effects of Compound 1 do not act directly on the central nervous system and overcome the difficulties that have caused the failure of many pharmaceutical candidates targeting the disease in the CNS. Pharmacokinetic Profiles in P.O.

[00325] Plasma from 2-month-old male C57BL/6 mice was measured for concentrations of Compound 1 at time points 20 minutes, 2 hours, 8 hours and 12 hours after oral gavage in 2 doses: 30 mg/kg and 150 mg/kg. A dose of 30 mg/kg was found to be sufficient to achieve a concentration greater than 100 nM of Compound 1 for 8 hours (Figure 8). Third Experimental Group (See Figures 9-11):

Two-month-old C57BL/6 mice were dosed with vehicle control or Compound 1 by oral gavage twice daily for 18 days. During the last week of treatment, the mice underwent behavioral tests before perfusion on the last day of treatment. All mice received, for 5 consecutive days, an injection of BrdU at 150 mg/kg IP immediately before the start of treatment. Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. The solutions were prepared fresh weekly and stored at 4 ºC. Treatment Groups: * Treatment group 1a, vehicle treatment: young C57BL/6 mice (n = 15), 7 weeks of age, received twice daily oral treatment (PO) (BID) of the solution of the vehicle for 18 days, with only 1 injection on the last day, for a total of 35 injections.

* Treatment group 1b, treatment with Compound 1:

Young C57BL/6 mice (n = 15), 7 weeks of age, received oral treatment (PO) twice daily (BID) of Compound 1, 30 mg/kg, for 18 days, with only 1 injection into the last day, for a total of 35 injections.

* Treatment group 2a, vehicle treatment with rmMCCL11: young C57BL/6 mice (n = 15), 7 weeks of age, received oral treatment (PO) twice daily (BID) of vehicle solution for 18 days, with just 1 injection on the last day for a total of 35 injections. The mice simultaneously received peripheral (PI) injections of rmCCL11 from day 1 of treatment, every 3 days, for a total of 5 injections.

* Treatment group 2b, treatment with Compound 1 with rmCCL11: young C57BL/6 mice (n = 15), 7 weeks old, received oral treatment (PO) twice daily (BID) of Compound 1, 30 mg/kg for 18 days, with only 1 injection on the last day for a total of 35 injections. The mice simultaneously received peripheral (PI) injections of rmCCL11 from day 1 of treatment, every 3 days, for a total of 5 injections.

Recombinant mouse CCL11 ("rmE") treatment significantly worsened anxiety in the Open Field, but two weeks of twice-daily Compound 1 treatment improved anxiety (see Figure 9). mMCCL11 impaired Y-maze memory; however, mice treated with Compound 1 were no longer significantly different from control mice (see Figure 10). rmMCCL11 also impaired memory in the Barnes maze and treatment with Compound 1 significantly improved memory performance (see Figure 11). thus, rmE worsened anxiety through the Open Field test and memory, as evidenced by performance.

performance measured in the Y-maze and Barnes's maze tests. However, Compound 1 treatment was able to attenuate these effects.

[00328] Fourth Experimental Group (See Figure 12): 23-month-old C57B1/6 mice were dosed with vehicle control or Compound 1 by oral gavage twice a day for 19 days. After 11 days of treatment, the mice were submitted to the Y-maze test.

Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment group 1, vehicle treatment: elderly C57B1/6 mice (n = 8), 23 months of age, received twice daily oral gavage (PO) treatment (BID) of the solution of the vehicle for 19 days.

* Treatment Group 2, treatment with Compound 1: Elderly C57B1/6 mice (n = 11), 23 months of age, received twice daily oral gavage (PO) treatment (BID) from Compound 1, 30 mg/kg for 19 days.

Compound 1 treatment significantly improved memory in the Y-maze. Compound 1 treated mice exhibited intact memory for the new arm in the number of visits (Figures 12A). Treatment with Compound 1 also significantly increased the distance walked by the mice during the test (Figure 12B).

[00331] Fifth Experimental Group (See Figures 13 to 17): 23-month-old C57B1/6 mice were dosed with vehicle control or Compound 1 subcutaneously twice daily for 21 days. Three weeks later, the mice were subjected to behavioral tests and sacrificed the day after the last behavior test.

Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment group 1b, vehicle treatment: elderly C57B1/6 mice (n = 9), 23 months of age, received twice daily subcutaneous (SQ) treatment (BID) of vehicle solution for 21 days.

* Treatment group 4, treatment with Compound 1: Elderly C57B1/6 mice (n = 17), 23 months of age, received twice daily subcutaneous (SQ) treatment (BID) of Compound 1, 30 mg /kg, for 21 days.

Compound 1 treatment significantly improved Y-maze and Barnes-maze memory. Mice treated with Compound 1 exhibited intact memory for the new arm, both in the number of visits (Figures 13A-B) and time spent in the new arm (Figures 13C-D). Treatment with Compound 1 also significantly increased the mice's velocity during the test (Figure 13E). Mice treated with Compound 1 performed significantly better in the Barnes maze for spatial memory (Figure 14A) and also exhibited increased speed during the test (Figure 14B). The locomotor activity was also improved in Campo Aberto, where there were strong trends of improvement both in the distance.

running and speed (Figures 15A and 15B, respectively).

[00334] Inflammatory cytokine levels were measured by the Luminex assay from mouse plasma (Figure 16). There were strong trends in the decrease of several inflammatory markers, including TNFa, IL6, IL1beta, IL5 and IL17. Activated microglia were also quantified by IHC staining in the mouse hippocampus (Figure 17). Treatment with Compound 1 resulted in a strong tendency to decrease microgliosis.

[00335] Sixth Experimental Group (See Figure 18): 23-month-old C57B1/6 mice were dosed with vehicle control or Compound 1 subcutaneously twice daily for 30 days and then sacrificed on the day of the last injection. Drug Formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment group 1a, vehicle treatment: elderly C57B1/6 mice (n = 9), 23 months of age, received twice daily subcutaneous treatment (SQ) (BID) of vehicle solution for 30 days.

* Treatment group 3, treatment with Compound 1: Elderly C57B1/6 mice (n = 18), 23 months of age, received twice daily subcutaneous (SQ) treatment (BID) of Compound 1, 30 mg /kg, for 30 days.

Treatment with Compound 1 resulted in a strong trend towards decreased blood eosinophils by FACS analysis in a subset of animals (n=2,5) (Figure 18).

[00337] Seventh Experimental Group (See Figure 19): camun-

Three-month-old hairless dongos were treated with oxazolone (Ox) every other day and treated with control saline or 30 mg/kg Compound 1 for 2 weeks BID, PO. Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment group 1, vehicle treatment: 3 month hairless mice (n = 3) received twice daily oral gavage (PO) treatment (BID) of vehicle solution for 2 weeks.

* Treatment group 2, vehicle treatment and oxazolone treatment: 3-month-old hairless mice (n = 6) received twice daily oral gavage (PO) treatment (BID) of vehicle solution for 2 weeks.

* Treatment Group 3, Compound 1 treatment and Oxazolone treatment: 3-month-old hairless mice (n = 6) received twice daily oral gavage (PO) treatment (BID) of Compound 1, 30 mg/ kg for 2 weeks.

Compound 1 decreased the oxazolone-induced increase in blood eosinophils by complete blood count (CBC) analysis. N = 3, 6, 8. *p < 0.05, **p < 0.01. Compound 1 drastically reduced the number of eosinophils in blood in an oxazolone-induced model of eosinophilia (Figure 19). This shows that CCR3 inhibition may be sufficient to normalize eosinophil levels and function especially in diseased states, demonstrating a second mechanism (in addition to decreased brain inflammation) by which Compound 1 may be effective in treating neurovascular loss.

impairment and associated motor and cognitive impairments.

Eighth Experimental Group (See Figures 20-22): 24-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle via an Alzet osmotic pump, which were implanted to release conti- the two treatments.

Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment Group 1, Elderly Controls: Elderly C57BL/6 mice (n = 15), aged 23 months, received vehicle infusion through the Alzet model 2002 minipump (0.5 uL/h). ), for four weeks with a replacement.

* Treatment Group 2, Compound 1 (dose 2) in elderly: elderly C57BL/6 mice (n = 15), 23 months of age, received infusion of — 50 mg/ml of Compound 1 via the Alzet minipump , model 2002 (0.5 uL/h), for four weeks with a replacement.

[00341] The mice were tested on Rotarod for motor coordination. Success or failure was recorded in the last test, with success defined by a latency that drops to >90 seconds. Mice treated with Compound 1 achieved more than mice treated with vehicle by the binomial test. N = 15 each, *p < 0.05. A greater proportion of mice treated with Compound 1, 47%, were able to remain on the stem for more than 90 seconds, a threshold at which only 20% of control-treated mice could remain after three successive tests (Figure

20). These results suggest that there is a consistent effect of Compound 1 on motor function in eotaxin elevation models.

[00342] The mice were tested in the T-maze for cognitive function (Figure 21). The number of successes or failures in shutting down the correct arm has been recorded. Mice treated with Compound 1 achieved more than mice treated with vehicle by the binomial test. *p<0.05.

[00343] Fecal production was measured by weighing the dry weight of fecal pellets overnight (Figure 22). Gastric function is a well-known symptom of Parkinson's disease. Food and water intake was measured over the same period. Mice treated with Compound 1 had significantly lower fecal production compared to control mice. They also had a significantly higher water intake overnight compared to control mice. *p<0.05. these results indicate that deficits in gastric function can be altered by treatment with Compound 1.

Ninth Experimental Group (See Figure 23): Three month old C57 mice received a 10 mg/kg IP dose of lipopolysaccharide (LPS) to induce inflammation and treated with Compound 1 for 18 days.

Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C. Treatment Groups: * Treatment group 1, vehicle treatment: young C57BL/6 mice (n = 15), 3 months of age, received a single injection of LPS and were treated with vehicle, BID, during

18 days by oral gavage.

* Treatment group 2, treatment with Compound 1: young C57BL/6 mice (n = 15), 3 months of age, received a single injection of LPS and were treated with Compound 1, 30 mg/kg, IDB for 18 days by oral gavage.

[00346] Brain sections were immunostained for detection of CD68+ activated microglia. Mice treated with Compound 1 exhibited significantly reduced CD68+ immunoreactivity (decrease in activated microglia) in contrast to mice treated with vehicle (saline) (Figure 23) N=9, 10, 8. *p <0.05 by one-way ANOVA.

These data indicate a potent anti-neuroinflammatory effect of Compound 1, with therapeutic potential to reduce neuroinflammation-induced toxicity to neurons in diseases that exhibit neurodegeneration or cognitive or motor decline.

[00348] “Tenth Experimental Group (See Figure 24-29): Three-month-old C57 mice received daily doses of lipopolysaccharide (LPS) 0.5 mg/kg IP to induce inflammation and treated with Compound 1 accordingly. chronic for up to 4 weeks.

Drug formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. Kolliphor was added to each 10% solution per week and stored at 4°C.

Treatment Groups: * Treatment group 1, vehicle treatment: three-month-old C57 mice (n = 10) received daily |P injection of LPS for 7 weeks and treatment by oral gavage (PO) twice daily (BID) of the vehicle solution for up to 4 weeks.

* Treatment group 2, vehicle treatment and oxazolone treatment: three-month-old C57 mice (n = 10) received daily |P injection of LPS for 7 weeks and treatment by oral gavage (PO) twice per day (BID) of the vehicle solution for up to 4 weeks.

* Treatment group 3, treatment with Compound 1 and treatment with oxazolone: three-month-old C57 mice (n = 9) received daily |P injection of LPS for 7 weeks and twice-daily oral gavage (PO) treatment ( BID) of Compound 1, 30 mg/kg, for up to 4 weeks.

[00350] Figure 24A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 24B was performed. Anxiety was tested in the Open Field test after 1 week of treatment with Compound 1 (Figure 24B). LPS treatment significantly increased anxiety in the Open Field and Compound 1 strongly decreased the increase in anxiety, *p < 0.05.

[00351] Figure 25A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 25B was performed. Cognition was tested in the Y-maze after 3 weeks of treatment with Compound 1 (Figure 25B). LPS-treated mice did not show a significant preference for the new arm. However, mice treated with Compound 1 showed a significant preference for the new arm, similar to mice treated with vehicle, *p < 0.05, **p < 0.01.

[00352] Figure 26A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 26B was performed. Inflammatory cytokine IL-1beta mRNA levels were measured by quantitative PCR 4 weeks after treatment with Compound 1 (Figure 26B). Mice treated with LPS showed a trend towards increased levels of |L-1beta and mice treated with Compound 1 showed a significant decrease in IL-1beta expression, *p < 0.05.

Figure 27A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 27B was performed. Brain sections were immunostained for detection of CD68+ activated microglia. Mice treated with Compound 1 exhibited drastically reduced CD68+ immunoreactivity (decrease in activated microglia) in contrast to mice treated with LPS alone (Figure 27B).

[00354] Figure 28A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 28B was performed. Brain sections were immunostained to detect Ibai-positive microglia. Mice treated with Compound 1 exhibited dramatically reduced Iba1+ immunoreactivity (decreased total microglia) in contrast to mice treated with LPS alone (Figure 28B).

[00355] Figure 29A depicts the dosing paradigm for the tenth experimental group. The section of the paradigm highlighted by the square represents the points in time at which the test in Figure 29B was performed. Brain sections were immunostained for detection of GFAP-positive astroglia. Mice treated with Compound 1 exhibited drastically decreased GFAP+ immunoreactivity (decreased total astrocytes) in contrast to mice.

dongos treated only with LPS (Figure 29B).

[00356] These data indicate a potent anti-neuroinflammatory effect of Compound 1, with therapeutic potential to reduce neuroinflammation-induced toxicity to neurons in diseases that exhibit neurodegeneration or cognitive or motor decline.

[00357] “Eleventh Experimental Group (See Figure 30): Forty-five (42) 2-month-old C57BL/6 mice were allocated into three groups: vehicle-treated controls, vehicle-treated LPS mice and LPS-treated mice. dosed with Compound 1. Vehicle or compound was given twice daily orally (PO BID) for a total of 6 doses. Histological evaluations were performed in the hippocampus with the microglia marker Iba-1.

Drug Formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. The solutions were prepared fresh weekly and stored at 4°C.

[00359] LPS formulation: LPS was formulated at 0.55 mg/ml in saline and dosed at 5 mg/kg. Treatment Groups: * Treatment Group 1, vehicle treatment controls: young C57BL/6 mice (n = 13), 2 months of age, received a single IP injection of saline followed by PO BID vehicle for 3 days for a total of 6 injections.

* Treatment Group 2, LPS vehicle treatment: young C57BL/6 mice (n = 19), 2 months of age, received a single IP injection of LPS (5 mg/kg) followed by PO BID vehicle during 3 days for a total of 6 injections.

* Treatment Group 3, LPS treatment with Com-

station 1: young C57BL/6 mice (n = 18), aged 2 months, received a single IP injection of LPS (5 mg/kg) followed by Compound 1 (30 mg/kg) PO BID for 3 days for a total of 6 injections.

[00360] Tissue Processing and Histology: The hemibrains of mice were sectioned at 30 µm in a microtome at -22 ºC. The brain sections were sequentially collected in 12 tubes, so that each hippocampus section 12 was represented in a specific tube. Brain sections were stored in cryoprotectant medium at -20 ºC until needed for staining. Free-floating sections were blocked in the appropriate serum at 10% serum in 0.5% PBST. Anti-Ilba1 primary antibodies (Wako, 1:1000) were incubated overnight at 4°C. Appropriate fluorescent secondary antibodies were applied the following day at a concentration of 1:300 for one hour at room temperature. Half Prolong Gold Mounting was used to cover the blades.

[00361] Quantification of Neuroinflammation: The positive area for Iba-1 was quantified using the threshold in Image Pro Premier v9.2 software as a percentage of an ROI around the entire hippocampus. The percent positive area for Iba-1 was calculated, on average, from approximately 5 sections for each mouse. One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups.

[00362] Figure 30 shows the results of histological analysis of mouse brains in a model of acute inflammation induced by LPS. It reveals a significant reduction in LPS-induced microgliosis in the hippocampus of mice treated with Compound 1 for three days, when both treatments with

Compound 1 and LPS were started on the same day. Microgliosis was measured by determining the percentage of lba-1 positive area in the hippocampus. One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups. (* P < 0.05; *** P < 0.001).

[00363] “Twelfth Experimental Group (see Figure 31): Fifteen (15) 2-month-old C57BL/6 mice were allocated into three groups: vehicle-treated controls, vehicle-treated LPS mice and LPS-treated mice Compound 1. Vehicle or compound was given twice daily orally (PO BID) for a total of 6 doses. Histological evaluations were performed in the hippocampus with an Iba-1 microglia marker.

Drug Formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. The solutions were prepared fresh weekly and stored at 4°C.

[00365] LPS formulation: LPS was formulated at 0.55 mg/ml in saline and dosed at 5 mg/kg. Treatment Groups: * Treatment Group 1, vehicle treatment controls: young C57BL/6 mice (n = 13), 2 months of age, received a single IP injection of saline, then 72 hours more In the afternoon, they were dosed with PO BID vehicle for 3 days for a total of 6 injections.

* Treatment Group 2, LPS from vehicle treatment: young C57BL/6 mice (n = 19), 2 months of age, received a single IP injection of LPS (5 mg/kg), then 72 hours later then, they were dosed with PO BID vehicle for 3 days for a total of 6 injections.

* Treatment Group 3, LPS treatment of Compound 1: Young C57BL/6 mice (n = 18), aged 2 months, received a single IP injection of LPS (5 mg/kg), then , 72 hours later, were dosed with Compound 1 (30 mg/kg) PO BID for 3 days for a total of 6 injections.

[00366] Tissue Processing and Histology: The hemibrains of mice were sectioned at 30 µm in a microtome at -22 ºC. The brain sections were sequentially collected in 12 tubes, so that each section 12 of the hippocampus was represented in a specific tube. Brain sections were stored in cryoprotectant medium at -20 ºC until needed for staining. Free-floating sections were blocked in the appropriate 10% serum in 0.5% PBST. Anti-Iba1 primary antibodies (Wako, 1:1000) were incubated overnight at 4°C. Appropriate fluorescent secondary antibodies were applied the following day at a concentration of 1:300 for one hour at room temperature. Prolong Gold Ontario medium was used to cover the blades.

[00367] Quantification of Neuroinflammation: The positive area for Iba-1 was quantified using threshold in Image Pro Premier v9.2 software as a percentage of an ROI around the entire hippocampus. The percent positive area for Iba-1 was calculated, on average, from approximately 5 sections for each mouse. One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups.

[00368] Figure 31 shows the results of histological analysis of mouse brains in a model of acute inflammation induced by LPS. It reveals a significant reduction in LPS-induced microgliosis in the hippocampus of mice treated with Compound 1 for three days, when Compound 1 administration started after LPS had been given for three days before. Microgliosis was measured by determining the percentage of positive area for Iba-1 in the hippocampus. One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups. (* P < 0.05; *** P < 0.001).

3. Parkinson's Mouse MPTP Model

[00369] A mouse model using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is used to determine the level of alleviation of MPTP-induced parkinsonian deficits. MPTP is a prodrug of MPP+, which can cause permanent Parkinson's symptoms. MPP+ works by killing dopaminergic neurons in the substantia nigra region of the brain.

In total, seventy-four (74) 8-week-old male C57BI/6J mice were used in the experiment. Animals were divided into two separate study arms, a 12- and 4-day study arm, and treated similarly in both arms. The mice were grouped into three groups within a study arm, so that one group served as a control that received MPTP vehicle and composite vehicle, while the other two groups received MPTP twice daily on days 1 and 2, and beyond of vehicle compound or Compound 1 per day (30 mg/kg) on days 1-12 with only one dose on day 12 (Figure 32). After ten days of treatment on the 11th day of study, the motor functions of the 12-day study arm, mice were evaluated in fine motor kinematic analysis. On day 12 of the study and on day 4, tissue endpoint processing was performed. Samples were processed for hematology, immunohistochemistry and HPLC measurements.

The striatal levels of dopamine (DA), 3,2-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were evaluated on day 12 by means of HPLC. Tyrosine hydroxylase (TH) immunoreactivity was evaluated from brain sections collected through the substantia nigra.

[00371] Due to the large number of ninety-seven individual parameters, the Principal Component Analysis (PCA) was performed. The PCA combined all parameter data together and revealed correlations between the different parameters, providing an overview of fine motor characteristics and gait. Figure 33A illustrates views of the ten major components or PCs, showing how the original parameters are correlated into datasets. The more intensity (blue or red) there is for each parameter, the more strongly the particular parameter will be implied in the corresponding PC. The heat map is formed from the PCA of all available parameter data. The PC scores are presented as an overall gait analysis score in Figure 33B, based on the differences between Group 2: MPTP + Vehicle and Group 1: Mice with Vehicle + Vehicle across all PC scores.

[00372] Figure 34 shows the off-gait property of the forepaw toe on day 11 of the study. The group treated with MPTP + vehicle exhibited a statistically significant variation in the toe clearance of the forepaw compared to the group treated with vehicle + vehicle. And the group treated with MPTP + Compound 1 showed a positive trend compared to the group treated with MPTP + vehicle. Data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 n = 13). Statistical significance

ca: * p < 0.05, Group 2: MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (unpaired t-test).

[00373] Figure 35 shows the property of the swing speed gait of the forepaw on day 11 of the study. The group treated with MPTP + vehicle exhibited a statistically significant variation in the swing speed of the forepaw compared to the group treated with vehicle + vehicle. And the group treated with MPTP + Compound 1 exhibited a positive trend compared to the group treated with MPTP + vehicle. Data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 (30 mg/kg), n = 13). Statistical significance: * p < 0.05, Group 2: MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (unpaired t-test).

[00374] Figure 36 shows the gait property of range of motion of the ankle on day 11 of the study. The group treated with MPTP + vehicle exhibited a statistically significant variation in ankle range of motion compared to the group treated with vehicle + vehicle. And the group treated with MPTP + Compound 1 showed a positive trend compared to the group treated with MPTP + vehicle. Data are presented as mean + SEM (Group 1: Vehicle + Vehicle, n = 15; Group 2: MPTP + Vehicle, n = 14; Group 3: MPTP + Compound 1 (30 mg/kg), n = 13). Statistical significance: * p < 0.05, Group 2: MPTP + Vehicle vs. Group 1: Vehicle + Vehicle (unpaired t-test).

[00375] Figure 37 reports the short-term effects of MPTP and Compound 1 on T cell infiltration in the brain. The total number of CD3-positive T cells counted in the black matter of three 30 µm thick sections for each mouse on Day 4 of the study is shown. Data presented are mean + s.e.m; ***P<0.001; One-way ANOVA, Sidak post-hoc multiple comparison test. Mice treated with MPTP + Compound 1 showed a trend towards fewer CD3-positive cells, indicating a trend towards less infiltration of T cells into the brain.

[00376] Figure 38 reports the short-term effects of MPTP and Compound 1 on microgliosis on Day 4 of the study. Figure 38A represents the degree of CD68 positive area measured in the striatum from three 30 µm thick sections for each mouse on Day 4 of the study. Figure 38B depicts the degree of CD68 positive area measured in the substantia nigra pars compact of three 30 µm thick sections for each Day 4 mouse of the study. These data demonstrate that there is marked microgliosis in the substantia nigra, the primary site of neuronal loss seen in Parkinson's disease, but not in the striatum, the main region of the brain where neurons in the substantia nigra protrude - suggesting that treatment affects the central site of pathological disease, but not secondary projection areas.

4. Synuclein Transgenic Mouse Model for Parkinson's Disease

[00377] A transgenic mouse model for synuclein was used to determine the effects of chronic inhibition of CCR3 by Compound 1 and its ability to delay, halt or reverse the progression of Parkinson-like symptoms. This model overexpresses human α-synuclein can test whether an interventional treatment can prevent behavioral and pathological effects induced by α-synuclein. To select an optimal synuclein model for testing, plasma eotaxin levels were measured as a biomarker in multiple synuclein mouse models at different ages. The models included A53T, DxJ9M and Lineage 61. Plasma from 6-month-old synuclein transgenic mice of lineage 61 was measured by ELISA to detect plasma levels of eotaxin as a biomarker. Line 61 mice (QPS Neuro, Grambach, Austria) at 6 months of age exhibited a transgene-induced increase in eotaxin levels (Figure 39), showing that plasma eotaxin levels may serve as an appropriate clinical biomarker to select populations of treatment.

Thirty-three (33) 4.5-month-old male alpha-synuclein transgenic mice (Line 61) were allocated into two groups (Group A, n = 17, Compound 1 1 mg/mL; Group B, n = 16, Vehicle) and a group of 15 age-matched non-transgenic littermates (Group C, Vehicle) were treated with their drinking water for 6 weeks. Animals received vehicle or Compound 1. Animal behavior was assessed at the end of the treatment period. Subsequently, tissue processing was performed.

[00379] Figure 40 reports the results of the wire suspension test. Mean wire suspension times per group are shown, with Group C animals (non-transgenic, vehicle-treated) exhibiting significantly longer wire suspension time. Animals in Group A (transgenic, treated with Compound 1) exhibited a significantly longer wire suspension time compared to Group B (transgenic, treated with vehicle). Data are displayed as mean + SEM of all animals per group; ***P<0.001; Dunnett's post-test; * P < 0.05 Mann-Whitney test for group A vs. group B). These data demonstrate a dramatic loss of function in the ability to hang from the wire in mice transgenic for synuclein, which was at least partially rescued through treatment with Compound 1.

[00380] Figure 41 reports the results of the grip strength test. The average maximum grip strength [g] per group is shown. Animals in Group A and Group C (transgenic, treated with Compound 1 and non-transgenic, treated with vehicle, respectively) showed significantly greater grip strength compared to Group B (transgenic, treated with vehicle). Data are displayed as mean + SEM of all animals per group. The groups were compared to vehicle-treated transgenic animals (group B); One-way ANOVA, followed by Bonferroni post-test. These data demonstrate a statistically significant deficit in synuclein transgenic mice in forelimb strength, which was completely rescued by treatment with Compound 1.

[00381] Figure 42 reports the results of the beam walk test. The number of animals per group for each trial that were able to cross the beam completely is shown. No animals from Group B (transgenic, treated with vehicle) were able to cross the fifth beam (more difficult), indicating that the transgenic mice from Group A treated with Compound 1 had a better performance than vehicle-treated transgenic mice from Group B and better performance in the beam walk test closer to non-transgenic controls.

[00382] Figure 43 reports the results of the five trials to cross the beam without slipping or stepping made in each trial for three groups of mice (group A, transgenics treated with Compound 1; group B, transgenics, treated with vehicle; and group C, non-transgenic, treated with vehicle). The graphs represent the average number of slips [n] per group and each graph represents an attempt (1-5). Data are the mean + SEM of all animals per group. The groups were compared with group B; One-way ANOVA, followed by Bonferroni post-test. These data clearly show that mice with overexpression of synuclein are highly impaired in their ability to traverse the beams and treatment with Compound 1 at least partially rescues this effect, showing a dramatic improvement in motor function.

[00383] Figure 44 shows the peripheral blood eosinophil count. Figure 44A reports the percentage of eosinophils in the peripheral blood of three groups of mice (Tg Cmpd 1 = transgenic, treated with Compound 1; Tg Veh = transgenic, treated with vehicle; nTG Veh = non-transgenic, treated with vehicle ). Data were compared using a t-test. Figure 44B reports the absolute peripheral blood eosinophil count of three groups of mice (Tg Cmpd 1 = transgenic, treated with Compound 1; Tg Veh = transgenic, treated with vehicle; Veh nTG = non-transgenic, treated with vehicle) . Data were compared using a t-test. These data demonstrate that the Parkinson's disease model by synuclein overexpression results in a decrease in eosinophils, which are restored to levels in non-transgenic mice through treatment with Compound 1, suggesting beneficial immune modulation in this disease model. Parkinson's. This also suggests that determining eosinophil levels in Parkinson's disease patients treated with Compound 1 may be a biomarker for the disease, including determining the level of disease progression, stasis or regression as well. as the effectiveness of the treatment.

[00384] Figure 45 reports the effect of Compound 1 on neuroinflammation. Figure 45A reports the quantified CD68-positive area in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and camun-

transgenic dongos treated with Compound 1 (n = 14, 12 and 15, respectively). Figure 45B reports the CD68-positive area quantified in the striatum of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 15, 11, and 16, respectively). Figure 45C reports the quantified Iba1 positive area in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 13 and 16, respectively). Figure 45D reports the quantified Iba1 positive area in the striatum of: non-transgenic mice treated with vehicle; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 15, 11, and 16, respectively). Data are mean +/- s.e.m .; * P < 0.05. Figure 45E reports GFAP-positive astrocytes quantified in the hippocampus of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 13, and 15, respectively). Figure 45F reports the GFAP-positive area quantified in the striatum of: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 15, 13 and 15, respectively). Data are mean +/- s.e.m .; * P < 0.05. Figure 45G reports the lba-1 positive area quantified in the pars compact of the substantia nigra of vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1.

[00385] These data demonstrate that, although synuclein overexpression does not result in dramatic microgliosis evidenced by CD68 and lba1, or astrocytosis evidenced by immunoreactivity of

GFAP, Compound 1 treatment decreases microgliosis via both markers and astrogliosis via GFAP, potentially having a global anti-inflammatory effect, ie not simply on one type of inflammatory cell. In addition, the striatum was more impacted than the hippocampus, demonstrating that the regions relevant to Parkinson's disease are specifically reduced in microgliosis and astrogliosis markers. This is further evidenced by the effect of Compound 1 on the reversal of microgliosis in the substantia nigra pars compacta.

[00386] Figure 46 reports the effect of Compound 1 on circulating levels of cytokines IL-4 and IL-6 in: vehicle-treated non-transgenic mice; vehicle-treated transgenic mice; and transgenic mice treated with Compound 1 (n = 14, 15, and 17, respectively). Figure 46A reports the measured IL-4 levels in end-stage cardiac plasma from all three groups. Figure 46B reports the measured IL-6 levels in cardiac terminal plasma from all three groups. Data shown are mean +/- s.e.m; * P < 0.05, ** P < 0.01; One-way ANOVA, post-hoc Dunnett's multiple comparison test. These changes in key cytokines indicate a general effect of Compound 1 treatment on proteins involved in immune function and inflammation.

5. Brain T-Cell Infiltration (a) Tissue Processing and Histology

The mice were sacrificed two hours after the last PO administration on the day following 9 days of dosing. Anesthesia was induced by 2,2,2-tribromoethanol. Mice were subsequently transcardially perfused with 1% EDTA in PBS, followed by 4% PFA in PBS. Brains were dissected and cut sagittally into two equal halves and fixed with 4% PFA in PBS. After two days of fixation, the hemibrains were transferred to a 30% sucrose solution in PBS and changed after two days. Plasma was collected and stored on dry ice.

The hemibrains were sectioned sagittal at 35 µm in a microtome at -22°C. The brain sections were sequentially collected into 12 tubes, so that each 12th brain section was represented in a given tube. Brain sections were stored in cryoprotectant medium at -20 ºC until needed for staining. Free-floating sections were blocked in the appropriate serum at 10% serum in 0.5% PBST. Primary antibodies were incubated overnight at 4°C or room temperature as described below.

Mouse anti-CD8a antibodies (63-0081-80, Thermo Fisher Scientific) was used at a concentration of 1:100 at room temperature, mouse anti-CD3 antibody (555273, BD Biosciences) was used at one concentration of 1:100 at room temperature, rabbit anti-lba-1 antibody (016-26721, Wako) was used at a concentration of 1:1000 at 4°C, rat anti-CD68 antibody (MCA1957, Bio- Rad) was used at 1:1000 at 4ºC and Lycopersicon Esculentum (Tomato) Lectin (DL-1177, Fisher Scientific) labeled with Dylight 448/594 was used at a concentration of 1:200 at room temperature. Appropriate fluorescent secondary antibodies (Alexa-488/555/647, Invitrogen) were applied the following day at a concentration of 1:300 for one hour at room temperature. Half Prolong Gold Mounting was used to cover the blades. Images were acquired on the Hamamatsu Nanozoomer 2.0HT slide scanner at 20x. (b) Quantification of T-Cell Infiltration

CD3 and CD8 positive cells were counted from images acquired in the Hamamatsu slide scanner of the cerebellum. The total number of CD3 and CD8 positive cells in the cerebellum was summed from approximately 5 sections of 35 one each. One-way common ANOVA was used to test statistical significance, with Dunnett's post-hoc multiple comparison test between treatment groups. (c) Quantification of Neuroinflammation

[00391] The positive area for Iba-1 and CD68 was quantified using the threshold in Image Pro Premier v9.2 software as a percentage of an ROI around the entire cerebellum. The percent positive area for lIba-1 and CD68 was calculated, on average, from approximately 5 sections for each mouse. One-way common ANOVA was used to test statistical significance with Dunnett's post-hoc multiple comparison test between treatment groups. Treatment Groups

Two-month-old C57BI/6 mice were divided into three treatment groups: vehicle controls, vehicle-treated EAE (Experimental Autoimmune Encephalomyelitis, see Methods Mol Biol. 2012; 900: 381-401 , incorporated herein by way of reference in full) and EAE treated with Compound 1. EAE was induced on day O with subcutaneous (SQ) injection of MOG + CFA emulsification and intravenous (IV) injection of pertussis toxin (PT) . An additional injection of PT occurred on day 2. Dosing of vehicle or Compound 1 occurred via an oral gavage (PO) on day 0 and continued twice daily (BID) until day 9. Mice were removed 2 hours after last dose PO.

Drug Formulation: Compound 1 was formulated in 40% HP-B-cyclodextrin and adjusted to pH 6.5 with NaOH (1M). The vehicle solution was formulated and pH adjusted similarly. The solutions were prepared fresh weekly and stored at 4°C.

EAE Emulsion: MOG 35-55 (Anaspec AS-60130-5) was reconstituted in PBS at 4 mg/ml. M. Tuberculosis H37 Ra (Fisher Scientific DF3114-33-8) was dissolved in 4 mg/ml Freud's Incomplete adjuvant. These two solutions were then emulsified using glass syringes (Thermo Scientific Male Luer-LOK Priming Syringes 03-170-301) and a 3-way adapter (Cadence 6001). Solutions were prepared immediately prior to dosing.

Pertussis toxin: Pertussis toxin (Sigma P7208-50UG) was dissolved at 0.002 mg/ml in saline and injected at 100 ul IV on the day of induction and again two days later. Treatment Groups: * Treatment Group 1, vehicle treatment: young C57BL/6 mice (n = 5), aged 2.5 months, received 100 ul of PO BID vehicle for 9 days, starting 2 hours later the SQ saline injection and only 1 injection on the first and last day for a total of 19 treatment injections.

* Treatment Group 2, EAE vehicle treatment: young C57BL/6 mice (n = 10), 2.5 months old, received 100 ul PO BID vehicle for 9 days, starting 2 hours after induction of EAE and only 1 injection on the first and last day for a total of 19 treatment injections.

* Treatment Group 3, EAE treatment of Compound 1: Young C57BL/6 mice (n = 10), 2.5 months old, received 100 ul Compound 1 (30 mg/kg) PO BID for 9 days starting 2 hours after EAE induction and only 1 injection on the first and last day for a total of 19 treatment injections.

Induction of EAE resulted in an increase in CD3 and CD8 positive infiltrating T cells in the cerebellum. These T cell numbers were significantly reduced by treatment with Compound 1. Induction of EAE also resulted in a significant increase in microgliosis in the cerebellum, which was also significantly rescued by treatment with Compound 1 after 9 days. Figure 47A shows an increase in CD3 positive T cell infiltration into the cerebellum which is significantly reduced after treatment with Compound 1 for 9 days. Figure 47B shows an increase in CD8 positive infiltrating T cells in the cerebellum that is significantly reduced after treatment with Compound 1 for 9 days. Figure 47C shows a significant increase in the positive area for lIba-1 in the cerebellum after EAE, which was significantly reduced in the cerebellum after 9 days of treatment. Figure 47D shows a significant increase in the CD68 positive area in the cerebellum after EAE, which was significantly reduced in the cerebellum after 9 days of treatment. d. Examples in Human Beings

1. Levels of Eotaxin and Aging

Human eotaxin-1l levels were determined using a commercially available affinity-based assay (SOMAscan, SomaLogic, Inc., Boulder, Colorado). Blood plasma samples were collected from 18, 30, 45, 55 and 66 year old donors and for testing by SomaLogic using an affinity assay based on the SOMAscan aptamer that tested, among other things, relative levels of human eotaxin-1 . Eotaxin-1 levels were determined and represented by age group (Figure 45). The relative concentrations of eotaxin-1 increased with age, indicating that the eotaxin-1 pathway, including its primary receptor, CCR3, is a target for the treatment of diseases associated with aging, such as neurodegenerative diseases. and cognitive decline.

2. Human Biomarker Assays

Whole blood from humans treated with Compound 1 was incubated with recombinant human eotaxin-1 to elicit change in eosinophil shape (Figure 48A) or CCR3 receptor internalization (Figure 49B). Both assays showed a strong concentration-dependent effect of Compound 1 on their respective functional biomarker readings.

[00399] Together, the results obtained in the internalization assays of the ESC and CCR3 receptor confirm that Compound 1 acts as an inhibitor of the human eotaxin-1 pathway. In particular, Compound 1 can act as a potent inhibitor of CCR3 by binding to this receptor.

[00400] Furthermore, the data obtained in Figure 44 show that, in a transgenic mammalian Parkinson's model, eosinophils were expressed at lower levels than in non-transgenic animals, which was reversed with the administration of Com - rank 1. These data, applied to a patient with Parkinson's disease, can therefore help in the diagnosis, monitoring and determination of the prognosis of the disease.

3. Treating Individuals with Parkinson's Disease Using Compound 1

[00401] — Individuals diagnosed with Parkinson's disease receive 400 mg of compound or placebo twice daily (BID) orally. Subjects are treated for 12 weeks and follow-up is carried out for the next 2 weeks. Subjects are evaluated for the effects of Compound 1 on motor function in the virtually defined drug-free state that is greater than or equal to 12 hours without levodopa. Individuals are also evaluated through flow cytometry, pharmacogenomic analyzes and biomarkers that are conducted on blood and blood plasma samples, including eosinophil levels. Gait analysis is assessed using the Zeno Walkway. Bradykinesia, tremor, general activity and sleep are assessed using a wearable device.

[00402] Changes in baseline motor function (day 1) during the virtually defined drug-free state at week 12 are determined using the Movement Disorders Society Unified Parkinson's Rating Scale (MDS-UPDRS) , Part 3. The variation from baseline (day 1) in clinical function, motor function, and activities of daily living at week 12 during the medication state are assessed by: MDS-UPDRS Parts 1-4; Montreal Cognitive Assessment (MoCA); Schwab and England Activities of Daily Living Scale (SE-ADL); Clinical Severity Impression Index - PD (CISI-PD); PD-39 Quality of Life Questionnaire (PDQ-39); Sheehan's Suicide Screening Scale (S-STS); and a timed 10-meter walk (also assessed in the non-medication state).

[00403] "It should be understood that the present invention is not limited to the particular aspects described, since they may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[00404] "Where a range of values is provided, it must be understood that each intermediate value, up to the tenth of the unit of the minimum limit, unless the context clearly indicates otherwise, between the maximum and minimum limits of this range and any other established or intermediate value in this established range is covered by the invention. The maximum and minimum limits of these secondary bands po-

they must independently be included in the secondary ranges and are also included in the invention, subject to any specifically excluded limit in the established range. Where the established range includes one or both of the limits, ranges that exclude either or both of the included limits are also included in the invention.

[00405] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. While any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention, representative illustrative methods and materials have been described.

[00406] All publications and patents cited in this descriptive report are incorporated herein by reference as if each individual publication or patent were specific and individually indicated as being incorporated by reference and are incorporated herein document as a reference to disclose and describe the methods and/or related materials to which the publications are cited. Citation of any publication is for its description prior to the date of deposit and should not be construed as an admission that the present invention is not intended to predate such publication by virtue of the foregoing invention. In addition, the publication dates provided may differ from the actual publication dates, which you may need to confirm independently.

[00407] Note that, as used throughout this document and the appended claims, the singular forms "a, a", and "o, a" include plural references unless the context clearly indicates otherwise. It should also be noted that claims can be drafted to exclude any optional element. As such, this statement is intended to serve as a antecedent basis for the use of unique terminology, such as "only", "only" and so on, in relation to citation of claim elements or use of a "negative limitation". ".

[00408] "As will be apparent to those skilled in the art upon reading this description, each of the individual aspects described and illustrated in this document has distinct components and characteristics that can be easily separated or combined with the characteristics of any of the other various aspects, without departing from the scope or spirit of the present invention. Any cited method can be performed in the order of the cited events or in any other order that is logically possible.

[00409] "Although the foregoing invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it is readily evident to those skilled in the art, in light of the teachings of the present invention, that certain al- amendments and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[00410] Consequently, the foregoing merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various configurations which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. In addition, all the examples and the conditional language cited in this document are intended to help the reader understand the principles of the invention and the concepts contributed by the inventors to facilitate the technique and should be construed as being without limitation to such examples and specific conditions

cited. In addition, all statements contained in this document that cite principles, aspects and characteristics of the invention, as well as specific examples thereof, must cover their structural and functional equivalents.

[00411] In addition, it is intended that such equivalents include both currently known equivalents, as the equivalents developed in the future, that is, any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary aspects shown and described herein. Rather, the scope and spirit of the present invention are incorporated by the appended claims.

Claims (15)

1. Method of treating neurodegenerative disease in an individual diagnosed with neurodegenerative disease, characterized in that it comprises administering a therapeutically effective amount of a compound of formula 1, the N SA Rº v R Ré 1 where A is CH, O or N-C1.6-alkyl; R' is selected from *NHR!I, NMeR'*; and NHR!?, NMeRI?; and NHCHR'?; * NH-Cae-cycloalkyl, whereas optionally one carbon atom is replaced by a nitrogen atom, whereas the ring is optionally substituted with one or two residues selected from the group consisting of C1,6-alkyl, O-C1.6-alkyl, NHSO>-phenyl, NHCONH-phenyl, halogen, CN, SO>z-C1.6-alkyl, COO-C1-6-alkyl; * a Co or 10-bicyclic ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is attached via a nitrogen atom to the basic structure of formula 1 and whereas the ring system is optionally substituted with one or two residues selected from the group consisting of C1,6-alkyl, COO-C1-6-alkyl, C1-6-haloalkyl, O-C1-6-alkyl, NO>, halogen, CN, NHSO»2-C1-6-alkyl, methoxy-phenyl; *and a group selected from NHCH(pyridinyl))CH2COO- C1-6-alkyl, NHCH(CH20-C1-6-alkyl)-benzoimidazolyl optionally substituted with halogen or CN; and or -aminocyclopentyl optionally substituted with methyl-oxadiazole; R is phenyl optionally substituted with one or two residues selected from the group consisting of C1,5-alkyl, C2,6-alkenyl, C1-6-alkynyl, C1-6e-haloalkyl, C1-6-alkylene- OH, Ca6-alkenylene-OH, Ca2-6-alkynylene-OH, CHXCON(C1-6-alkyl)>—-, CHANHCONH-C3a.6-cycloalkyl, CN, CO-pyridinyl, CONR1-- IR1H2, COO-C1.6-alkyl, N(SO2-C1-6-alkyl (CHCCON(C1-1-alkyl)-) O-C1-6-alkyl, O-pyridinyl, SO>2-C1-6 -alkyl, SO>2-C1-6-alkylen-OH, SO>2-C3a.6-cycloalkyl, SO>- piperidinyl, SO2NH-C1.6-alkyl, SO2N(C1-6-alkyl)2, halogen, CN, CO-morpholinyl, CHa-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, NHC1-6-alkyl and =O; RH, Cis-alkyl, Case-cycloalkyl, C1-e-haloalkyl, CH2CON(C1-6-alkyl)—-, = CH2CO-azetindinyl, C1.6-alkylen-Ca.6-cycloalkyl, CHa-pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, C 1-6 -alkylen-OH or thiadiazolyl optionally substituted with C 1-6 -alkyl; R112 H, C1.6-alkyl, SO2C1-6-alkyl; or R111 and R11-2 together form a four, five or six membered carbocyclic ring, optionally containing an N or O, replacing an optionally substituted ring carbon atom with one or two residues selected from the group consisting of C1-6- alkyl, C1-4-alkylene-OH, OH, =O; or R is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently of one another, one or two N, S, or SO;>, substituting a ring carbon atom , wherein the ring is optionally substituted with C 1-1 -alkyl or =O; Ri ? is selected from * —heteroaryl optionally substituted with one or two residues selected from the group consisting of C1,6-alkyl, C2,6-alkenyl, C2,6-alkynyl, Ca.e-cycloalkyl, CHXCOO-C1-6-alkyl, CONR! 21 R122, COR123, COO-C1.6-alkyl, CONH2, O-C1.6-alkyl, halogen, CN, SO2N(C1-6-alkyl), or heteroaryl optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl; and heteroaryl optionally substituted with a five- or six-membered non-aromatic carbocyclic ring containing independently of one another two N, O, S, or SO', substituting a ring carbon atom; and a Cs or 1o-bicyclic aromatic or non-aromatic ring, whereas one or two carbon atoms are replaced by N, O or S each optionally substituted with one or two residues selected from the group consisting of N(C1-6 -alkyl)-, CONH-C1-6-alkyl, =O; *and a non-aromatic heterocyclic ring optionally substituted with pyridinyl; and 4,5-dihydro-naphtho[2,1-dlthiazole optionally substituted with NHCO-C1-alkyl, R121 H, C1.6-alkyl, C1.6-alkylene-C3a.6-cycloalkyl, C14-alkylene-phenyl, C1-12-alkylene-furanyl, Ca.e-cycloalkyl, C1-2-alkylene-O -Cr14-alkyl, C1-6e-haloalkyl or a five- or six-membered non-aromatic carbocyclic ring, optionally containing independently of one another, one or two N, O, S, or SO;>, substituting a carbon atom of the ring optionally substituted with 4-cyclopropylmethyl-piperazinyl R122 H,C16-alkyl; R'23 is a five- or six-membered non-aromatic carbocyclic ring, optionally containing independently of one another, one or two N, O, S, or SO;> substituting a ring carbon atom; R'3 is selected from phenyl, heteroaryl or indolyl, each optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, Ca-e-cycloalkyl, O-C1-6-alkyl , O-C1,6-haloalkyl, phenyl, heteroaryl; R? is selected from the group consisting of C1-6-alkylene-phenyl, C1-6-alkylene-naphthyl, and C1-6-alkylene-heteroaryl; each optionally substituted with one, two or three residues selected from the group consisting of C1-6-alkyl, C1-and-haloalkyl, O-C1-6-alkyl, O-C1.6-haloalkyl, halogen; R° is H,Ciealkyl; R° is H,Cie-alkyl; or R? and R° together form a CH2-CH> group; to treat the individual for a neurodegenerative disease. 2. Method according to claim 1, characterized in that the compound of formula 1, A is CH, O or N-C14-alkyl; R' is selected from *NHR!I, NMeR'*; and NHR!?, NMeRI?; and NHCHR'*; * NH-Cae-cycloalkyl, whereas optionally one carbon atom is replaced by a nitrogen atom, whereas the ring is optionally substituted with one or two residues selected from the group consisting of C1,6-alkyl, O-C1.6-alkyl, NHSO>-phenyl, NHCONH-phenyl, halogen, CN, SO>z-C1.6-alkyl, COO-C1-6-alkyl; * a Co or 10-bicyclic ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is attached via a nitrogen atom to the basic structure of formula 1 and whereas the ring system is optionally substituted with one or two residues selected from the group consisting of C1,6-alkyl, COO-C1-6-alkyl, C1-6-haloalkyl, O-C1-6-alkyl, NO>, halogen, CN, NHSO»2-C1-6-alkyl, m-methoxyphenyl; *and a group selected from NHCH(pyridinyl))CH 2 COO-C 1-6 -alkyl, NHCH(CH 20 -C 1-6 -alkyl)-benzoimidazolyl optionally substituted with CI; and or -aminocyclopentyl optionally substituted with methyl-oxadiazolyl; R is phenyl optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, C1-6-haloalkyl, CH2CON(C1-6-alkyl)., CHANHCONH-C3.6-cycloalkyl, CN, CONR!R1-12, COO-C1.6-alkyl, O-C1.6-alkyl, SO2-C1.6-alkyl, SO2-C1.6-alkylen-OH, SO2-C3-6-cycloalkyl, SO>z-piperidinyl, SONH-C1-6-alkyl, SO2N(C1-6-alkyl)-, - halogen, CN, CO-morpholinyl, CH>-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from group consisting of C1-6-alkyl, NHC1.6-alkyl, =O; RH, C1-6-alkyl, y Cae-cycloalkyl, C1-6-haloalkyl, CH2CON(1-6-alkyl)-, CH2CO-azetindinyl, C1-6-alkylen-C3.6-cycloalkyl, CHa-pyranyl, CH >-tetrahydrofuranyl, CH2-furanyl, C1-6-alkylen-OH or thiadiazolyl optionally substituted with C1-6-alkyl; R1-12 H, C1.6-alkyl, SO2C1-6-alkyl; or R!!! and R112 together form a four-, five- or six-membered carbocyclic ring, optionally containing an O, replacing an optionally substituted ring carbon atom with one or two residues selected from the group consisting of CH20H R* ? is selected from * —heteroaryl optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, Ca-e-cycloalkyl, CH2COO-C1.6-alkyl, CONR12/R122, COO-C1.5 -alkyl, CONH>, O-C1.6-alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally substituted with one or two residues selected from the group consisting of C1.6-alkyl; and benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N(C1-6-alkyl)>, CONH-C1- 6-alkyl, =O; and piperidinyl optionally substituted with pyridinyl; and 4,5-dihydro-naphtho[2,1-dlthiazole optionally substituted with NHCO-C1-alkyl, R121 H, C1.6-alkyl; R12? H, C 1-6 -alkyl; A! 3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, C1-6-cycloalkyl, O-C1-6- alkyl, O-C1-6-haloalkyl; R? is selected from CH>-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of Ca1.-alkyl, C1.-haloalkyl, O-C1-6-alkyl, O -C1.6-haloalkyl, halogen; or CH>-thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen; R° is H, C 1 -alkyl; R° is H, C1 ,alkyl; or R? and Rº together form a CH2-CH> group. 3. Method according to claim 1, characterized in that the compound of formula 1 is A is CH7z, O or NMe; R' is selected from * NHR!I, NMeR'*; and NHR!?, NMeRI?; and NHCHR'?; and "NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of C1 -alkyl, NHSO; -phenyl, NHCONH-phenyl, halogen; and NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO>2-C1-1-alkyl, COO-C1-4+-alkyl; and piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO>2-C1-4-alkyl, m-methoxyphenyl; and dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl optionally substituted with one or two residues selected from the group consisting of C 1 -alkyl, COO-C 1 . +-alkyl, C1-4-haloalkyl, O-C1-4-alkyl, NO>2, halogen; *and a group selected from NHCH(pyridinyl))CH 2 COO-C 14 -alkyl, NHCH(CH 20 -C 1-4 -alkyl)-benzoimidazolyl optionally substituted with CI; and or -aminocyclopentyl optionally substituted with methyl-oxadiazolyl; R1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1.4-alkyl, C1-4-haloalkyl, CH2CON(C1-4-alkyl), CHANHCONH-C;3.6-cycloalkyl , CN, CONR 1 -R 1-2, COO -C 14 -alkyl, O-C 14 -alkyl, SO 2 -C 14 -alkyl, SO 2 -C 1-4 -alkylen-OH, SO 2 -C 3-6 -cycloalkyl, SO 2 -z- piperidinyl, SONH- C14-alkyl, SO2N(C1-4-alkyl), halogen, CO-morpholinyl, CH2-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each which optionally substituted with one or two residues selected from the group consisting of C1.4-alkyl, NHC1.4-alkyl, =O; RH, C18-alkyl, Cae-cycloalkyl, C14-haloalkyl, CH2CON(C1-1-alkyl)., CH2CO-azetindinyl, C1-4-alkylen-C1-6-cycloalkyl, CHa-pyranyl, CH>-tetra -hydrofuranyl, CH 2 -furanyl, C 1-4 -alkylen-OH or thiadiazolyl optionally substituted with C 1-4 -alkyl; R1-12 H, C14-alkyl, SO2C1-4-alkyl; or R111 and R11-2 together form a four-, five- or six-membered carbocyclic ring, optionally containing an O, replacing an optionally substituted ring carbon atom with one or two residues selected from the group consisting of CH2OH R 1 is selected from e pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, Ca.6-cycloalkyl, — CHXCOO-C1...-alkyl, CONR!2IR122, — COO-C14-alkyl, CONH>2, O-C1-1-alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C14-alkyl; and benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N(C1-1-alkyl)>, CONH-C1- 4-alkyl, =O; and piperidinyl optionally substituted with pyridinyl; and 4,5-dihydro-naphtho[2,1-dlthiazole optionally substituted with NHCO-C1+4-alkyl, R121 H, C 1 -alkyl; R12? H, C 1 -alkyl; A! 3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C1-4-alkyl, C1-4-cycloalkyl, O-C1-1- alkyl, O-C1-14-haloalkyl; R? is selected from CH>-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of C1-4-alkyl, C14-haloalkyl, O-C14-haloalkyl, halogen; or CH 2 -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen; Rº is H; Rº is H; or R? and Rº together form a CH2-CH> group. 4. Method according to claim 1, characterized in that the formula 1 is A is CH7z, O or NMe; R' is selected from *NHR!I, NMeR'*; and NHR!?, NMeRI?; and NHCHR'*; and "NH-piperidinyl optionally substituted with pyridinyl; and "NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO>-phenyl, NHCONH-phenyl, F; and NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO>Me, COO-t-Bu; and piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO;>-n-Bu, m-methoxyphenyl; and dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl optionally substituted with one or two residues selected from the group consisting of Me, COO-Me, CF3, OMe, NO ;, F, Br; * a group selected from NHCH(pyridinyl))CH2xCOOMe, NHCH(CH2OMe)-benzoimidazolyl optionally substituted with CI; and or -aminocyclopentyl optionally substituted with methyl-oxadiazolyl; R phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CHANHCONH-cyclohexyl, CN, CONR!-IR1-12, COO-Me, COOEt, OMe, SO2Me, SO2CH2CH2O0H, SO2Et, SO>z-cyclopropyl, SO>>-piperidinyl, SONHEt, SO2NMEEt, F, CI, CO-morpholinyl, CH2-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl , oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; R1-11 H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH2-i-Pr, CH2-t-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2- cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, = CH 2 -tetrahydrofuranyl, CH 2 -furanyl, CH 2 XCH 2 O0H or thiadiazolyl optionally substituted with Me; R1-12 H, Me, Et, SO2Me, SO-2Et or R111 and R11-2 together form a four, five or six membered carbocyclic ring, optionally containing an O, replacing an optionally substituted ring carbon atom with one or two residues selected from the group consisting of CH20H R1 is selected from e pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR121R1- 22, COOMe, COOEt, CONH>2, OMe, CI, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted by Me; and benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONH-Me, =O; and 4,5-dihydro-naphtho[2,1-dlthiazole optionally substituted with NHCOMEe, R'2° H, Me; R12? H, Me; R1 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF>2; R? is selected from CH>-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et; or CH 2 -thiophenyl optionally substituted with one or two residues selected from the group consisting of CI, Br; Rº is H; Rº is H; or R? and Rº together form a CH2-CH> group. 5. Method according to claim 1, characterized in that the formula 1 is A is CH7z, O or NMe; R' is selected from and NHR!! and NHR"?, R1 is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Bu, CF3, CHCONMe2, CHANHCONH-cyclohexyl, CN, CONR1-IR1:2, Coo-Me, COOEt, OMe, SO2Me, SO2CH2CH2O0H, SO2Et, SO>z-cyclopropyl, SO>>-piperidinyl, SONHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH2-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl , oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; R111 H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH2-i-Pr, CH2-t-Bu, CH(CH3)CH2CH3, CH2CHF2, CH2CONMe>2, CH2CO-azetindinyl, CH2-cyclopropyl, CHaz -cyclobutyl, CH>-pyranyl, =CH>-tetrahydrofuranyl, CH>2-furanyl, CH2XCH2O0H or thiadiazolyl optionally substituted with Me; R1-1-2 H, Me, Et, SOoMe, SO2Et or R!!! and R112 together form a four, five or six membered carbocyclic ring, optionally containing an O, replacing an optionally substituted ring carbon atom with one or two residues selected from the group consisting of CH20H R* is selected from e pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH 2 COOEt, CONR 1 - 21R1-22, COOMe, COOEt, CONH>2, OMe, CI, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted by Me; and benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONH-Me, =O; and 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMEe, R121 H, Me; R1.22 H, Me; R? is selected from CH>-phenyl or CHa-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, CI, Br, Et R° is H; Rº is H. 6. Method according to claim 1, characterized in that the formula 1 is A is CH7z, O or NMe; R' is selected from 2 CH, N x x X N o À N o / N x) Cs nO, SN No. Ss N. W ! E IF Ne N ” F dd Neon, CH, x AT N N O=Sx, >x; 9 1 1 nes No ne O CH, x, X A HC o x, í A CH. ' Ss XY N S % o Ne 2 Hs E r = *s= ( Í Ox o ' OO O ' ne "Nor, “ N. bS p x & RA, Á O Te CO dv He Ne, ne W He N CH, CH. CH, RE or LOS O N. Os; SB DR O aa O, Õ, O, O, O. À À À À À X x x x x Nº CH OH FX : x N N h o os” = K ( ok o N.O, - TA x O, D N À À x no x CH, X Y N N. -* OD. Y Estao x OH =— N nv N. ES Oo N x À ! NEN x AZ or HN. CH no oo" N LO ' ' “y o * x x CH. He o F H. x N FOOL r as OO O ' x = nv x a " He x nv N N q h V SO 78 CH; NON N x x x x x í ] N R N= o | | to O. Pa and A Õ N N N À À À X X x AX ê neo SOS N NO o AO dd” F no HC 3 N NO X X O-cH He b h AMX P N os No À o. TO. XX in N AO W He cm, x Br F DO ça, oo x, NS. FE F F F Is =N N N CH, OE OO, Oo x X NODE AX = Ns j N NX N CH, DA | Nnooa N o cl N = N = N 7 À À He NO JAR co N N N N NR | À À No? x x x x x o , , , , , , K N Ú N s o R & No E N Ss x F AX Do O £ E O=S, N RR À HnÊ o CH, , , , , X, x W N. o x He Ns Nº x v ? Ne <& S <j Scr, N X o ne o P WON HC | o 7 DS AO SEN eH, CH, CH, o , , , , x, X, xh N NM o X oo NO and o OS / / NH, ne HÉ , , , , x—N x — * N x 'o PA no o NAS NA = e —= = ne Vs , , ”. , He x o NA, H H o — x N x N — o o o N TN JAN AORA, Ex nº — o / o / n and x HC , , , , FH, q x o HN d=N o o: / x Ss x—N À É — o o-CH, | N N He NA N oÊ No / | ; the CH, x | , , , , (> Õ JN o A )=zx NN Ss > o Ho NO o * )=ro Co fa ADA CH, cn, , , , , X, o HN” 1 nº CH, X = & nº NS x N x nd X / oN ho AS À N CH, NOS cn — Y box NNW” no , , , , Q eqe N N x ec, x vn vn NA A “(OD “OD ue o o HC — Hen º V J ' “om, Í “o, , , , , q e o HN x 7 XxN H x CH ox NN o 2H, A 4 / o DO N oo HN CH, / F , , , , H —N # No HX—NH x |ON XxX N o XxX N À N oo / o 4 HH o— o— MeO cl SH, , , , , FAN Xx Xx Xx N Xx N N S O DD) O O N N Wes o x , , , , , CH, JN HCN NS = ne ca, JN “o der No “o ENO o TZ N 1 Nsy x” x xo x” x” H;C—N A e, NS À d o ENO o NÊ 1 NX À [x N N N AN x x x x x rá O He, READ À À NN TR x en NN o N o ONLY N = o CH, HC N ne cH, A “NCH, x NOS N Hex eH, Né À YW VN N o N o N o ne A a A Pá N o) ANN Õ Vas NN ne N—CH, NN—C! O * OS : = fo) ne o HC CH, F - a Y b ADA ú AX N o SO N o N o A oj X Hex ú NN He xvx : “) N ( = 4 N—CH, N o N o In OA bo O = o CH, N No. The AZ; O, xx NY k NN o N o CH, N. o , , , , Ho CH, W a neon, xo WIZ x A À NR x N Ç Fox NYNN o N o dio, bo , , , , Ho WA o — x OA) x NOH (> x do x N NR N o N N. o = o , , , , CH, He H CH, Ç +—N x o o. Y=N CH, Y N NOR fo] N ONO ) TO | HÉ X , , , , o o x A X OH x Ho-N N “o N N dh N N—CH, : CH, CH, o o ne ec a , , , , o o C CH o om No q x ca x DA N V x N bh À h EN CH, N A CH, CH, CH, HC o Injures Ae” Hs e e ne , , , , o “x N x o o o CH N. " ", N ne ú Y 5 ú N N DI "SE "O o o 7 He He F F , , , , o OH o o x PA x CH, x 2H, À N v N a N N 1 N. V N. CH, CH, o fo] o Í Í Í CH, CH, CH, , , , Q and q q e N N N NS W x = Mm XxX = en XxX = CH, = N N. N NE Y NE Ne PNN q N — N— CH, o Br / He ne , , , , nd nº, eN |O "N x XL 4 e ú ' N à N Ni] sn CH. " “om, : ne í A neo x / o N. = He o is O í CH, and o NE h or , , , , x CH. CH, 1 N. b HH 5 Ds xo X—N XxX N Z =NN 0 is N 7 EN 7 ad = o— = o— HE-NÚR CH, Br Meo N=N , , , , ox—N x N x N x Po Do Oo "O 7 4 4 ne"N ne Na ne N : , , , , Q oooxxxxh DA. No No W CH, CH, CH, CH, , , , , o o o x x x = N N N N N N He N CH, CH, CH, x , , , , CN NA. N x AN N nv “ = XH, À N = NO NE A. x NX | 7 v NE N/AN/A CH, N SHOVEL N SHOVEL ne qe " NX—NH x — CH, o X—NA / NS ' o N — o— NEN — = R? is selected from xx FF HC. c1 o F Cc Cc F el xxxxx Br [(°) F Cc F rxx % Xo CH, cl Ls F Br . R° is H; R° is H; or R' and R° together form a CH2-CH> group. 7. Method according to claim 1, characterized in that the compound is a cocrystal of the formula O: Dr R), CG And the "Hm Rº in which R' is C1-6-alkyl, C1-6-haloalkyl, O-C1-6-haloalkyl, halogen; mean 1.20u3; R?? and R?? are each independently selected from H, C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C1-6-cycloalkyl, COO-C1-6-alkyl, O- C1-6-alkyl, CONR2'p1R2b2, halogen; R** is H Cisalkylay, Cosalkyl-Cae-cycloalkyl, C1-6-haloalkyl; R2p? is H, C1,6-alkyl; or R?* and R2??? together are a C3-alkylene group which forms, with the nitrogen atom, a heterocyclic ring, in which optionally a carbon atom or the ring is replaced by an oxygen atom R° is H, C1,6-alkyl; X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p-toluenesulfonate; j is 0,0.5,1,1.50u2; with a cocrystal former selected from the group consisting of orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, acid 3-hydroxy-2-naphthoic acid, mucic acid (galactaric), pamoic acid (embonic), stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L- lysine, L-proline, D-valine, L-arginine, glycine. 8. Method according to claim 1, characterized in that the compound is a crystalline salt of the formula below, O; O. K Ni A O rs DO = *2HCI 9. Method according to claim 1, characterized in that the compound comprises at least one co-crystal of a compound of the formula according to claim 7, and a pharmaceutically acceptable carrier. 10. Method according to claim 1, characterized in that the compound of formula 1 is administered in the form of the individual optical isomers, a mixture of the individual enantiomers, a racemate or in the form of the compounds enantiomerically pure. 11. Method according to claim 1, characterized in that the compound is a pharmaceutical composition comprising, as an active ingredient, one or more compounds of the formula below, SO CG VE — NR? IV) OD (Hm, 1 wherein R' is H, C1-6-alkyl, Cos-C1-6-alkyl-cycloalkyl, C1-6-haloalkyl; R' is H, C1-6-alkyl; X is an anion selected from the group consisting of chloride or 1-dibenzoyltartrate; j is 1 or -2, a first diluent, a second diluent, a binder, a disintegrant and a lubricant. 12. Method according to claim 11, characterized in that the pharmaceutical composition further comprises an additional disintegrant. 13. Method according to claim 11 or 12, characterized in that the pharmaceutical composition further comprises an additional glidant. 14. Method according to claim 11, 12 or 13, characterized in that the pharmaceutical composition diluent further comprises cellulose powder, dibasic calcium phosphate anhydride, dibasic calcium phosphate dehydrate, erythritol, hydroxypropyl low-substituted cellulose, mannitol, pregelatinized starch or xylitol. 15. Method according to any one of the preceding claims, characterized in that the neurodegenerative disease belongs to the group consisting of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, lateral sclerosis amyotrophic, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy. Dex 1000: 166.2 i EE 19G, 2 weeks 900. am FSSSIBEICEA 800 í SN 19G, 2 weeks 700 sã i In Compound 1, HI.2 weeks , x : õ : In Compound 1, LI, 2 weeks to 6oo Í In Comp g Soo : In Compound 1, LI, 4 weeks = 1st x Õ [RE * í NE SS o SSESSESSN 2months — 18 months Bra 46 ; i EERE 19G, 2 weeks E, 1gG, 2 weeks pa > 30 i Compound 1, HI, 2 weeks & : mm Compound 1,LI,2 weeks 8 i 3 20 i E i Ô Í 10- ô Â peê 10 ps o AES ss 2months — 18 months