Methods and compositions for treating aging-associated impairments using CCR3-inhibitors

Abstract

Methods of improving neurodegenerative disease with CCR3 modulating agents are provided, including compounds of the following formula: [Image disponible dans le document PDF, Image available in the PDF document] The methods include administering a therapeutically effective amount of the CCR3 modulating agent to the subject, with a concomitant improvement in cognition, motor, or other neurodegenerative-affected function. Cognitive and motor diseases upon 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

METHODS AND COMPOSITIONS FOR TREATING AGING-ASSOCIATED IMPAIRMENTS USING CCR3- INHIBITORS I. Cross-Reference to Related Applications This application claims priority to the filing dates of: United States Provisional Patent Application No. 62 / 482,137, filed April 5, 2017; United States Provisional Patent Application No. 62 / 560,940, filed September 20, 2017; and United States Provisional Patent Application No. 62 / 620,921, filed January 23, 2018. II. Introduction The following is offered as background information only and is not admitted to be prior art to the present invention. Aging is an important risk factor for multiple 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 to the neuronal and cognitive impairment associated with these conditions. As such, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases such as Alzheimer's disease (AD) (Bishop, N.A. et al., Neural mechanisms of ageing and cognitive decline. Nature 464(7288), 529-535 (2010); Heeden, T. et al., Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5(2), 87-96 (2004); Mattson, M.P., et al., Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7(4), 278-294 (2006)). Aging affects all tissues and functions of the body including the central nervous system, and a decline in functions such as cognition and motor activity can severely impact quality of life. Treatment for cognitive and motor decline associated with neurodegeneration has achieved limited success in preventing and reversing impairment. It is therefore important to identify new treatments for maintaining cognitive integrity by protecting against, countering, or reversing the effects of aging. Unfortunately, drug treatments for cognitive and motor impairment face significant hurdles. For example, it is thought that for treatments such as small molecules to be effective in treating cognitive decline and motor activity, they must cross the 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 Am. Society for Experimental NeuroTherapeutics, 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 has one of the highest failure rates for clinical development of any disease area (99.6% failure in the last 20 years). (Id.; and Burke, M., Renewed focus on dementia checked by drug challenges, Chemistry World, Jul. 3, 2014). Those BBB-permeable drugs that are approved for treatment of cognitive disease like Alzheimer's, such as donepezil, exhibit temporary effects and do not work on all patients. (Banks, W.A., Drug Delivery to the Brain in Alzheimer's Disease: Consideration of the Blood-brain Barrier, Adv. Drug. Deliv. Rev. 64(7):629-39 (2012); and Burke, M. supra). Similarly, levodopa which treats Parkinson's disease symptoms like motor deficits and crosses the BBB, eventually loses its efficacy. An additional hurdle for treatments that do cross the BBB is that making compounds more lipophilic (which tends to make them more BBB-penetrating) also often results in increased removal from the blood, leading to decreased bioavailability. Hence, the increase in lipophilicity offsets the plasma area under the curve (AUC), minimizing brain uptake. (Pardridge, William M, supra). ПІ. Summary The present invention overcomes these drawbacks. For example, Compound 1, a compound of the invention, has exhibited resistance in crossing the BBB in significant concentrations yet unexpectedly results in improvement of symptoms associated with age-related neurodegeneration and age-related motor decline. Thus, the present invention can act in a peripheral manner, forgoing what was considered to be a requirement for effective cognitive- acting pharmaceuticals, i.e. to work directly on central nervous system. And although certain embodiments of the invention may cross the BBB in significant concentrations, their ability to antagonize the CCL11 / CCR3 pathway offers an alternative mechanism of action to current therapy for cognitive and motor defects. The compounds of the invention act as antagonists of c-c motif chemokine receptor 3 (CCR3), the receptor for Eotaxin-1. Eotaxin-1 (CCL11) is a protein that is increased in levels in blood plasma with aging and which has been shown to cause decreases 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 primarily on the G-protein coupled receptor CCR3 which is expressed on eosinophils in the periphery and on neurons and glial cells in the central nervous system. (Xia, M, et al., Immunohistochemical Study of the <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>- 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 disease, it has been observed that CCR3 levels are increased in the CNS. (Id.) The cognitive effects of antagonizing CCR3 in Alzheimer's disease and related disorders would thus be expected to be mediated by centrally located eotaxin-1 / CCR3 interaction. However, Compound 1 (a compound of the invention), unexpectedly resulted in improving cognitive function and stimulating neurogenesis despite its inability to cross the BBB in significant concentrations. Methods of treating patients for aging-associated impairments, 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 disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy, and the like. Aspects of the methods include modulation of CCR3, the principal receptor of CCL11 / eotaxin-1 through the administration of a therapeutically effective amount of CCR3 antagonists of the invention. The methods include administering an effective therapeutic dose of CCR3 antagonists to subjects or patients as well as monitoring for specific clinical endpoints. Also included are methods of treating neurodegenerative disease and associated cognitive and motor decline with an agent that acts peripherally, i.e. does not cross the blood-brain barrier in significant concentrations, yet exhibits improvement in the disease, such as improved cognition or motor activity. IV. Incorporation by Reference V. Brief Description of the Figures Figure 1A depicts the sum of doublecortin (DCX) positive cells in the hippocampus of: 2-month-old 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 either a high (n=16) or low dose (n=31); and 18-month-old mice treated with Compound 1 ("Cmpd 1") for 4 weeks at a low dose (n=16). Data shown are the mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m., where *P<0.05, ***P<0.001. Figure 1B depicts the sum of 5-bromo-2'-deoxyuridine (BrdU) positive cells in the hippocampus of: 2-month-old 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 either a high (n=16) or low dose (n=24). Data shown are the mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m., where ***P<0.001. Figure 2A depicts the effect of Compound 1 on the time spent by young and old C57B1 / 6 mice in the novel (N) versus familiar / old ("F" or "O") arm during a Y-maze test. 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 the mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m., where **P<0.05, ***P<0.01 Figure 2B depicts the effect of Compound 1 on the total number of visits made by young and old C57B1 / 6 mice into the novel (N) versus familiar (F) arm during a Y-maze test. 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 the mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m., where *P<0.05, **P<0.01, ***P<0.001. Figure 3 depicts the effect of Compound 1 on bouts of entry ("number of visits") into the novel and familiar arms by C57B1 / 6 mice in the Y-maze test. The number of visits to each arm was plotted for each treatment group and subjected to paired t-test. 3-month-old mice (n=15) received an infusion of vehicle (veh) subcutaneously by Alzet mini-pump (0.5µL / hour) for four weeks, with one replacement. 16.5-month-old mice were infused subcutaneously with either vehicle (veh, n=16) or 50 mg / mL Compound 1 (n=16) by Alzet mini-pump (0.5μL / hour) for four weeks with one replacement. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05. Figure 4A depicts the effect of Compound 1 on average time taken by C57B1 / 6 mice to find the target hole in the Barnes Maze test. Average times were plotted for each treatment group. 3-month-old mice (n=18) received an infusion of vehicle (veh) subcutaneously by Alzet mini-pump (0.5µL / hour) for four weeks, with one replacement. 16.5-month-old mice were infused subcutaneously with either vehicle (veh, n=15) or 50 mg / mL Compound 1 (n=15) by Alzet mini-pump (0.5<com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L / hour) for four weeks with one replacement. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 4B depicts the effect of Compound 1 on the difference in latency to find the target hole between the last and first trial of the last day of the Barnes Maze test in C57B1 / 6 mice. The differences were plotted for each treatment group and the data subjected to an unpaired t-test. 3- month-old mice (n=18) received an infusion of vehicle (veh) subcutaneously by Alzet mini- pump (0.5µL / hour) for four weeks, with one replacement. 16.5-month-old mice were infused subcutaneously with either vehicle (veh, n=15) or 50 mg / mL Compound 1 (n=15) by Alzet mini- pump (0.5<com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L / hour) for four weeks with one replacement. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 5 depicts the effect of Compound 1 on neurogenesis in C57B1 / 6 mice by detection of BrdU positive cells from all sections in the dentate gyrus. The number of cells positive for BrdU from the dentate gyrus were plotted for each treatment group and the data subjected to an unpaired t-test between the 16.5-month-old groups. 3-month-old mice (n=17) received an infusion of vehicle (veh) subcutaneously by Alzet mini-pump (0.5µL / hour) for four weeks, with one replacement. 16.5-month-old mice were infused subcutaneously with either vehicle (veh, n=17) or 50 mg / mL Compound 1 (n=17) by Alzet mini-pump (0.5μL / hour) for four weeks with one replacement. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05. Figure 6 depicts the levels of Compound 1 detected in the CSF of C57BL / 6 mice in both young (n=2) and old groups (n=3) (levels were both below 10 nM). Levels of Compound 1 were detected using mass spectrometry. Figure 7 depicts the distribution (measured as area under the curve (AUC)) of Compound 1 in C57BL / 6JOlaHsd mouse tissues over a time course. Compound was tagged with carbon-14 label, and measurements taken at 1, 24, and 168 hours. Figure 8 depicts the pharmacokinetic profiles of Compound 1 after per os (P.O.) dosing. Blood plasma from male 2-month-old C57Bl / 6 mice receiving either 30 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 administration. Plasma concentration after drug administration was plotted over time. Figure 9 depicts the effect of Compound 1 on exploratory preference during the Open Field test in young C57B1 / 6 mice. Exploratory preference was plotted as the ratio of time spent in the periphery vs. center and data was subjected to a one-way ANOVA. 2-month-old mice were treated with: vehicle p.o. b.i.d. (n=11); Compound 1 p.o. b.i.d. 30 mg / kg (n=12); vehicle p.o. b.i.d. plus recombinant mouse CCL11 (eotaxin-1, or "rmE") i.p. (n=14); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=14). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; **P<0.01. Figure 10A depicts the effect of Compound 1 on the time spent in the novel versus familiar arms of the Y-maze test in young C57B1 / 6 mice. The time spent in the novel versus familiar arms were plotted for each treatment group and data was 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 recombinant mouse CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=15). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; **P<0.01. Figure 10B depicts the effect of Compound 1 on the ratio of time spent in the novel versus familiar arm of the Y-maze test in young C57B1 / 6 mice. Ratios were plotted for each treatment group and data was subjected to an ANOVA Kruskal-Wallis test post-hoc. 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 recombinant mouse CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=15). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *P<0.05. Figure 10C depicts the effect of Compound 1 on the ratio of number of entries made into the novel versus familiar arm of the Y-maze test in young C57B1 / 6 mice. Ratios were plotted for each treatment group and data was subject to a t-test between vehicle and recombinant mouse CCL11 treatment. 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 recombinant mouse CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=15). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *P<0.05. Figure 11A depicts the effect of Compound 1 on the average latency to find the target hole during the Barnes Maze test in young C57B1 / 6 mice. Average latencies were plotted as units of time for each treatment group on each trial. 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 recombinant mouse CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=15). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 11B depicts the effect of Compound 1 on the latency to find the target hole during the Barnes Maze test in young C57B1 / 6 mice. Latencies averaged over the last three trials for each treatment group were plotted and data was subjected 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 recombinant mouse CCL11 (eotaxin-1) i.p. (n=15); or Compound 1 p.o. b.i.d. 30 mg / kg plus recombinant mouse CCL11 (n=15). Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *P<0.05. Figure 12A depicts the effect of Compound 1 on memory for the novel arm in the Y maze, by number of entries made into the novel arm over 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 <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; **P<0.01. Figure 12B depicts the effect of Compound 1 on total distance travelled 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 <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *P<0.05. Figure 13A depicts the effect of Compound 1 on bouts of entry ("number of visits") into the novel and familiar arms by C57B1 / 6 mice in the Y-maze test in 24-month-old mice. The number of visits to each arm was plotted for each treatment group and subjected to a paired t- test. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Y-maze testing. All mice received 5 consecutive days of BrdU injection at 50 mg / kg IP immediately prior to start of treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, ***<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.001 novel vs familiar arm by paired student's t-test. Figure 13B depicts the effect of Compound 1 on the ratio of number of entries made into the novel versus familiar arm of the Y-maze test in 24-month-old mice. Ratios were plotted for each treatment group and data was subject to a t-test between vehicle and Compound 1 treatment. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Y- maze testing. All mice received 5 consecutive days of BrdU injection at 50 mg / kg IP immediately prior to start of treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, ***P<0.001 compared to control by student's t-test. Figure 13C depicts the effect of Compound 1 on the time spent in the novel versus familiar arms of the Y-maze test in 24-month-old C57B1 / 6 mice. The time spent in the novel versus familiar arms were plotted for each treatment group and data was subjected to a paired t- test. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Y-maze testing. All mice received 5 consecutive days of BrdU injection at 50 mg / kg IP immediately prior to start of treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, ***<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.001 novel vs familiar arm by paired student's t-test. Figure 13D depicts the effect of Compound 1 on the ratio of time spent ("duration") in the novel versus familiar arm of the Y-maze test in 24-month-old C57B1 / 6 mice. Ratios were plotted for each treatment group and data was subjected to a t-test. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Y-maze testing. All mice received 5 consecutive days of BrdU injection at 50 mg / kg IP immediately prior to start of treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, ***<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.001 compared to control by student's t-test. Figure 13E depicts the effect of Compound 1 on the average velocity during the Y-Maze test of 24-month-old C57B1 / 6 mice. Average velocities were plotted for each treatment group and data was subject to a t-test. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Y-maze testing. All mice received 5 consecutive days of BrdU injection at 50 mg / kg IP immediately prior to start of treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, ***<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.001 compared to control by student's t-test. Figure 14A depicts the effect of Compound 1 on average time taken by 24-month-old C57B1 / 6 mice to find the target hole in the Barnes Maze test. Average times were plotted for each treatment group. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Barnes Maze testing. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05 compared to control by student's t-test. Figure 14B depicts the effect of Compound 1 on velocity in 24-month-old C57B1 / 6 mice in Barnes Maze test, averaged over all trials for each treatment group. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Barnes Maze testing. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; *P<0.05 compared to control by student's t-test. Figure 15A depicts the effect of Compound 1 on distance traveled in the Open Field test in 24-month-old C57B1 / 6 mice. Average distance traveled was plotted for each treatment group. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Open Field testing. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 15B depicts the effect of Compound 1 on velocity in the Open Field test in 24- month-old C57B1 / 6 mice. Average velocity of the mice was plotted for each treatment group. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Three weeks later, mice were subjected to Open Field testing. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 16A depicts the effect of Compound 1 on TNFalpha cytokine levels in the plasma of 24-month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of the inflammatory cytokine trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 16B depicts the effect of Compound 1 on IL6 cytokine levels in the plasma of 24- month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of the inflammatory cytokine trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 16C depicts the effect of Compound 1 on IL1beta cytokine levels in the plasma of 24-month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of the inflammatory cytokine trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 16D depicts the effect of Compound 1 on IL5 cytokine levels in the plasma of 24- month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of the inflammatory cytokine trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 16E depicts the effect of Compound 1 on IL17 cytokine levels in the plasma of 24-month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of the inflammatory cytokine trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 17 depicts the effect of Compound 1 on activated microglia in 24-month-old C57Bl / 6 mice. Mice 23 months-old were dosed with either vehicle control or Compound 1 subcutaneously BID (twice daily) for 21 days. Levels of CD68+ activated microglia trend lower in Compound 1 treated mice than in vehicle treated mice. Figure 18 depicts the effect of Compound 1 on the percentage of eosinophils in complete white blood cell (WBC) count, in 24-month-old C57BI / 6 mice treated with control saline or 30 mg / kg of Compound 1 for 3 weeks BID, SQ. Compound 1 decreased an endogenous age-related increase in blood eosinophils. Figure 19 depicts the effect of Compound 1 on the percentage of eosinophils in complete white blood cell (WBC) count, in 3-month-old hairless mice treated with control saline or 30 mg / kg of Compound 1 for 2 weeks BID, PO. Compound 1 decreased an oxazolone-induced increase in blood eosinophils. Figure 20 shows the results of Compound 1 on a rotarod test for motor coordination. Twenty-four-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle by osmotic pump. Treated mice succeeded more than vehicle-treated mice in a binomial test, <com:Math><semantics>P<0.05<annotation encoding="application / x-tex">P < 0.05< / annotation>< / semantics>< / com:Math>. Figure 21 shows the results of Compound 1 on the T maze test for memory. Twenty- four-month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle by osmotic pump. Treated mice succeeded more than vehicle-treated mice in a binomial test, <com:Math><semantics>*P<0.05<annotation encoding="application / x-tex">*P < 0.05< / annotation>< / semantics>< / com:Math>. Figure 22A shows the results of Compound 1 on fecal output overnight. Twenty-four- month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle by osmotic pump. The weight of fecal pellets was measured overnight. Compound 1 treated mice had significantly lower fecal output compared to vehicle treated mice by student's t- test, <com:Math><semantics>*P<0.05<annotation encoding="application / x-tex">*P < 0.05< / annotation>< / semantics>< / com:Math>. Figure 22B shows the results of Compound 1 on water drinking overnight. Twenty-four- month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle by osmotic pump. The total water drank was measured overnight. Compound 1 treated mice drank significantly more water compared to vehicle treated mice by student's t-test, *P < 0.05. Figure 22C shows the results of Compound 1 on food intake overnight. Twenty-four- month-old C57 mice were treated for 4 weeks with continuous infusion of Compound 1 or vehicle by osmotic pump. The total food eaten was measured overnight. There were no differences in total food intake overnight between the two groups. Figure 23 depicts the effect of Compound 1 (Cmpd 1) on the numbers of CD68-positive (CD68+) activated microglia within the brains of three-month-old mice treated with LPS and treated with Compound 1 for 18 days. Compound 1-treated mice exhibited decreased CD68+ immunoreactivity, and thus decreased gliosis. Figures 24A-24B depict the effect of Compound 1 on anxiety in the Open Field test in three-month-old mice treated with LPS IP for 4 weeks and treated with Compound 1 per orally BID (twice daily) for 1 week. LPS treatment increased the preference for the periphery of the Open Field, indicating increased anxiety. Compound 1 treatment decreased the LPS-induced anxiety in the Open Field. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m; *P < 0.05 by student's t-test. Figures 25A-25B depict the effect of Compound 1 on number of entries into the novel and familiar arms in the Y-maze test by 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. Mice 3 months-old were dosed with either vehicle or LPS IP for 6 weeks, and dosed with vehicle control or Compound 1 per orally BID (twice daily) for 3 weeks. Compound 1-treated mice showed a significant preference for the novel arm while vehicle-treated mice did not. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; **<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.01, *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, novel vs familiar arm by paired student's t-test. Figures 26A-26B depict the effect of Compound 1 on IL1beta mRNA in the brains from 3-month-old C57B1 / 6 mice treated with LPS and / or Compound 1. Mice were dosed with either vehicle control or LPS IP for 7 weeks, and dosed with vehicle or Compound 1 per orally BID (twice daily) for 4 weeks. Tissues were harvested and RNA was prepared from cortical brain tissues. Levels of IL1beta mRNA were measured by qPCR and data are presented relative to vehicle control. There was a trend towards increased levels of IL1beta mRNA with LPS treatment and a significant decrease with Compound 1 treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m; *<com:Math><semantics>P<0.05<annotation encoding="application / x-tex">P < 0.05< / annotation>< / semantics>< / com:Math> by student's t-test. Figures 27A-27C depict the effect of Compound 1 on microglia activation in the hippocampus from 3-month-old C57B1 / 6 mice treated with LPS and / or Compound 1. Mice were dosed with either vehicle control or LPS IP for 7 weeks, and dosed with vehicle or Compound 1 per orally BID (twice daily) for 4 weeks. Tissues were harvested and brain sections were subjected to immunohistochemistry for CD68, a marker for activated microglia. There was a trend towards increased levels of CD68 with LPS treatment and a robust trend towards decrease with Compound 1 treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figures 28A-28C depict the effect of Compound 1 on total microglia in the hippocampus from 3-month-old C57B1 / 6 mice treated with LPS and / or Compound 1. Mice were dosed with either vehicle control or LPS IP for 7 weeks, and dosed with vehicle or Compound 1 per orally BID (twice daily) for 4 weeks. Tissues were harvested and brain sections were subjected to immunohistochemistry for Iba1, a marker for microglia. There was a significant increase in Iba1 with LPS treatment and a trend towards decrease with Compound 1 treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m.; ***<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.001, *<com:Math><semantics>P<annotation encoding="application / x-tex">P< / annotation>< / semantics>< / com:Math><0.05, by student's t-test. Figures 29A-29B depict the effect of Compound 1 on total astrocytes in the hippocampus from 3-month-old C57B1 / 6 mice treated with LPS and / or Compound 1. Mice were dosed with either vehicle control or LPS IP for 7 weeks and dosed with vehicle or Compound 1 per orally BID (twice daily) for 4 weeks. Tissues were harvested, and brain sections were subjected to immunohistochemistry for GFAP, a marker for astrocytes. There was a trend towards decrease with Compound 1 treatment. Data shown are mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> s.e.m. Figure 30A depicts the treatment study timeline for a mouse MPTP model of Parkinson's Disease. Figure 30B summarizes the behavioral, biochemical, and histological endpoints for a mouse MPTP model of Parkinson's Disease. Figure 31 depicts plasma eotaxin-1 levels in 6-month-old Line 61 synuclein- overexpressing transgenic mice. Eotaxin-1 levels (CCL11) in Non-transgenic (NTg) versus transgenic Line 61 synuclein mice (Tg) were plotted at pg / mL concentrations. Figure 32 summarizes behavioral, biochemical, and histological endpoints for synuclein transgenic mouse models treated with vehicle and Compound 1. Figure 33 depicts the concentrations of human eotaxin-1 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 18, 30, 45, 55, and 66-year-old donors were plotted. Figure 34A depicts the effect of Compound 1 on inhibition of eosinophil shape change. Whole blood from humans treated with Compound 1 was incubated with recombinant eotaxin to trigger eosinophil shape change. Inhibition of shape change was plotted against plasma Compound 1 concentrations. Figure 34B 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 internalization by Compound 1 was plotted against plasma Compound 1 concentrations. VI. Detailed Description Aspects of the invention include methods of treating aging-associated impairments / neurodegenerative diseases. The aging-associated impairment may manifest in a number of different ways, e.g., as aging-associated cognitive impairment and / or physiological impairment, e.g., in the form of damage to central or peripheral organs of the body, such as but not limited to: cell injury, tissue damage, organ dysfunction, aging-associated lifespan shortening and carcinogenesis, where specific organs and tissues of interest include, but are not limited to skin, neuron, muscle, pancreas, brain, kidney, lung, stomach, intestine, spleen, heart, adipose tissue, testes, ovary, uterus, liver and bone; in the form of decreased neurogenesis, etc. In some embodiments, the aging-associated impairment is an aging-associated impairment in cognitive ability in an individual, i.e., an aging-associated cognitive impairment. By cognitive ability, or "cognition", it is meant the mental processes that include attention and concentration, learning complex tasks and concepts, memory (acquiring, retaining, and retrieving new information in the short and / or long term), information processing (dealing with information gathered by the five senses), visuospatial function (visual perception, depth perception, using mental imagery, copying drawings, constructing objects or shapes), producing and understanding language, verbal fluency (word-finding), solving problems, making decisions, and executive functions (planning and prioritizing). By "cognitive decline", it is meant a progressive decrease in one or more of these abilities, e.g., a decline in memory, language, thinking, judgment, etc. By "an impairment in cognitive ability" and "cognitive impairment", it is meant a reduction in cognitive ability relative to a healthy individual, e.g., an age-matched healthy individual, or relative to the ability of the individual at an earlier point in time, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years or more previously. Aging- associated cognitive impairments include impairments in cognitive ability that are typically associated with aging, including, for example, cognitive impairment associated with the natural aging process, e.g., mild cognitive impairment (M.C.I.); and cognitive impairment associated with an aging-associated disorder, that is, a disorder that is seen with increasing frequency with increasing senescence, e.g., 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 the like. By "treatment" it is meant that at least an amelioration of one or more symptoms associated with an aging-associated impairment afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., a symptom associated with the impairment being treated. As such, treatment also includes situations where a pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the adult mammal no longer suffers from the impairment, or at least the symptoms that characterize the impairment. In some instances, "treatment", "treating" and the like refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. "Treatment" may be any treatment of a disease in a subject, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease. Treatment may result in a variety of different physical manifestations, e.g., modulation in gene expression, increased neurogenesis, rejuvenation of tissue or organs, etc. Treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, occurs in some embodiments. Such treatment may be performed prior to complete loss of function in the affected tissues. The subject therapy may be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease. In some instances where the aging-associated impairment is aging-associated cognitive decline, treatment by methods of the present disclosure slows, or reduces, the progression of aging-associated cognitive decline. In other words, cognitive abilities in the individual decline more slowly, if at all, following treatment by the disclosed methods than prior to or in the absence of treatment by the disclosed methods. In some instances, treatment by methods of the present disclosure stabilizes the cognitive abilities of an individual. For example, the progression of cognitive decline in an individual suffering from aging-associated cognitive decline is halted following treatment by the disclosed methods. As another example, cognitive decline in an individual, e.g., an individual 40 years old or older, that is projected to suffer from aging-associated cognitive decline, is prevented following treatment by the disclosed methods. In other words, no (further) cognitive impairment is observed. In some instances, treatment by methods of the present disclosure reduces, or reverses, cognitive impairment, e.g., as observed by improving cognitive abilities in an individual suffering from aging-associated cognitive decline. In other words, the cognitive abilities of the individual suffering from aging-associated cognitive decline following treatment by the disclosed methods are better than they were prior to treatment by the disclosed methods, i.e., they improve upon treatment. In some instances, treatment by methods of the present disclosure abrogates cognitive impairment. In other words, the cognitive abilities of the individual suffering from aging-associated cognitive decline are restored, e.g., to their level when the individual was about 40 years old or less, following treatment by the disclosed methods, e.g., as evidenced by improved cognitive abilities in an individual suffering from aging-associated cognitive decline. In some instances where the aging-associated impairment is aging-associated motor impairment or decline, treatment by methods of the present disclosure slows, or reduces, the progression of aging-associated impairment or decline. In other words, motor abilities in the individual decline more slowly, if at all, following treatment by the disclosed methods than prior to or in the absence of treatment by the disclosed methods. In some instances, treatment by methods of the present disclosure stabilizes the motor abilities of an individual. For example, the progression of motor decline in an individual suffering from aging-associated motor decline is halted following treatment by the disclosed methods. As another example, motor decline in an individual, e.g., an individual 40 years old or older, that is projected to suffer from aging- associated motor decline, is prevented following treatment by the disclosed methods. In other words, no (further) motor impairment is observed. In some instances, treatment by methods of the present disclosure reduces, or reverses, motor impairment, e.g., as observed by improving motor coordination or abilities in an individual suffering from aging-associated motor decline. In other words, the motor abilities of the individual suffering from aging-associated motor decline following treatment by the disclosed methods are better than they were prior to treatment by the disclosed methods, i.e., they improve upon treatment. In some instances, treatment by methods of the present disclosure abrogates motor impairment. In other words, the motor coordination or abilities of the individual suffering from aging-associated motor decline are restored, e.g., to their level when the individual was about 40 years old or less, following treatment by the disclosed methods, e.g., as evidenced by improved motor coordination or abilities in an individual suffering from aging-associated motor decline. In some instances, treatment of an adult mammal in accordance with the methods results in a change in a central organ, e.g., a central nervous system organ, such as the brain, spinal cord, etc., where the change may manifest in a number of different ways, e.g., as described in greater detail below, including but not limited to molecular, structural and / or functional, e.g., in the form of enhanced neurogenesis. Methods of treating dysfunction caused by neurodegenerative disease are provided, the method comprising administering compounds from the formulae discussed below. An embodiment of the invention comprises a method of improving cognition or motor activity in subjects with brain-associated, cognitive-associated, or motor disease, the method comprising administering a therapeutically effective amount of a compound from the chemical formulae discussed below. Additional embodiments of the invention comprise a method of increasing neurogenesis in subjects with brain- or cognitive-associated disease, the method comprising administering a therapeutically effective amount of a compound from the chemical formulae discussed below. Additional embodiments of the invention comprise a method of alleviating or treating symptoms of brain- or cognitive-associated disease, the method comprising administering a therapeutically effective amount of a compound from the chemical formulae below. Additional embodiments of the invention include methods of alleviating symptoms of central nervous system-associated disease, the method comprising administering a therapeutically effective amount of a primarily peripheral-acting agent from the chemical formulae below. Further additional embodiments of the invention include methods of improving motor activity in a subject with age-related motor dysfunction, the method comprising administering a therapeutically effective amount of a compound from the chemical formulae discussed below. The methods of the invention may also comprise monitoring improvement in age-related disease, including for example, improvement in cognition, motor activity, neurogenesis and the like in a subject diagnosed with one or more such disease or dysfunction. Additional embodiments of the invention include administering a therapeutically effective amount of a compound wherein the compound is in the form of the co-crystals or salts of the formulae discussed below. Further 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 the 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 the pharmaceutical compositions and formulations further discussed below. Additional embodiments of the invention that treat aging-associated motor impairment or decline include modifying agents which inhibit the eotaxin / CCR3 pathway. Such modifying agents include not only compounds from the formulae discussed below, but other eotaxin and CCR3 inhibiting agents. Modifying agents that are contemplated include by way of example and not of limitation: the compounds of the formulae discussed below and other CCR3 small molecule inhibitors (e.g. bipiperdine derivatives described for example in U.S. Patent No. 7,705,153, cyclic amine derivatives described for example in U.S. 7,576,117, and the CCR3 antagonists described in Pease JE and Horuk R, Expert Opin Drug Discov (2014) 9(5):467-83); anti-eotaxin antibodies; anti-CCR3 antibodies; aptamers that inhibit either eotaxin or CCR3 expression or function (methods of producing such aptamers include U.S. Pat. Nos. 5,270,163, 5,840,867, 6,180,348); antisense oligonucleotides or siRNAs that inhibit expression or function of either eotaxin or CCR3 (e.g. described in U.S. Pat. No. 6,822,087); soluble CCR3 receptor protein (e.g. decoys); and the like. a. Compounds The methods of the invention further comprise administration to a subject of the compounds that follow. In the groups, radicals, or moieties defined in this "Compounds" section, the number of carbon atoms is often specified preceding the group, for example, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups which are disclosed in this "Compounds" section, the last- named group is the radical attachment point, for example, "thioalkyl" means a monovalent radical of the formula HS-Alk-. Unless otherwise specified below, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. An embodiment of the invention further comprises administration to a subject of the compounds of formula 1, wherein [Image disponible dans le document PDF, Image available in the PDF document] A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-6< / com:Sub>-alkyl; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^{1}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; • NH-C<com:Sub>3-6< / com:Sub>-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 <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NHSO2<annotation encoding="application / x-tex">NHSO_2< / annotation>< / semantics>< / com:Math>-phenyl, NHCONH-phenyl, halogen, CN, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, COO-C<com:Sub>1-6< / com:Sub>-alkyl; • a C<com:Sub>9 or 10< / com:Sub>-bicyclic-ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound 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 C<com:Sub>1-6< / com:Sub>-alkyl, COO-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, NO<com:Sub>2< / com:Sub>, halogen, CN, NHSO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, methoxy-phenyl; a group selected from NHCH(pyridinyl)CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-6< / com:Sub>-alkyl, NHCH(CH<com:Sub>2< / com:Sub>O-C<com:Sub>1-6< / com:Sub>-alkyl)-benzoimidazolyl, optionally substituted with halogen or CN; • or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazole <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-6< / com:Sub>-alkenyl, C<com:Sub>2-6< / com:Sub>-alkynyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, C<com:Sub>1-6< / com:Sub>-alkylene- OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenylene-OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynylene-OH, <com:Math><semantics>CH2CON(C1−6<annotation encoding="application / x-tex">CH_2CON(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-C<com:Sub>3-6< / com:Sub>-cycloalkyl, CN, CO-pyridinyl, <com:Math><semantics>CONR1.1.1R1.1.2<annotation encoding="application / x-tex">CONR^{1.1.1}R^{1.1.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COO−C1−6<annotation encoding="application / x-tex">COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>N(SO2−C1−6−alkyl)(CH2CON(C1−4−alkyl)2)<annotation encoding="application / x-tex">N(SO_2-C_{1-6}-alkyl)(CH_2CON(C_{1-4}-alkyl)_2)< / annotation>< / semantics>< / com:Math> O-C<com:Sub>1-6< / com:Sub>-alkyl, O-pyridinyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkylen-OH, SO<com:Sub>2< / com:Sub>-C<com:Sub>3-6< / com:Sub>-cycloalkyl, <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>-piperidinyl, <com:Math><semantics>SO2NH−C1−6<annotation encoding="application / x-tex">SO_2NH-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2N(C1−6<annotation encoding="application / x-tex">SO_2N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, halogen, CN, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, NHC<com:Sub>1-6< / com:Sub>-alkyl and <com:Math><semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one N or O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-OH, OH, =O; or <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently from each other one or two N, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, wherein the ring is optionally substituted with <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COR<com:Sup>1.2.3< / com:Sup>, COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONH<com:Sub>2< / com:Sub>, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, halogen, CN, <com:Math><semantics>SO2N(C1−6<annotation encoding="application / x-tex">SO_2N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub> or heteroaryl optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>, replacing a carbon atom of the ring; a aromatic or non-aromatic <com:Math><semantics>C9 or 10<annotation encoding="application / x-tex">C_{9 \text{ or } 10}< / annotation>< / semantics>< / com:Math>-bicyclic-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 <com:Math><semantics>N(C1−6<annotation encoding="application / x-tex">N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, <com:Math><semantics>CONH−C1−6<annotation encoding="application / x-tex">CONH-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, =0; a heterocyclic non-aromatic ring, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-furanyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-O-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl <com:Math><semantics>𝑹1.2.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹1.2.3<annotation encoding="application / x-tex">\mathbf{R}^{1.2.3}< / annotation>< / semantics>< / com:Math> a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, heteroaryl or indolyl, each optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, phenyl, heteroaryl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-heteroaryl; each optionally substituted with one, two or three residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹4<annotation encoding="application / x-tex">\mathbf{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1 (above), wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-4< / com:Sub>-alkyl; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ1.1<annotation encoding="application / x-tex">\mathbb{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-6< / com:Sub>-alkenyl, C<com:Sub>2-6< / com:Sub>-alkynyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, C<com:Sub>1-6< / com:Sub>-alkylene- OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenylene-OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynylene-OH, <com:Math><semantics>CH2CON(C1−6<annotation encoding="application / x-tex">CH_2CON(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-C<com:Sub>3-6< / com:Sub>-cycloalkyl, CN, CO-pyridinyl, <com:Math><semantics>CONR1.1.1R1.1.2<annotation encoding="application / x-tex">CONR^{1.1.1}R^{1.1.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COO−C1−6<annotation encoding="application / x-tex">COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>N(SO2−C1−6<annotation encoding="application / x-tex">N(SO_2-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)(<com:Math><semantics>CH2CON(C1−4<annotation encoding="application / x-tex">CH_2CON(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>) <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-pyridinyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkylen-OH, SO<com:Sub>2< / com:Sub>-C<com:Sub>3-6< / com:Sub>-cycloalkyl, <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>-piperidinyl, <com:Math><semantics>SO2NH−C1−6<annotation encoding="application / x-tex">SO_2NH-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2N(C1−6<annotation encoding="application / x-tex">SO_2N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, halogen, CN, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NHC1−6<annotation encoding="application / x-tex">NHC_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl,, =0; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one N or O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-OH, OH, =O; or <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently from each other one or two N, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, wherein the ring is optionally substituted with <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1.2<annotation encoding="application / x-tex">R^{1.2}< / annotation>< / semantics>< / com:Math> is selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COR<com:Sup>1.2.3< / com:Sup>, COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONH<com:Sub>2< / com:Sub>, O-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, halogen, CN, <com:Math><semantics>SO2N(C1−4<annotation encoding="application / x-tex">SO_2N(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub> or heteroaryl optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring; <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-furanyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-O-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl <com:Math><semantics>𝑹1.2.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹1.2.3<annotation encoding="application / x-tex">\mathbf{R}^{1.2.3}< / annotation>< / semantics>< / com:Math> a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring; <com:Math><semantics>R1.3<annotation encoding="application / x-tex">R^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, heteroaryl or indolyl, each optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, phenyl, heteroaryl; where in some instances <com:Math><semantics>R1.3<annotation encoding="application / x-tex">R^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, phenyl, pyrrolidinyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-thiophenyl; each optionally substituted with one, two or three residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1 (above), wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-4< / com:Sub>-alkyl; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene- OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenylene-OH, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynylene-OH, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-C<com:Sub>3-6< / com:Sub>-cycloalkyl, CN, CO-pyridinyl, <com:Math><semantics>CONR1.1.1R1.1.2<annotation encoding="application / x-tex">CONR^{1.1.1}R^{1.1.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COO−C1−6<annotation encoding="application / x-tex">COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>N(SO2−C1−6<annotation encoding="application / x-tex">N(SO_2-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)(<com:Math><semantics>CH2CON(C1−4<annotation encoding="application / x-tex">CH_2CON(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>) <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-pyridinyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkylen-OH, SO<com:Sub>2< / com:Sub>-C<com:Sub>3-6< / com:Sub>-cycloalkyl, <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>-piperidinyl, <com:Math><semantics>SO2NH−C1−6<annotation encoding="application / x-tex">SO_2NH-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2N(C1−6<annotation encoding="application / x-tex">SO_2N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, halogen, CN, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NHC1−6<annotation encoding="application / x-tex">NHC_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one N or O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-OH, OH, =O; or <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently from each other one or two N, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, wherein the ring is optionally substituted with <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-thiophenyl; each optionally substituted with one, two or three residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>𝑹3<annotation encoding="application / x-tex">\mathbf{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>𝑪1−4<annotation encoding="application / x-tex">\mathbf{C}_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein <com:Math><semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-4< / com:Sub>-alkyl; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^{1}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COR<com:Sup>1.2.3< / com:Sup>, COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONH<com:Sub>2< / com:Sub>, O-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, halogen, CN, <com:Math><semantics>SO2N(C1−4<annotation encoding="application / x-tex">SO_2N(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub> or heteroaryl optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>, replacing a carbon atom of the ring; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>N(C1−6<annotation encoding="application / x-tex">N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, <com:Math><semantics>CONH<annotation encoding="application / x-tex">CONH< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>< / com:Math>; piperidinyl, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>𝑹1.2.1<annotation encoding="application / x-tex">\mathbf{R}^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-furanyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-O-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <Formule mathématique disponible dans le document PDF, Math available in the PDF document>${\bf R}^{1.2.3}$ a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-thiophenyl; each optionally substituted with one, two or three residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1 (above), wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-4< / com:Sub>-alkyl; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>R1.2<annotation encoding="application / x-tex">R^{1.2}< / annotation>< / semantics>< / com:Math> is selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>CH2COO−C1−6<annotation encoding="application / x-tex">CH_2COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>CONR1.2.1R1.2.2<annotation encoding="application / x-tex">CONR^{1.2.1}R^{1.2.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COR1.2.3<annotation encoding="application / x-tex">COR^{1.2.3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COO−C1−6<annotation encoding="application / x-tex">COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>CONH2<annotation encoding="application / x-tex">CONH_2< / annotation>< / semantics>< / com:Math>, O-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, halogen, CN, <com:Math><semantics>SO2N(C1−4<annotation encoding="application / x-tex">SO_2N(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub> or heteroaryl optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>, replacing a carbon atom of the ring; <com:Math><semantics>𝑹1.2.1<annotation encoding="application / x-tex">\mathbf{R}^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-furanyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene-O-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl <com:Math><semantics>𝑹1.2.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹1.2.3<annotation encoding="application / x-tex">\mathbf{R}^{1.2.3}< / annotation>< / semantics>< / com:Math> a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO<com:Sub>2< / com:Sub>, replacing a carbon atom of the ring; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-thiophenyl; each optionally substituted with one, two or three residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or <com:Math><semantics>N−C1−4<annotation encoding="application / x-tex">N-C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, phenyl, pyrrolidinyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkylene-phenyl, C<com:Sub>1-6< / com:Sub>-alkylene-naphthyl, and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-thiophenyl; each optionally substituted with one, two or three residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹4<annotation encoding="application / x-tex">\mathbf{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or N-C<com:Sub>1-4< / com:Sub>-alkyl; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; NH-C<com:Sub>3-6< / com:Sub>-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 <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NHSO2<annotation encoding="application / x-tex">NHSO_2< / annotation>< / semantics>< / com:Math>-phenyl, NHCONH-phenyl, halogen, CN, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-6< / com:Sub>-alkyl, COO-C<com:Sub>1-6< / com:Sub>-alkyl; • a C<com:Sub>9 or 10< / com:Sub>-bicyclic-ring, whereas one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound 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 <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, COO-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NO2<annotation encoding="application / x-tex">NO_2< / annotation>< / semantics>< / com:Math>, halogen, CN, <com:Math><semantics>NHSO2−C1−6<annotation encoding="application / x-tex">NHSO_2-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, m-methoxyphenyl; a group selected from NHCH(pyridinyl)CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-6< / com:Sub>-alkyl, NHCH(CH<com:Sub>2< / com:Sub>O-C<com:Sub>1-6< / com:Sub>-alkyl)-benzoimidazolyl, optionally substituted with Cl; • or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>CH2CON(C1−6<annotation encoding="application / x-tex">CH_2CON(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-C<com:Sub>3-6< / com:Sub>-cycloalkyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COO-C<com:Sub>1-6< / com:Sub>-alkyl, <com:Math><semantics>O−C1−6<annotation encoding="application / x-tex">O-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2−C1−6<annotation encoding="application / x-tex">SO_2-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2−C1−6<annotation encoding="application / x-tex">SO_2-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylen-OH, <com:Math><semantics>SO2−C3−6<annotation encoding="application / x-tex">SO_2-C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>SO2<annotation encoding="application / x-tex">SO_2< / annotation>< / semantics>< / com:Math>-piperidinyl, <com:Math><semantics>SO2NH−C1−6<annotation encoding="application / x-tex">SO_2NH-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>SO2N(C1−6<annotation encoding="application / x-tex">SO_2N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, halogen, CN, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>NHC1−6<annotation encoding="application / x-tex">NHC_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, =0; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH <com:Math><semantics>𝑹1.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from • heteroaryl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>CH2COO−C1−6<annotation encoding="application / x-tex">CH_2COO-C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COO-C<com:Sub>1-6< / com:Sub>-alkyl, CONH<com:Sub>2< / com:Sub>, O-C<com:Sub>1-6< / com:Sub>-alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>N(C1−6<annotation encoding="application / x-tex">N(C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, CONH-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, =0; piperidinyl, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}^2< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-4< / com:Sub>-alkyl, NHSO<com:Sub>2< / com:Sub>-phenyl, NHCONH-phenyl, halogen; NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO<com:Sub>2< / com:Sub>-C<com:Sub>1-4< / com:Sub>-alkyl, COO-C<com:Sub>1-4< / com:Sub>-alkyl; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO<com:Sub>2< / com:Sub>-C<com:Sub>1-4< / com:Sub>-alkyl, m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro- isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-4< / com:Sub>-alkyl, COO-C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>1-4< / com:Sub>-haloalkyl, O-C<com:Sub>1-4< / com:Sub>-alkyl, NO<com:Sub>2< / com:Sub>, halogen; a group selected from NHCH(pyridinyl)CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-4< / com:Sub>-alkyl, NHCH(CH<com:Sub>2< / com:Sub>O-C<com:Sub>1-4< / com:Sub>-alkyl)-benzoimidazolyl, optionally substituted with Cl; • or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; is phenyl, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-haloalkyl, <com:Math><semantics>CH2CON(C1−4−alkyl)2<annotation encoding="application / x-tex">CH_2CON(C_{1-4}-alkyl)_2< / annotation>< / semantics>< / com:Math>, CH<com:Sub>2< / com:Sub>NHCONH-C<com:Sub>3-6< / com:Sub>-cycloalkyl, CN, <com:Math><semantics>CONR1.1.1R1.1.2<annotation encoding="application / x-tex">CONR^{1.1.1}R^{1.1.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>COO−C1−4<annotation encoding="application / x-tex">COO-C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, O-C<com:Sub>1-4< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-4< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>-C<com:Sub>1-4< / com:Sub>-alkylen-OH, SO<com:Sub>2< / com:Sub>-C<com:Sub>3-6< / com:Sub>-cycloalkyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NH-C<com:Sub>1-4< / com:Sub>-alkyl, SO<com:Sub>2< / com:Sub>N(C<com:Sub>1-4< / com:Sub>-alkyl)<com:Sub>2< / com:Sub>, halogen, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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 <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, NHC<com:Sub>1-4< / com:Sub>-alkyl, =O; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH <com:Math><semantics>𝑹1.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, CH<com:Sub>2< / com:Sub>COO-C<com:Sub>1-4< / com:Sub>-alkyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COO-C<com:Sub>1-4< / com:Sub>-alkyl, CONH<com:Sub>2< / com:Sub>, O-C<com:Sub>1-4< / com:Sub>-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 <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>N(C1−4<annotation encoding="application / x-tex">N(C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl)<com:Sub>2< / com:Sub>, <com:Math><semantics>CONH−C1−4<annotation encoding="application / x-tex">CONH-C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>< / com:Math>; piperidinyl, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO-C<com:Sub>1-4< / com:Sub>-alkyl, <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math> is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, O-C<com:Sub>1-4< / com:Sub>-alkyl, O-C<com:Sub>1-4< / com:Sub>-haloalkyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-phenyl or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, C<com:Sub>1-4< / com:Sub>-haloalkyl, O-C<com:Sub>1-4< / com:Sub>-haloalkyl, halogen; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; NH-piperidinyl, optionally substituted with pyridinyl; NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO<com:Sub>2< / com:Sub>-phenyl, NHCONH-phenyl, F; • NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO<com:Sub>2< / com:Sub>Me, COO-t-Bu; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO<com:Sub>2< / com:Sub>-n-Bu, m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF<com:Sub>3< / com:Sub>, OMe, NO<com:Sub>2< / com:Sub>, F, Br; a group selected from NHCH(pyridinyl)CH<com:Sub>2< / com:Sub>COOMe, NHCH(CH<com:Sub>2< / com:Sub>OMe)-benzoimidazolyl, optionally substituted with Cl; • or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; <com:Math><semantics>ℝ1.1<annotation encoding="application / x-tex">\mathbb{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1,1,1< / com:Sup> and R<com:Sup>1,1,2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH <com:Math><semantics>R1.2<annotation encoding="application / x-tex">R^{1.2}< / annotation>< / semantics>< / com:Math> is selected from 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<com:Sub>2< / com:Sub>COOEt, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, <com:Math><semantics>R1,2,1<annotation encoding="application / x-tex">R^{1,2,1}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>𝑹1.2.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2.2}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> 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<com:Sub>2< / com:Sub>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>𝑹4<annotation encoding="application / x-tex">\mathbf{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.2< / com:Sup>, <com:Math><semantics>ℝ1.1<annotation encoding="application / x-tex">\mathbb{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> <com:Math><semantics>𝑹1,1,1<annotation encoding="application / x-tex">\mathbf{R}^{1,1,1}< / annotation>< / semantics>< / com:Math> H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH<com:Sub>2< / com:Sub>-i-Pr, CH<com:Sub>2< / com:Sub>-t-Bu, CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, <com:Math><semantics>CH2CHF2<annotation encoding="application / x-tex">CH_2CHF_2< / annotation>< / semantics>< / com:Math>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CO-azetindinyl, CH<com:Sub>2< / com:Sub>-cyclopropyl, CH<com:Sub>2< / com:Sub>-cyclobutyl, CH<com:Sub>2< / com:Sub>-pyranyl, CH<com:Sub>2< / com:Sub>-tetrahydrofuranyl, CH<com:Sub>2< / com:Sub>-furanyl, CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or thiadiazolyl, optionally substituted with Me; <com:Math><semantics>𝑹1,1,2<annotation encoding="application / x-tex">\mathbf{R}^{1,1,2}< / annotation>< / semantics>< / com:Math> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH <com:Math><semantics>𝑹1.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from 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<com:Sub>2< / com:Sub>COOEt, CONR<com:Sup>1,2,1< / com:Sup>R<com:Sup>1,2,2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; • benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, R<com:Sup>1.2.1< / com:Sup> H, Me; R<com:Sup>1.2.2< / com:Sup> H, Me; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein <com:Math><semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sup>1,1,1< / com:Sup> and R<com:Sup>1,1,2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH <com:Math><semantics>R1.2<annotation encoding="application / x-tex">R^{1.2}< / annotation>< / semantics>< / com:Math> is selected from 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<com:Sub>2< / com:Sub>COOEt, CONR<com:Sup>1,2,1< / com:Sup>R<com:Sup>1,2,2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, <com:Math><semantics>R1,2,1<annotation encoding="application / x-tex">R^{1,2,1}< / annotation>< / semantics>< / com:Math> H, Me; <Formule mathématique disponible dans le document PDF, Math available in the PDF document>${\bf R}^{1.2.2}$ H, Me; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> 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<com:Sub>2< / com:Sub>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>ℝ1.1<annotation encoding="application / x-tex">\mathbb{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R1.1.2<annotation encoding="application / x-tex">R^{1.1.2}< / annotation>< / semantics>< / com:Math> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et or R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>CH2OH<annotation encoding="application / x-tex">CH_2OH< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>1.1.2< / com:Sup> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et or R<com:Sup>1,1,1< / com:Sup> and R<com:Sup>1,1,2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of <com:Math><semantics>CH2OH<annotation encoding="application / x-tex">CH_2OH< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein <com:Math><semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics>< / com:Math> is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> and R<com:Sup>1.1.1< / com:Sup> and R<com:Sup>1.1.2< / com:Sup> together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>2< / com:Sub>OH; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>ℝ1.1<annotation encoding="application / x-tex">\mathbb{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, F, Cl; <com:Math><semantics>𝑹1.1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1.1}< / annotation>< / semantics>< / com:Math> H, Me, Et, Bu, Pr, cyclopropyl, CH<com:Sub>2< / com:Sub>-Pr, CH<com:Sub>2< / com:Sub>-Bu, CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CHF<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CO-azetindinyl, CH<com:Sub>2< / com:Sub>-cyclopropyl, CH<com:Sub>2< / com:Sub>-cyclobutyl, CH<com:Sub>2< / com:Sub>-pyranyl, CH<com:Sub>2< / com:Sub>-tetrahydrofuranyl, <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-furanyl, CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or thiadiazolyl, optionally substituted with Me; <com:Math><semantics>𝑹1.1.2<annotation encoding="application / x-tex">\mathbf{R}^{1.1.2}< / annotation>< / semantics>< / com:Math> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein <com:Math><semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics>< / com:Math> is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one or two residues selected from the group consisting of SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt; <com:Math><semantics>R1,1,1<annotation encoding="application / x-tex">R^{1,1,1}< / annotation>< / semantics>< / com:Math> H, Me, Et, Bu, Pr, cyclopropyl, CH<com:Sub>2< / com:Sub>-Pr, CH<com:Sub>2< / com:Sub>-Bu, CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, <com:Math><semantics>CH2CHF2<annotation encoding="application / x-tex">CH_2CHF_2< / annotation>< / semantics>< / com:Math>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CO-azetindinyl, CH<com:Sub>2< / com:Sub>-cyclopropyl, CH<com:Sub>2< / com:Sub>-cyclobutyl, CH<com:Sub>2< / com:Sub>-pyranyl, CH<com:Sub>2< / com:Sub>-tetrahydrofuranyl, CH<com:Sub>2< / com:Sub>-furanyl, CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or thiadiazolyl, optionally substituted with Me; R<com:Sup>1.1.2< / com:Sup> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.1< / com:Sup>, NMeR<com:Sup>1.1< / com:Sup>; <com:Math><semantics>𝑹1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1}< / annotation>< / semantics>< / com:Math> is phenyl, optionally substituted with one residue selected from the group consisting of Me, Et, t-Bu, CF<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>NHCONH-cyclohexyl, CN, CONR<com:Sup>1.1.1< / com:Sup>R<com:Sup>1.1.2< / com:Sup>, COOMe, COOEt, OMe, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, SO<com:Sub>2< / com:Sub>Et, SO<com:Sub>2< / com:Sub>-cyclopropyl, SO<com:Sub>2< / com:Sub>-piperidinyl, SO<com:Sub>2< / com:Sub>NHEt, SO<com:Sub>2< / com:Sub>NMeEt, F, Cl, and additionally with one residue selected from the group consisting of CO-morpholinyl, CH<com:Sub>2< / com:Sub>-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, <com:Math><semantics>NHMe,=0;<annotation encoding="application / x-tex">NHMe, =0;< / annotation>< / semantics>< / com:Math> <com:Math><semantics>𝑹1.1.1<annotation encoding="application / x-tex">\mathbf{R}^{1.1.1}< / annotation>< / semantics>< / com:Math> H, Me, Et, Bu, Pr, cyclopropyl, CH<com:Sub>2< / com:Sub>-Pr, CH<com:Sub>2< / com:Sub>-Bu, CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CHF<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CONMe<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>CO-azetindinyl, CH<com:Sub>2< / com:Sub>-cyclopropyl, CH<com:Sub>2< / com:Sub>-cyclobutyl, CH<com:Sub>2< / com:Sub>-pyranyl, CH<com:Sub>2< / com:Sub>-tetrahydrofuranyl, CH<com:Sub>2< / com:Sub>-furanyl, CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH or thiadiazolyl, optionally substituted with Me; <com:Math><semantics>𝑹1.1.2<annotation encoding="application / x-tex">\mathbf{R}^{1.1.2}< / annotation>< / semantics>< / com:Math> H, Me, Et, SO<com:Sub>2< / com:Sub>Me, SO<com:Sub>2< / com:Sub>Et <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH<com:Sub>2< / com:Sub>COOEt, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, <com:Math><semantics>ℝ1,2,1<annotation encoding="application / x-tex">\mathbb{R}^{1,2,1}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein <com:Math><semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics>< / com:Math> is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, n-Pr, i-Pr, Bu, cyclopropyl, CH2COOEt, CONR<com:Sup>1,2,1< / com:Sup>R<com:Sup>1,2,2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> H, Me; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from • NHCH<com:Sub>2< / com:Sub>-<com:Math><semantics>ℝ1.3<annotation encoding="application / x-tex">\mathbb{R}^{1.3}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹1.3<annotation encoding="application / x-tex">\mathbf{R}^{1.3}< / annotation>< / semantics>< / com:Math> 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<com:Sub>2< / com:Sub>; <com:Math><semantics>𝑹𝟐<annotation encoding="application / x-tex">\mathbf{R^2}< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or NMe; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^{1}< / annotation>< / semantics>< / com:Math> is selected from • NH-piperidinyl, optionally substituted with pyridinyl; NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO<com:Sub>2< / com:Sub>-phenyl, NHCONH-phenyl, F; • NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO<com:Sub>2< / com:Sub>Me, COO-t-Bu; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO<com:Sub>2< / com:Sub>-n-Bu, m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF<com:Sub>3< / com:Sub>, OMe, NO<com:Sub>2< / com:Sub>, F, Br; a group selected from NHCH(pyridinyl)CH<com:Sub>2< / com:Sub>COOMe, NHCH(CH<com:Sub>2< / com:Sub>OMe)-benzoimidazolyl, optionally substituted with Cl; or 1-aminocyclopentyl, optionally substituted with Methyl-Oxadiazolyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from CH<com:Sub>2< / com:Sub>-phenyl or CH<com:Sub>2< / com:Sub>-naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH<com:Sub>3< / com:Sub>, CF<com:Sub>3< / com:Sub>, OCF<com:Sub>3< / com:Sub>, F, Cl, Br, Et; or CH<com:Sub>2< / com:Sub>-thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>𝑹4<annotation encoding="application / x-tex">\mathbf{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, O or <com:Math><semantics>NMe<annotation encoding="application / x-tex">NMe< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>NHR1.2<annotation encoding="application / x-tex">NHR^{1.2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NMeR1.2<annotation encoding="application / x-tex">NMeR^{1.2}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is and <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from pyridinyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, cyclopropyl, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me; pyrrolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; pyrazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; isoxazolyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt; thiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CH<com:Sub>2< / com:Sub>COOEt, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>; thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of COOEt; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, <com:Math><semantics>=0;<annotation encoding="application / x-tex">=0;< / annotation>< / semantics>< / com:Math> 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, and <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> is H or Me; <com:Math><semantics>𝑹1.2.2<annotation encoding="application / x-tex">\mathbf{R}^{1.2.2}< / annotation>< / semantics>< / com:Math> is H or Me. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is and <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is selected from pyridinyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR<com:Sup>1,2,1< / com:Sup>R<com:Sup>1,2,2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br; pyrrolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; • pyrazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; • isoxazolyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt; • thiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>; thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of COOEt; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, <com:Math><semantics>=0;<annotation encoding="application / x-tex">=0;< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> is H or Me; <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> is H or Me. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein • A is CH<com:Sub>2< / com:Sub>, O or NMe, <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is pyridinyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR<com:Sup>1.2.1< / com:Sup>R<com:Sup>1.2.2< / com:Sup>, COOMe, COOEt, CONH<com:Sub>2< / com:Sub>, OMe, Cl, Br; R<com:Sup>1.2.1< / com:Sup> is H or Me and R<com:Sup>1.2.2< / com:Sup> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1,2< / com:Sup>, NMeR<com:Sup>1,2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is pyrrolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; R<com:Sup>1.2.1< / com:Sup> is H or Me and <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1,2< / com:Sup>, NMeR<com:Sup>1,2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is pyrazolyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; <com:Math><semantics>R1,2,1<annotation encoding="application / x-tex">R^{1,2,1}< / annotation>< / semantics>< / com:Math> is H or Me and <com:Math><semantics>R1,2,2<annotation encoding="application / x-tex">R^{1,2,2}< / annotation>< / semantics>< / com:Math> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is isoxazolyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, COOE; R<com:Sup>1,2,1< / com:Sup> is H or Me and R<com:Sup>1,2,2< / com:Sup> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1,2< / com:Sup>, NMeR<com:Sup>1,2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is thiazolyl, optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, <com:Math><semantics>CONR1.2.1R1.2.2<annotation encoding="application / x-tex">CONR^{1.2.1}R^{1.2.2}< / annotation>< / semantics>< / com:Math>; ; <com:Math><semantics>R1.2.1<annotation encoding="application / x-tex">R^{1.2.1}< / annotation>< / semantics>< / com:Math> is H or Me and <com:Math><semantics>R1.2.2<annotation encoding="application / x-tex">R^{1.2.2}< / annotation>< / semantics>< / com:Math> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1.2< / com:Sup>, NMeR<com:Sup>1.2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of COOEt; R<com:Sup>1,2,1< / com:Sup> is H or Me and R<com:Sup>1,2,2< / com:Sup> is H or Me. • A is CH<com:Sub>2< / com:Sub>, O or NMe, R<com:Sup>1< / com:Sup> is selected from NHR<com:Sup>1,2< / com:Sup>, NMeR<com:Sup>1,2< / com:Sup>; R<com:Sup>2< / com:Sup> is defined as in Table 1 shown below; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ1.2<annotation encoding="application / x-tex">\mathbb{R}^{1.2}< / annotation>< / semantics>< / com:Math> is benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe<com:Sub>2< / com:Sub>, CONHMe, =O; R<com:Sup>1,2,1< / com:Sup> is H or Me and R<com:Sup>1,2,2< / com:Sup> is H or Me. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein all groups are defined as above except R<com:Sup>1.3< / com:Sup> is selected from phenyl, optionally substituted with OCHF<com:Sub>2< / com:Sub>; pyrazolyl, optionally substituted with Me or Et; isoxazolyl, optionally substituted with Pr; pyrimidinyl, optionally substituted with two OMe; • indolyl; oxadiazolyl, optionally substituted with cyclopentyl. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein all groups are defined as above except <com:Math><semantics>A<annotation encoding="application / x-tex">A< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein all groups are defined as above except A is O. Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein all groups are defined as above except A is NMe. Another embodiment of the present invention are compounds of formula 1, wherein A is CH<com:Sub>2< / com:Sub>, O or NMe; <com:Math><semantics>𝑹𝟏<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{1}}< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] . 1 [Image disponible dans le document PDF, Image available in the PDF document] ri - ii [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ~1 € [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > 9 7 [Image disponible dans le document PDF, Image available in the PDF document] , <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; or <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> together are forming a <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math> group. Another embodiment of the present invention are compounds of formula 1, wherein A is defined as above; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; and <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] H C [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 ) 7 , , , F , , [Image disponible dans le document PDF, Image available in the PDF document] Þ Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is defined as above; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; and <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 11 - [Image disponible dans le document PDF, Image available in the PDF document] Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is defined as above; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from - - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] H C [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 ) 7 , , , F , , 2 [Image disponible dans le document PDF, Image available in the PDF document] , Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is defined as above; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; and <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] - - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 > , , ٠ Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein A is defined as above; <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math> is H; and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as in Table 1 shown below; <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 1: <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is defined as one of the groups shown below in the definitions 1 to 4: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Another embodiment of the present invention further comprises administration to a subject of the compounds of formula 1, wherein the compounds of formula 1 are present in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, e.g., in the form of the enantiomerically pure compounds. Another embodiment of the present invention further comprises administration to a subject of 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 the solvates and / or hydrates. b. Co-Crystals and Salts Additional embodiments of the present invention further comprise administration to a subject of the co-crystals of the compounds of formula 2 (below). In general, for groups comprising two or more subgroups in this "Co-Crystals and Salts" section, the first named subgroup is the radical attachment point, for example, the substituent "<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl-aryl" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; m is 1, 2 or 3; and in some instances 1 or 2; <com:Math><semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>< / com:Math> are each independently selected from H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkynyl, C<com:Sub>3-6< / com:Sub>-cycloalkyl, COO-C<com:Sub>1-6< / com:Sub>-alkyl, O-C<com:Sub>1-6< / com:Sub>-alkyl, CONR<com:Sup>2b.1< / com:Sup>R<com:Sup>2b.2< / com:Sup>, halogen; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; or R<com:Sup>2b.1< / com:Sup> and R<com:Sup>2b.2< / com:Sup> are together a C<com:Sub>3-6< / com:Sub>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; X is an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p- toluenesulphonate; and in some instances chloride or dibenzoyltartrate j is 0, 0.5, 1, 1.5 or 2; and in some instances 1 or 2; with a co-crystal 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-hydroxy-2-naphtoic acid, mucic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine, in some instances ascorbic acid, mucic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, l-lysine, l-proline. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or <com:Math><semantics>R2b.1<annotation encoding="application / x-tex">R^{2b.1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> are together a <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or <com:Math><semantics>R2b.1<annotation encoding="application / x-tex">R^{2b.1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> are together a <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein [Image disponible dans le document PDF, Image available in the PDF document] Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein [Image disponible dans le document PDF, Image available in the PDF document] or <com:Math><semantics>R2b.1<annotation encoding="application / x-tex">R^{2b.1}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> are together a <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^{1}< / annotation>< / semantics>< / com:Math> is C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl, O-C<com:Sub>1-6< / com:Sub>-haloalkyl, halogen; m is 1 or 2; <com:Math><semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>CONR2b.1R2b.2<annotation encoding="application / x-tex">CONR^{2b.1}R^{2b.2}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2b.1<annotation encoding="application / x-tex">\mathbb{R}^{2b.1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C0−4<annotation encoding="application / x-tex">C_{0-4}< / annotation>< / semantics>< / com:Math>-alkyl-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-haloalkyl; <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; or R<com:Sup>2b.1< / com:Sup> and R<com:Sup>2b.2< / com:Sup> are together a C<com:Sub>3-6< / com:Sub>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>𝑿<annotation encoding="application / x-tex">\mathbf{X}< / annotation>< / semantics>< / com:Math> is an anion selected from the group consisting of chloride or dibenzoyltartrate j is 1 or 2. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein <com:Math><semantics>𝑹2a<annotation encoding="application / x-tex">\mathbf{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, CONR<com:Sup>2b.1< / com:Sup>R<com:Sup>2b.2< / com:Sup>; <com:Math><semantics>𝑹2b.1<annotation encoding="application / x-tex">\mathbf{R}^{2\mathrm{b.1}}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b.2<annotation encoding="application / x-tex">\mathbb{R}^{2b.2}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>CONR2b.1R2b.2<annotation encoding="application / x-tex">CONR^{2b.1}R^{2b.2}< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>2b.2< / com:Sup> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances H, Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>CONR2b.1R2b.2<annotation encoding="application / x-tex">CONR^{2b.1}R^{2b.2}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R2b.1<annotation encoding="application / x-tex">R^{2b.1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-haloalkyl; <com:Math><semantics>𝑹2b.2<annotation encoding="application / x-tex">\mathbf{R}^{2\mathrm{b.2}}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alky; in some instances H, Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein R<com:Sup>2b.1< / com:Sup> and R<com:Sup>2b.2< / com:Sup> are together a C<com:Sub>3-6< / com:Sub>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup>, X and j are defined as above and the co-crystal 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 of the same. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2a, wherein R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup>, X and j are defined as above [Image disponible dans le document PDF, Image available in the PDF document] la. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2a, wherein <com:Math><semantics>𝑹2a<annotation encoding="application / x-tex">\mathbf{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>CONR2b.1R2b.2<annotation encoding="application / x-tex">CONR^{2b.1}R^{2b.2}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>ℝ2b.1<annotation encoding="application / x-tex">\mathbb{R}^{2b.1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b.2<annotation encoding="application / x-tex">\mathbb{R}^{2b.2}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2a, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, CONR<com:Sup>2b.1< / com:Sup>R<com:Sup>2b.2< / com:Sup>; <com:Math><semantics>R2b.1<annotation encoding="application / x-tex">R^{2b.1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C0−4<annotation encoding="application / x-tex">C_{0-4}< / annotation>< / semantics>< / com:Math>-alkyl-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math>-cycloalkyl; <com:Math><semantics>𝑹2b.2<annotation encoding="application / x-tex">\mathbf{R}^{2b.2}< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances H, Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2a, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>ℝ2b<annotation encoding="application / x-tex">\mathbb{R}^{2b}< / annotation>< / semantics>< / com:Math> is H, CONR<com:Sup>2b.1< / com:Sup>R<com:Sup>2b.2< / com:Sup>; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>2b.2< / com:Sup> is H, C<com:Sub>1-4< / com:Sub>-alky; in some instances H, Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2a, wherein R<com:Sup>2b.1< / com:Sup> and R<com:Sup>2b.2< / com:Sup> are together a C<com:Sub>3-6< / com:Sub>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. The free bases of compounds of formula 2 <com:Math><semantics>(j=0)<annotation encoding="application / x-tex">(j = 0)< / annotation>< / semantics>< / com:Math> are often amorphous and are used for a process of manufacturing co-crystal, nevertheless salts of compounds of formula 2 are employed in some instances for a process of manufacturing co-crystal. Thus, another aspect of the invention are salts of compounds of formula 2 wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the co-crystals above and <com:Math><semantics>𝑿<annotation encoding="application / x-tex">\mathbf{X}< / annotation>< / semantics>< / com:Math> is an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p- toluenesulphonate; in some instances chloride, or dibenzoyltartrate j is 0, 0.5, 1, 1.5 or 2; in some instances 1 or 2. Another aspect of the present invention further comprises administration to a subject of the co- crystals of the compounds of formula 2, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the co- crystals above and X is an anion selected from the group consisting of chloride or dibenzoyltartrate 1 is 1 or 2. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the salts above and X is chloride and j is 2. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the salts above and X is dibenzoyltartrate and j is 1. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup>, X and j are defined as above [Image disponible dans le document PDF, Image available in the PDF document] Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>< / com:Math> is H, CONR<com:Sup>2b.1< / com:Sup>R<com:Sup>2b.2< / com:Sup>; <com:Math><semantics>ℝ2b.1<annotation encoding="application / x-tex">\mathbb{R}^{2b.1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; <com:Math><semantics>R2b.2<annotation encoding="application / x-tex">R^{2b.2}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl; in some instances Methyl, Ethyl, Propyl; and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein <com:Math><semantics>ℝ2a<annotation encoding="application / x-tex">\mathbb{R}^{2a}< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-4< / com:Sub>-alkyl; in some instances Methyl, Ethyl, Propyl; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein R<com:Sup>2b,1< / com:Sup> and R<com:Sup>2b,2< / com:Sup> are together a C<com:Sub>3-6< / com:Sub>-alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residues are defined as above. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the salts above and X is chloride and j is 2. Another aspect of the present invention further comprises administration to a subject of the salts of the compounds of formula 2a, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the salts above and X is dibenzoyltartrate and j is 1. Another aspect of the invention are salts of compounds of formula 2a, wherein R<com:Sup>1< / com:Sup>, m, R<com:Sup>2a< / com:Sup>, R<com:Sup>2b< / com:Sup>, R<com:Sup>3< / com:Sup> are defined as for the salts above and X is (S)-(S)-(+)- 2,3-dibenzoyl-tartrate and j is 1. C. Formulations Additional embodiments of the present invention further comprise administration to a subject of a pharmaceutical composition containing compounds of formula 3 [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is H, C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>0-4< / com:Sub>-alkyl-C<com:Sub>3-6< / com:Sub>-cycloalkyl, C<com:Sub>1-6< / com:Sub>-haloalkyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; X is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate j is 1 or 2. An embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds of formula 3 wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; X is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate J is 1 or 2. An embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds of formula 3 wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is H, Methyl, Ethyl, Propyl, Butyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is H, Methyl, Ethyl, Propyl, Butyl; X is an anion selected from the group consisting of chloride or <com:Math><semantics>12<annotation encoding="application / x-tex">\frac{1}{2}< / annotation>< / semantics>< / com:Math> dibenzoyltartrate, such as chloride; j is 1 or 2, in some instances 2. An embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds of formula 3 wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is H, Methyl, Ethyl, Propyl, Butyl; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}^2< / annotation>< / semantics>< / com:Math> is H, Methyl; <com:Math><semantics>𝑿<annotation encoding="application / x-tex">\mathbf{X}< / annotation>< / semantics>< / com:Math> is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate, such as chloride; j is 1 or 2, in some instances 2. An embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds of formula 3 wherein <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}^1< / annotation>< / semantics>< / com:Math> is H, Methyl; <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> is H, Methyl; <com:Math><semantics>𝑿<annotation encoding="application / x-tex">\mathbf{X}< / annotation>< / semantics>< / com:Math> is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate, such as chloride; j is 1 or 2, in some instances 2. An embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds described in Table 2 as a hydrochloride. An additional embodiment of the present invention further comprises administration to a subject of a pharmaceutical composition containing compounds describe in Table 2 as a di-hydrochloride. TABLE 2 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Another object of the present invention is administration to a subject of a pharmaceutical dosage form of the compounds described above, wherein the dosage is an orally deliverable dosage form. Another object of the present invention is administration to a subject of a pharmaceutical dosage form of the compounds described above, which is in the form of a tablet, capsule, pellets, powder or granules. Another object of the present invention is administration to a subject of the pharmaceutical dosage forms described above for use as medicament. Another object of the present invention is the use of the above pharmaceutical dosage forms for the preparation of a medicament for the treatment of a neurodegenerative disease or condition selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, and progressive supranuclear palsy. Another object of the present invention is a process for the treatment and / or prevention of a disease or condition selected from neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, and progressive supranuclear palsy, characterized in that an effective amount of the above defined pharmaceutical dosage form is administered orally to a subject or patient once, twice, thrice or several times daily. d. Dosage Forms / Ingredients Solid pharmaceutical compositions ready for use / ingestion made from a compound of formula 3 comprise powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tables, troches and lozenges. In detail: Capsule formulations according to the invention comprise the powdery intermediate of a compound of formula 3, an intermediate blend comprising the powdery intermediate, pellets or granules obtained by conventional wet-, dry or hot-melt granulation or hot-melt extrusion or spray-drying of a suitable intermediate blend, filled in conventional capsules, e.g. hard gelatin or HPMC capsules. The Capsule formulations from above may also comprise the powdery intermediate of a compound of formula 3 in a compacted form. Capsule formulations according to the invention comprise the compound of formula 3 suspended or diluted in a liquid or mixture of liquids. Tablet formulations according to the invention comprise such tablets obtained by direct compression of a suitable final blend or by tableting of pellets or granules obtained by conventional wet-, dry or hot-melt granulation or hot-melt extrusion or spray-drying of a suitable intermediate blend. Another object of the present invention is a dosage form where a pH-adjusting or buffering agent is added for stability improvement of the active ingredient. The pH-adjusting / buffering agent may be a basic amino acid, which has an amino group and alkaline characteristics (isoelectric point, pI: 7.59—10.76), such as e.g. L-arginine, L-lysine or L-histidine. A buffering agent within the meaning of this invention is L-arginine. L-arginine has a particular suitable stabilizing effect on the compositions of this invention, e.g. by suppressing chemical degradation of compounds of formula 3. Thus, in an embodiment, the present invention is directed to a pharmaceutical composition (e.g. an oral solid dosage form, particularly a tablet) comprising a compound of formula 3 and L- arginine for stabilizing the composition, particularly against chemical degradation; as well as one or more pharmaceutical excipients. Suitably the pharmaceutical excipients used within this invention are conventional materials such as cellulose and its derivates, D-mannitol, corn starch, pregelatinized starch as a filler, copovidone as a binder, crospovidone as disintegrant, magnesium stearate as a lubricant, colloidal anhydrous silica as a glidant, hypromellose as a film-coating agent, polyethylene glycol as a plasticizer, titanium dioxide, iron oxide red / yellow as a pigment, and talc, etc. In detail pharmaceutical excipients can be a first and second diluent, a binder, a disintegrant and a lubricant; an additional disintegrant and an additional glidant are a further option. Diluents suitable for a pharmaceutical composition according to the invention are cellulose powder, microcrystalline cellulose, lactose in various crystalline modifications, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, starch or modified starch (eg pregelatinized or partially hydrolyzed) or xylitol. Among those diluents mannitol and microcrystalline cellulose are employed in some instances. • Diluents that find use as the second diluent are the above-mentioned diluents mannitol and microcrystalline cellulose. Lubricants suitable for a pharmaceutical composition according to the invention are talc, polyethyleneglycol, calcium behenate, calcium stearate, sodium stearylfumarate, hydrogenated castor oil or magnesium stearate. The lubricant in some instances is magnesium stearate. Binders suitable for a pharmaceutical composition according to the invention are copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, stearic-palmitic acid, low-substituted hydroxypropylcellulose (L-HPC), copovidone and pregelatinized starch being employed in some formulations. The above mentioned binders pregelatinized starch and L-HPC show additional diluent and disintegrant properties and can also be used as the second diluent or the disintegrant. Disintegrants suitable for a pharmaceutical composition according to the present invention are corn starch, crospovidone, polacrilin potassium, croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC) or pregelatinized starch; such as croscarmellose sodium. As an optional glidant colloidal silicon dioxide can be used. An exemplary composition according to the present invention comprises the diluent mannitol, microcrystalline cellulose as a diluent with additional disintegrating properties, the binder copovidone, the disintegrant croscarmellose sodium, and magnesium stearate as the lubricant. Typical pharmaceutical compositions comprise (% by weight) 10-50 % active ingredient 20-88 % diluent 1, 5-50 % diluent 2, 1-5 % binder, 1-15 % disintegrant, and 0.1-5 % lubricant. Pharmaceutical compositions according to some embodiments comprise (% by weight) 10-50 % active ingredient 20-75 % diluent 1, 5-30 % diluent 2, 2-30 % binder, 1-12 % disintegrant, and 0.1-3 % lubricant Pharmaceutical compositions according to some embodiments comprise (% by weight) 10-90 % active ingredient 5-70 % diluent 1, 5-30 % diluent 2, 0-30 % binder, 1-12 % disintegrant, and 0.1-3 % lubricant Pharmaceutical compositions according to some embodiments comprise (% by weight) 10-50 % active ingredient 20-75 % diluent 1, 5-30 % diluent 2, 2-30 % binder, 0,5-20 % buffering agent, 1-12 % disintegrant, and 0.1-3 % lubricant Pharmaceutical compositions according to some embodiments comprise (% by weight) 30-70 % active ingredient 20-75 % diluent 1, 5-30 % diluent 2, 2-30 % binder, 0,5-20 % buffering agent, 1-12 % disintegrant, and 0.1-3 % lubricant Pharmaceutical compositions containing 10-90% of active ingredient, such as 30-70 % active ingredient (% by weight) are employed in some instances. A tablet formulation according to the invention may be uncoated or coated, e.g. film- coated, using suitable coatings known not to negatively affect the dissolution properties of the final formulation. For instance the tablets can be provided with a seal coat for protection of the patients environment and clinical staff as well as for moisture protection purposes by dissolving a high molecular weight polymer as polyvinylpyrrolidone or hydroxypropyl-methylcellulose together with plasticizers, lubricants and optionally pigments and tensides in water or organic solvent as acetone and spraying this mixture on the tablet cores inside a coating equipment as a pan coater or a fluidized bed coater with wurster insert. Additionally, agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, film forming polymers such as hydroxypropyl cellulose, ethylcellulose and polymeric methacrylates can be applied to the tablets, provided that the coating has no substantial effect on the disintegration / dissolution of the dosage form and that the coated dosage form is not affected in its stability. After the dosage form is film-coated, a sugar coating may be applied onto the sealed pharmaceutical dosage form. The sugar coating may comprise sucrose, dextrose, sorbitol and the like or mixtures thereof. If desired, colorants or opacifiers may be added to the sugar solution. Solid formulations of the present invention tend to be hygroscopic. They may be packaged using PVC-blisters, PVDC-blisters or a moisture-proof packaging material such as aluminum foil blister packs, alu / alu blister, transparent or opaque polymer blister with pouch, polypropylene tubes, glass bottles and HDPE bottles optionally containing a child-resistant feature or may be tamper evident. The primary packaging material may comprise a desiccant such as molecular sieve or silica gel to improve chemical stability of the API. Opaque packaging such as colored blister materials, tubes, brown glass bottles or the like can be used to prolong shelf life of the API by reduction of photo degradation. e. Dosages A dosage range of the compound of formula 3 is usually 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 give one or two tablets, where in some instances two tablets for a daily oral dosage of 100, 200, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 mg, and in some instances 350, 400, 450, 750, 800, 850 are employed. The dosages range can be achieved by one tablet or by two tablets; in some instances two tablets are administered, each containing half of the dosage. The application of the active ingredient may occur up to three times a day, such as one or two times a day. Particular dosage strengths are 400 mg or 800 mg. Used Terms and Definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. The term, "about" means 5% more or less of the specified value. Thus, about 100 minutes could also be read as from 95 to 105 minutes. In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. 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 foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. The term "substituted" as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. By the term "optionally substituted" is meant within the scope of the invention the above- mentioned group, optionally substituted by a lower-molecular group. Examples of lower- molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Of interest are such groups that have no negative effect on the pharmacological efficacy of the compounds. For example the groups may comprise: Straight-chain or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups. Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups. A number of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups. The compounds disclosed herein can 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, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to 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 disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, Succinate, Sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl Sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like. 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 the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, 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. While it may be possible for the compounds of the subject 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 which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. "Heterocyclic rings" ("het") include five-, six- or seven-membered, saturated or unsaturated heterocyclic rings or 5-10 membered, bicyclic hetero rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen; the ring may be linked to the molecule by a carbon atom or, if present, by a nitrogen atom. The following are examples of five-, six- or seven-membered, saturated or unsaturated heterocyclic rings: [Image disponible dans le document PDF, Image available in the PDF document] Unless stated otherwise, a heterocyclic ring may be provided with a keto group. Examples include: [Image disponible dans le document PDF, Image available in the PDF document] Examples of 5-10-membered bicyclic hetero rings are pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofurane, benzopyrane, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine, [Image disponible dans le document PDF, Image available in the PDF document] 7 7 Although the term heterocyclic rings includes heterocyclic aromatic groups, the term heterocyclic aromatic groups ("hetaryl") denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic hetaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed. The ring may be linked 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: [Image disponible dans le document PDF, Image available in the PDF document] Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine. The term "halogen" as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo. By the term "C<com:Sub>1-6< / com:Sub>-alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, and by the term "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl" are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are present in some instances. Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the above- mentioned groups. Unless stated otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc. By the term "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylene" (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene" are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groups with 1 to 4 carbon atoms are present in some instances. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1- dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, <com:Math><semantics>2,2−<annotation encoding="application / x-tex">2,2-< / annotation>< / semantics>< / com:Math> dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless stated otherwise, the definitions propylene, butylene, pentylene and hexylene also include all the possible isomeric forms of the relevant groups with the same number of carbons. Thus for example propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1- dimethylethylene, 1,2-dimethylethylene. The term "<com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenyl" (including those which are part of other groups) denotes branched and unbranched alkenyl groups with 2 to 6 carbon atoms and the term "C<com:Sub>2-4< / com:Sub>-alkenyl" denotes branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Employed in some instances are alkenyl groups with 2 to 4 carbon atoms. 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, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc. By the term "<com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkenylene" (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term "C<com:Sub>2-4< / com:Sub>-alkenylene" are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are present in some instances. Examples include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1- dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2- dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unless stated otherwise, the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the respective groups with the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene and butenylene includes 1- methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene. By the term "<com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term "<com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math>-alkynyl" are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Alkynyl groups with 2 to 4 carbon atoms are present in some instances. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl include all the 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. By the term "<com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math>-alkynylene" (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 6 carbon atoms and by the term "C<com:Sub>2-4< / com:Sub>-alkynylene" are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groups with 2 to 4 carbon atoms are present in some instances. 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 hexynylene. Unless stated otherwise, the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the respective groups with the same number of carbons. Thus for example propynyl also includes 1-methylethynylene and butynylene includes 1- methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene. The term "C<com:Sub>3-6< / com:Sub>-cycloalkyl" (including those which are part of other groups) as used herein means cyclic alkyl groups with 3 to 8 carbon atoms, where in some instances such groups are cyclic alkyl groups with 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. By the term "C<com:Sub>1-6< / com:Sub>-haloalkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, such as fluorine and chlorine, e.g., fluorine. By the term "C<com:Sub>1-4< / com:Sub>-haloalkyl" are meant correspondingly branched and unbranched alkyl groups with 1 to 4 carbon atoms, wherein one or more hydrogen atoms are replaced analogously to what was stated above. <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-haloalkyl is presentin some instances. Examples include: CH<com:Sub>2< / com:Sub>F, CHF<com:Sub>2< / com:Sub>, CF<com:Sub>3< / com:Sub>. The term "<com:Math><semantics>C1−n<annotation encoding="application / x-tex">C_{1-n}< / annotation>< / semantics>< / com:Math>-alkyl", wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math>-alkyl embraces the radicals <com:Math><semantics>H3C−1<annotation encoding="application / x-tex">H_3C_{-1}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−1<annotation encoding="application / x-tex">H_3C_{-1}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>H3C−CH2−CH2−<annotation encoding="application / x-tex">H_3C-CH_2-CH_2-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>H3C−CH(CH3)−<annotation encoding="application / x-tex">H_3C-CH(CH_3)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−CH2−CH2−CH2−<annotation encoding="application / x-tex">H_3C-CH_2-CH_2-CH_2-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−CH2−CH(CH3)−<annotation encoding="application / x-tex">H_3C-CH_2-CH(CH_3)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−CH(CH3)−CH2−<annotation encoding="application / x-tex">H_3C-CH(CH_3)-CH_2-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−C(CH3)2−<annotation encoding="application / x-tex">H_3C-C(CH_3)_2-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−CH2−CH2−CH2−CH2−<annotation encoding="application / x-tex">H_3C-CH_2-CH_2-CH_2-CH_2-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>H3C−CH2−CH2−<annotation encoding="application / x-tex">H_3C-CH_2-CH_2-< / annotation>< / semantics>< / com:Math> H<com:Sub>3< / com:Sub>C-CH<com:Sub>2< / com:Sub>-CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-, H<com:Sub>3< / com:Sub>C-CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, H<com:Sub>3< / com:Sub>C-C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, H<com:Sub>3< / com:Sub>C-C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, <com:Math><semantics>H3C−CH(CH3)−CH(CH3)−<annotation encoding="application / x-tex">H_3C-CH(CH_3)-CH(CH_3)-< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>H3C−CH2−CH(CH2CH3)−<annotation encoding="application / x-tex">H_3C-CH_2-CH(CH_2CH_3)-< / annotation>< / semantics>< / com:Math>. The term "C<com:Sub>1-n< / com:Sub>-haloalkyl", wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, such as fluorine and chlorine, e.g., fluorine. Examples include: CH<com:Sub>2< / com:Sub>F, CHF<com:Sub>2< / com:Sub>, CF<com:Sub>3< / com:Sub>. The term "<com:Math><semantics>C1−n<annotation encoding="application / x-tex">C_{1-n}< / annotation>< / semantics>< / com:Math>-alkylene" wherein n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkylene includes -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>-CH(CH<com:Sub>3< / com:Sub>)-, -CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>- -CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>-CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>-C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-CH(CH<com:Sub>3< / com:Sub>)-CH(CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>3< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>3< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>3< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>3< / com:Sub>-, -CH<com:Sub>3< / com:Sub>-CH<com:Sub>3< / com:Sub>-, - 3)-, -CH<com:Sub>2< / com:Sub>-CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH(CH<com:Sub>3< / com:Sub>))<com:Sub>2< / com:Sub>- and -C(C <com:Math><semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>< / com:Math>)(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-. The term "<com:Math><semantics>C2−n<annotation encoding="application / x-tex">C_{2-n}< / annotation>< / semantics>< / com:Math>-alkenyl", is used for a group as defined in the definition for "<com:Math><semantics>C1−n<annotation encoding="application / x-tex">C_{1-n}< / annotation>< / semantics>< / com:Math>-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. The term "<com:Math><semantics>C2−n<annotation encoding="application / x-tex">C_{2-n}< / annotation>< / semantics>< / com:Math>-alkynyl", is used for a group as defined in the definition for "<com:Math><semantics>C1−n<annotation encoding="application / x-tex">C_{1-n}< / annotation>< / semantics>< / com:Math>-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. The term "<com:Math><semantics>C3−n<annotation encoding="application / x-tex">C_{3-n}< / annotation>< / semantics>< / com:Math>-cycloalkyl", wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math>-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the peptide" includes reference to one or more peptides and equivalents thereof, e.g. polypeptides, known to those having skill in the art, and so forth. By "an individual suffering from or at risk of suffering from an aging-associated cognitive impairment" is meant an individual that is about more than 50% through its expected lifespan, such as more than 60%, e.g., more than 70%, such as more than 75%, 80%, 85%, 90%, 95% or even 99% through its expected lifespan. The age of the individual will depend on the species in question. Thus, this percentage is based on the predicted life-expectancy of the species in question. For example, in humans, such an individual is 50 year old or older, e.g., 60 years old or older, 70 years old or older, 80 years old or older, 90 years old or older, and usually no older than 100 years old, such as 90 years old., i.e., between the ages of about 50 and 100, e.g., 50 . . . 55 . . . 60 . . . 65 . . . 70 . . . 75 . . . 80 . . . 85 . . . 90 . . . 95 . . . 100 years old or older, or any age between <com:Math><semantics>50−1000<annotation encoding="application / x-tex">50 - 1000< / annotation>< / semantics>< / com:Math>, that suffers from an aging-associated condition as further described below, e.g., cognitive impairment associated with the natural aging process; an individual that is about 50 years old or older, e.g., 60 years old or older, 70 years old or older, 80 years old or older, 90 years old or older, and usually no older than 100 years old, i.e., between the ages of about 50 and 100, e.g., 50 . . . 55 . . . 60 . . . 65 . . . 70 . . . 75 . . . 80 . . . 85 . . . 90 . . . 95 . . . 100 years old, that has not yet begun to show symptoms of an aging-associated condition e.g., cognitive impairment; an individual of any age that is suffering from a cognitive impairment due to an aging-associated disease, as described further below, and an individual of any age that has been diagnosed with an aging-associated disease that is typically accompanied by cognitive impairment, where the individual has not yet begun to show symptoms of cognitive impairment. The corresponding ages for non-human subjects are known and are intended to apply herein. As summarized elsewhere, in some instances the subject is a mammal. Mammalian species that may be treated with the present methods include canines and felines; equines; bovines; ovines; etc., and primates, including humans. The subject methods, compositions, and reagents may also be applied to animal models, including small mammals, e.g., murine, lagomorpha, etc., for example, in experimental investigations. As used herein and as described above, "treatment" refers to any of (i) the prevention of the disease or disorder, or (ii) the reduction or elimination of symptoms of the disease or disorder. Treatment may be effected prophylactically (prior to the onset of disease) or therapeutically (following the onset of the disease). The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. Thus, the term "treatment" as used herein covers any treatment of an aging-related disease or disorder in a mammal, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease. Treatment may result in a variety of different physical manifestations, e.g., modulation in gene expression, rejuvenation of tissue or organs, etc. The therapeutic agent may be administered before, during or after the onset of disease. The treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment may be performed prior to complete loss of function in the affected tissues. The subject therapy may be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease. In some embodiments, the condition that is treated is an aging-associated impairment in cognitive ability in an individual. By cognitive ability, or "cognition," it is meant the mental processes that include attention and concentration, learning complex tasks and concepts, memory (acquiring, retaining, and retrieving new information in the short and / or long term), information processing (dealing with information gathered by the five senses), visuospatial function (visual perception, depth perception, using mental imagery, copying drawings, constructing objects or shapes), producing and understanding language, verbal fluency (word-finding), solving problems, making decisions, and executive functions (planning and prioritizing). By "cognitive decline", it is meant a progressive decrease in one or more of these abilities, e.g., a decline in memory, language, thinking, judgment, etc. By "an impairment in cognitive ability" and "cognitive impairment", it is meant a reduction in cognitive ability relative to a healthy individual, e.g., an age-matched healthy individual, or relative to the ability of the individual at an earlier point in time, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years or more previously. By "aging-associated cognitive impairment," it is meant an impairment in cognitive ability that is typically associated with aging, including, for example, cognitive impairment associated with the natural aging process, e.g., mild cognitive impairment (M.C.I.); and cognitive impairment associated with an aging-associated disorder, that is, a disorder that is seen with increasing frequency with increasing senescence, e.g., a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy, ataxia, associated frailty, and the like. g. Combinations The compounds of general formula 1 may be used on their own or combined with other active substances of formula 1 according to the invention. The compounds of general formula 1 may optionally also be combined with other pharmacologically active substances. These include, B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti- inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1 / H3-receptor antagonists, PI3- kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF-κB signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DP1-receptor modulators, Thromboxane receptor antagonists, additional CCR3 antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR<com:Sup>2< / com:Sup> antagonists, CXCR1 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR3 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1- Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example A2a-agonists, modulators of purinergic receptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC- inhibitors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFa antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4 / IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds against swelling of the airways, compounds against cough, VEGF inhibitors, but also combinations of two or three active substances. In some embodiments, the other active substances are betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO- inhibitors, Histamine receptor antagonists and SYK-inhibitors, but also combinations of two or three active substances, i.e.: Betamimetics with corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, Anticholinergics with betamimetics, corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists CRTH2-inhibitors with LTD4-antagonists. In these embodiments, the compounds that make up the combination are co-administered to a subject. The terms "co-administration" and "in combination with" include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits. In one embodiment, the agents are present in the cell or in the subject's 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 unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent can be administered prior to (e.g., 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 (e.g., 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) the administration of a second therapeutic agent. "Concomitant administration" of a known therapeutic drug with a pharmaceutical composition of the present disclosure means administration of the compound and second agent at such time that both the known drug and the composition of the present invention will have a therapeutic effect. Such concomitant administration may involve concurrent (i.e. at the same time), prior, or subsequent administration of the drug with respect to the administration of a subject compound. Routes of administration of the two agents may vary, where representative routes of administration are described in greater detail below. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds of the present disclosure. In some embodiments, the compounds (e.g., a subject compound and the 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, within 3 hours of each other, or within 1 hour of each other. In certain embodiments, the compounds are administered within 1 hour of each other. In certain embodiments, the compounds are administered substantially simultaneously. By administered substantially simultaneously is meant that the compounds are administered to the subject within about 10 minutes or less of each other, such as 5 minutes or less, or 1 minute or less of each other. h. Pharmaceutical Forms Suitable preparations for administering the compounds of formula 1 and the co-crystal or salt forms of formulae 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 from 0.05 to 90 wt.-%, such as 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may 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 corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally 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 may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as 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. Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, while if water is used as diluent, for example, organic solvents may optionally be used as solubilisers or dissolving aids, and the solutions may be transferred into injection vials or ampoules or infusion bottles. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). For oral use the tablets may obviously contain, in addition to the carriers specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additional substances such as starch, e.g., potato starch, gelatine and the like. Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also be used to produce the tablets. In the case of aqueous suspensions the active substances may be combined with various flavor enhancers or colorings in addition to the abovementioned excipients. For administering the compounds of formula 1 or the co-crystal or salt forms of formulae 2 and 2a preparations or pharmaceutical formulations which are suitable for inhalation may be employed. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions. Within the scope of the present invention, the term propellant-free inhalable solutions also include concentrates or sterile inhalable solutions ready for use. The formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification. The inhalable powders which may be used according to the invention may contain a compound of formula 1 or a co-crystal or salt form of formulae 2 and 2a either on their own or in admixture with suitable physiologically acceptable excipients. If the active substances of the compounds of formula 1 or the co-crystal or salt forms of formulae 2 and 2a are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. In some instances, mono- or disaccharides are used, such as lactose or glucose, e.g., in the form of their hydrates, e.g., lactose, such as lactose monohydrate. Within the scope of the inhalable powders according to the invention the 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. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 µm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronized active substance of the compounds of formula 1 or the co-crystal or salt forms of formulae 2 and 2a, such as with an average particle size of 0.5 to 10 µm, including from 1 to 5 µm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be administered using inhalers known from the prior art. The inhalation aerosols containing propellant gas according to the invention may contain a compound of formula 1 or a co-crystal or salt form of formulae 2 and 2a dissolved in the propellant gas or in dispersed form. The compounds of formula 1 or the co-crystal or salt forms of formulae 2 and 2a may be contained in separate formulations or in a common formulation, in which they are either both dissolved, both dispersed or in each case only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases may be used on their own or mixed together. In some instances, propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof. The propellant-driven inhalation aerosols may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art. The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs = metered dose inhalers). Moreover, the active substances of the compounds of formula 1 or the co-crystal or salt forms of formulae 2 and 2a according to the invention may be administered in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, such as an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is in some instances 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. The solutions or suspensions containing a compound of formula 1 or a co-crystal or salt form of formulae 2 and 2a are adjusted to a pH of 2 to 7, such as 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric 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 instances, the inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are employed in some instances. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, in some instances hydrochloric acid is employed to adjust the pH. If desired, the addition of edetic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabilizer or complexing agent may be omitted in these formulations. Other embodiments may contain this compound or these compounds. In an embodiment the content based on sodium edetate is less than 100 mg / 100ml, such as less than 50mg / 100ml, and including less than 20mg / 100ml. Inhalable solutions in which the content of sodium edetate is from 0 to 10mg / 100ml are employed in some instances. Co-solvents and / or other excipients may be added to the propellant-free inhalable solutions, such as those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the physiologically suitable solvent in order to improve the qualitative properties of the active substance formulation. In some embodiments, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. In some embodiments excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly acetyl pyridinium chloride, ...

Claims

1. A use of a compound to treat aging-associated-neuronal loss, aging-associated-memory impairment, or aging-associated-loss of motor coordination in a subject, wherein the compound is of formula 1, [Image disponible dans le document PDF, Image available in the PDF document] wherein Α is CH 2 , O or N-C 1-6 -alkyl; R 1 R^1 is selected from • NHR 1.1 , NMeR 1.1 ; • NHR 1.2 , NMeR 1.2 ; NHCH 2 - ℝ 1.3 \mathbb{R}^{1.3} ; NH-C 3-6 -cycloalkyl, wherein optionally one carbon atom is replaced by a nitrogen atom, wherein the ring is optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, O − C 1 − 6 O-C_{1-6} -alkyl, N H S O 2 NHSO_2 -phenyl, N H C O N H NHCONH -phenyl, halogen, CN, SO 2 -C 1-6 -alkyl, and COO-C 1-6 -alkyl; a C 9 or 10 -bicyclic-ring, wherein one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound via a nitrogen atom to the basic structure of formula 1 and wherein the ring system is optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, COO- C 1 − 6 C_{1-6} -alkyl, C 1-6 -haloalkyl, O-C 1-6 -alkyl, NO 2 , halogen, CN, NHSO 2 -C 1-6 -alkyl, and methoxy-phenyl; a group selected from NHCH(pyridinyl)CH 2 COO-C 1-6 -alkyl, or NHCH(CH 2 O-C 1-6 -alkyl)-benzoimidazolyl, optionally substituted with halogen or CN; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO 2 -n-Bu and m-methoxyphenyl; and 1-aminocyclopentyl, optionally substituted with methyl-oxadiazole; R 1.1 R^{1.1} is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 2 − 6 C_{2-6} -alkenyl, C 2 − 6 C_{2-6} -alkynyl, C 1 − 6 C_{1-6} -haloalkyl, C 1 − 6 C_{1-6} -alkylene-OH, C 2 − 6 C_{2-6} -alkenylene-OH, C 2 − 6 C_{2-6} -alkynylene-OH, C H 2 C O N ( C 1 − 6 CH_2CON(C_{1-6} -alkyl) 2 , CH 2 NHCONH-C 3-6 -cycloalkyl, CN, CO-pyridinyl, CONR 1.1.1 R 1.1.2 , COO-C 1-6 -alkyl, N ( S O 2 − C 1 − 6 − a l k y l ) ( C H 2 C O N ( C 1 − 4 − a l k y l ) 2 ) O − C 1 − 6 − a l k y l , O − p y r i d i n y l , S O 2 − C 1 − 6 − a l k y l , N(SO_2-C_{1-6}-alkyl)(CH_2CON(C_{1-4}-alkyl)_2) O-C_{1-6}-alkyl, O-pyridinyl, SO_2-C_{1-6}-alkyl, SO 2 -C 1-6 -alkylen-OH, SO 2 -C 3-6 -cycloalkyl, SO 2 -piperidinyl, SO 2 NH-C 1-6 -alkyl, S O 2 N ( C 1 − 6 − a l k y l ) 2 SO_2N(C_{1-6}-alkyl)_2 , halogen, CN, CO-morpholinyl, CH 2 -pyridinyl and a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, NHC 1-6 -alkyl and =O; R 1.1 .1 R^{1.1.1} H, C 1 − 6 C_{1-6} -alkyl, C 3 − 6 C_{3-6} -cycloalkyl, C 1 − 6 C_{1-6} -haloalkyl, C H 2 C O N ( C 1 − 6 CH_2CON(C_{1-6} -alkyl,) 2 , C H 2 C O CH_2CO -azetindinyl, C 1 − 6 C_{1-6} -alkylen- C 3 − 6 C_{3-6} -cycloalkyl, C H 2 CH_2 -pyranyl, C H 2 CH_2 -tetrahydrofuranyl, C H 2 CH_2 -furanyl, C 1 − 6 C_{1-6} -alkylen-OH or thiadiazolyl, optionally substituted with C 1-6 -alkyl; R 1.1 .2 R^{1.1.2} H, C 1 − 6 C_{1-6} -alkyl, S O 2 C 1 − 6 SO_2C_{1-6} -alkyl; or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one N or O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 1 − 4 C_{1-4} -alkylene-OH, OH, and =O; or R 1.1 R^{1.1} is phenyl, wherein two adjacent residues are together forming a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing independently from each other one or two N, S, or SO 2 , replacing a carbon atom of the ring, wherein the ring is optionally substituted with C 1 − 4 C_{1-4} -alkyl or =0; R 1.2 R^{1.2} is selected from the group consisting of heteroaryl, optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 2 − 6 C_{2-6} -alkenyl, C 2 − 6 C_{2-6} -alkynyl, C 3 − 6 C_{3-6} -cycloalkyl, C H 2 C O O − C 1 − 6 CH_2COO-C_{1-6} -alkyl, C O N R 1.2 .1 R 1.2 .2 CONR^{1.2.1}R^{1.2.2} , C O R 1.2 .3 COR^{1.2.3} , C O O − C 1 − 6 COO-C_{1-6} -alkyl, C O N H 2 CONH_2 , O − C 1 − 6 O-C_{1-6} -alkyl, halogen, CN, S O 2 N ( C 1 − 6 SO_2N(C_{1-6} -alkyl) 2 and heteroaryl optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl; heteroaryl, optionally substituted with a five- or six-membered carbocyclic non-aromatic ring containing independently from each other two N, O, S, or SO 2 , replacing a carbon atom of the ring; an aromatic or non-aromatic C 9 or 10 -bicyclic-ring, wherein 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 ( C 1 − 6 N(C_{1-6} -alkyl) 2 , CONH-C 1-6 -alkyl, and = 0 =0 ; a heterocyclic non-aromatic ring, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO- C 1 − 6 C_{1-6} -alkyl, R 1.2 .1 R^{1.2.1} H, C 1 − 6 C_{1-6} -alkyl, C 1 − 6 C_{1-6} -alkylene- C 3 − 6 C_{3-6} -cycloalkyl, C 1 − 4 C_{1-4} -alkylene-phenyl, C 1 − 4 C_{1-4} -alkylene-furanyl, C 3 − 6 C_{3-6} -cycloalkyl, C 1 − 4 C_{1-4} -alkylene-O- C 1 − 4 C_{1-4} -alkyl, C 1-6 -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO 2 , replacing a carbon atom of the ring, optionally substituted with 4-cyclopropylmethyl-piperazinyl R 1.2 .2 R^{1.2.2} H, C 1 − 6 C_{1-6} -alkyl; R 1.2 .3 R^{1.2.3} a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently from each other one or two N, O, S, or SO 2 , replacing a carbon atom of the ring; R 1.3 R^{1.3} is selected from the group consisting of phenyl, heteroaryl or indolyl, each optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 3 − 6 C_{3-6} -cycloalkyl, O − C 1 − 6 O-C_{1-6} -alkyl, O − C 1 − 6 O-C_{1-6} -haloalkyl, phenyl, and heteroaryl; R 2 R^2 is selected from the group consisting of C 1 − 6 C_{1-6} -alkylene-phenyl, C 1 − 6 C_{1-6} -alkylene-naphthyl, and C 1 − 6 C_{1-6} -alkylene-heteroaryl; each optionally substituted with one, two or three residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 1 − 6 C_{1-6} -haloalkyl, O − C 1 − 6 O-C_{1-6} -alkyl, O-C 1-6 -haloalkyl, and halogen; ℝ 3 \mathbb{R}^3 is H, C 1 − 6 C_{1-6} -alkyl; R 4 R^4 is H, C 1 − 6 C_{1-6} -alkyl; or R 3 and R 4 together are forming a CH 2 -CH 2 group.

2. The use of claim 1 wherein in the compound of formula 1, Α is C H 2 CH_2 , O or N − C 1 − 4 N-C_{1-4} -alkyl; R 1 R^1 is selected from the group consisting of • NHR 1.1 , NMeR 1.1 ; • NHR 1.2 , NMeR 1.2 ; NHCH 2 - ℝ 1.3 \mathbb{R}^{1.3} ; NH-C 3-6 -cycloalkyl, wherein optionally one carbon atom is replaced by a nitrogen atom, wherein the ring is optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, O − C 1 − 6 O-C_{1-6} -alkyl, N H S O 2 NHSO_2 -phenyl, N H C O N H NHCONH -phenyl, halogen, CN, SO 2 -C 1-6 -alkyl, and COO-C 1-6 -alkyl; a C 9 or 10 -bicyclic-ring, wherein one or two carbon atoms are replaced by nitrogen atoms and the ring system is bound via a nitrogen atom to the basic structure of formula 1 and wherein the ring system is optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, COO- C 1 − 6 C_{1-6} -alkyl, C 1-6 -haloalkyl, O-C 1-6 -alkyl, NO 2 , halogen, CN, NHSO 2 -C 1-6 -alkyl, and m-methoxyphenyl; • a group selected from NHCH(pyridinyl)CH 2 COO-C 1-6 -alkyl, and NHCH(CH 2 O-C 1-6 -alkyl)-benzoimidazolyl, optionally substituted with Cl; and 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; R 1.1 R^{1.1} is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 1 − 6 C_{1-6} -haloalkyl, C H 2 C O N ( C 1 − 6 CH_2CON(C_{1-6} -alkyl) 2 , C H 2 N H C O N H − C 3 − 6 CH_2NHCONH-C_{3-6} -cycloalkyl, CN, C O N R 1.1 .1 R 1.1 .2 CONR^{1.1.1}R^{1.1.2} , C O O − C 1 − 6 COO-C_{1-6} -alkyl, O − C 1 − 6 O-C_{1-6} -alkyl, SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -alkylen-OH, SO 2 -C 3-6 -cycloalkyl, SO 2 -piperidinyl, S O 2 N H − C 1 − 6 SO_2NH-C_{1-6} -alkyl, S O 2 N ( C 1 − 6 SO_2N(C_{1-6} -alkyl) 2 , halogen, CN, CO-morpholinyl, CH 2 -pyridinyl and a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, NHC 1-6 -alkyl, and =O; R 1.1 .1 R^{1.1.1} H, C 1 − 6 C_{1-6} -alkyl, C 3 − 6 C_{3-6} -cycloalkyl, C 1 − 6 C_{1-6} -haloalkyl, C H 2 C O N ( C 1 − 6 CH_2CON(C_{1-6} -alkyl,) 2 , [Image disponible dans le document PDF, Image available in the PDF document] CH 2 -tetrahydrofuranyl, CH 2 -furanyl, C 1-6 -alkylen-OH or thiadiazolyl, optionally substituted with C 1-6 -alkyl; R 1.1 .2 R^{1.1.2} H, C 1 − 6 C_{1-6} -alkyl, S O 2 C 1 − 6 SO_2C_{1-6} -alkyl; or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH R 1.2 R^{1.2} is selected from the group consisting of heteroaryl, optionally substituted with one or two residues selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, CH 2 COO-C 1-6 -alkyl, C O N R 1.2 .1 R 1.2 .2 CONR^{1.2.1}R^{1.2.2} , C O O − C 1 − 6 COO-C_{1-6} -alkyl, C O N H 2 CONH_2 , O − C 1 − 6 O-C_{1-6} -alkyl, halogen, C N CN , CO-pyrrolidinyl, CO-morpholinyl and heteroaryl optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N ( C 1 − 6 − a l k y l ) 2 N(C_{1-6}-alkyl)_2 , CONH- C 1 − 6 − a l k y l C_{1-6}-alkyl , and =0; piperidinyl, optionally substituted with pyridinyl; and 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO- C 1 − 6 C_{1-6} -alkyl, R 1.2 .1 R^{1.2.1} H, C 1 − 6 C_{1-6} -alkyl; R 1.2 .2 R^{1.2.2} H, C 1-6 -alkyl; R 1.3 R^{1.3} is selected from the group consisting of phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 3 − 6 C_{3-6} -cycloalkyl, O − C 1 − 6 O-C_{1-6} -alkyl, and O − C 1 − 6 O-C_{1-6} -haloalkyl; R 2 R^2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of C 1 − 6 C_{1-6} -alkyl, C 1 − 6 C_{1-6} -haloalkyl, O − C 1 − 6 O-C_{1-6} -alkyl, O-C 1-6 -haloalkyl, halogen and CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen; ℝ 3 \mathbb{R}^3 is H, C 1-4 -alkyl; R 4 R^4 is H, C 1-4 -alkyl; or ℝ 3 \mathbb{R}^3 and ℝ 4 \mathbb{R}^4 together are forming a C H 2 CH_2 - C H 2 CH_2 group.

3. The use of claim 1 wherein in the compound of formula 1: Α is CH 2 , O or NMe; R 1 R^1 is selected from the group consisting of • NHR 1.1 , NMeR 1.1 ; • NHR 1.2 , NMeR 1.2 ; NHCH 2 - ℝ 1.3 \mathbb{R}^{1.3} ; NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, NHSO 2 -phenyl, NHCONH-phenyl, and halogen; NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO 2 -C 1-4 -alkyl, COO-C 1-4 -alkyl; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO 2 -C 1-4 -alkyl, m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, C O O − C 1 − 4 COO-C_{1-4} -alkyl, C 1 − 4 C_{1-4} -haloalkyl, O − C 1 − 4 O-C_{1-4} -alkyl, NO 2 , and halogen; a group selected from NHCH(pyridinyl)CH 2 COO-C 1-4 -alkyl, NHCH(CH 2 O-C 1-4 -alkyl)-benzoimidazolyl, optionally substituted with Cl; and 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; R 1.1 R^{1.1} is phenyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, C 1 − 4 C_{1-4} -haloalkyl, C H 2 C O N ( C 1 − 4 CH_2CON(C_{1-4} -alkyl) 2 , C H 2 N H C O N H − C 3 − 6 CH_2NHCONH-C_{3-6} -cycloalkyl, CN, C O N R 1.1 .1 R 1.1 .2 CONR^{1.1.1}R^{1.1.2} , C O O − C 1 − 4 COO-C_{1-4} -alkyl, O − C 1 − 4 O-C_{1-4} -alkyl, SO 2 -C 1-4 -alkyl, SO 2 -C 1-4 -alkylen-OH, SO 2 -C 3-6 -cycloalkyl, SO 2 -piperidinyl, S O 2 N H − C 1 − 4 SO_2NH-C_{1-4} -alkyl, S O 2 N ( C 1 − 4 SO_2N(C_{1-4} -alkyl) 2 , halogen, CO-morpholinyl, C H 2 CH_2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, and pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, N H C 1 − 4 NHC_{1-4} -alkyl,and =0; [Image disponible dans le document PDF, Image available in the PDF document] R 1.1 .2 R^{1.1.2} H, C 1 − 4 C_{1-4} -alkyl, S O 2 C 1 − 4 SO_2C_{1-4} -alkyl; or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH R 1.2 R^{1.2} is selected from the group consisting of pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, C 3 − 6 C_{3-6} -cycloalkyl, C H 2 C O O − C 1 − 4 CH_2COO-C_{1-4} -alkyl, C O N R 1.2 .1 R 1.2 .2 CONR^{1.2.1}R^{1.2.2} , COO-C 1-4 -alkyl, CONH 2 , O-C 1-4 -alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of N ( C 1 − 4 − a l k y l ) 2 N(C_{1-4}-alkyl)_2 , CONH- C 1 − 4 − a l k y l C_{1-4}-alkyl , and =O; piperidinyl, optionally substituted with pyridinyl; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCO- C 1 − 4 C_{1-4} -alkyl, R 1.2 .1 R^{1.2.1} H, C 1-4 -alkyl; R 1.2 .2 R^{1.2.2} H, C 1-4 -alkyl; R 1.3 R^{1.3} is selected from the group consisting of phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl and oxadiazolyl, each optionally substituted with one or two residues selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, O-C 1-4 -alkyl, and O − C 1 − 4 O-C_{1-4} -haloalkyl; R 2 R^2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of C 1 − 4 C_{1-4} -alkyl, C 1 − 4 C_{1-4} -haloalkyl, O-C 1-4 -haloalkyl, and halogen; or CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of halogen; R 3 R^3 is H; R 4 R^4 is H; or R 3 and R 4 together are forming a CH 2 -CH 2 group.

4. The use of claim 1 wherein in the compound of formula 1: Α is CH 2 , O or NMe; R 1 R^1 is selected from the group consisting of NHR 1.1 , NMeR 1.1 ; • NHR 1.2 , NMeR 1.2 ; NHCH 2 - R 1.3 R^{1.3} ; NH-piperidinyl, optionally substituted with pyridinyl; NH-cyclohexyl, optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO 2 -phenyl, NHCONH-phenyl, and F; NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of SO 2 Me, COO-t-Bu; piperidinyl, optionally substituted with one or two residues selected from the group consisting of NHSO 2 -n-Bu, m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF 3 , OMe, NO 2 , F, and Br; a group selected from NHCH(pyridinyl)CH 2 COOMe, NHCH(CH 2 OMe)-benzoimidazolyl, optionally substituted with Cl; and 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl; R 1.1 R^{1.1} is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF 3 , CH 2 CONMe 2 , CH 2 NHCONH-cyclohexyl, CN, CONR 1.1.1 R 1.1.2 , COOMe, COOEt, OMe, SO 2 Me, SO 2 CH 2 CH 2 OH, SO 2 Et, SO 2 -cyclopropyl, SO 2 -piperidinyl, SO 2 NHEt, SO 2 NMeEt, F, Cl, CO-morpholinyl, CH 2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, and pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, and =O; R 1.1 .1 R^{1.1.1} H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH 2 -i-Pr, CH 2 -t-Bu, CH(CH 3 )CH 2 CH 3 , CH 2 CHF 2 , CH 2 CONMe 2 , CH 2 CO-azetindinyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 OH or thiadiazolyl, optionally substituted with Me; R 1.1 .2 R^{1.1.2} H, Me, Et, SO 2 Me, SO 2 Et or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH R 1.2 R^{1.2} is selected from the group consisting of 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 1.2.1 R 1.2.2 , COOMe, COOEt, CONH 2 , OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and oxadiazolyl, each optionally substituted Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe 2 , CONHMe, and =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, R 1.2 .1 R^{1.2.1} H, Me; R 1.2 .2 R^{1.2.2} H, Me; R 1.3 R^{1.3} is selected from the group consisting of 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, and OCHF 2 ; R 2 R^2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH 3 , CF 3 , OCF 3 , F, Cl, Br, Et; and CH 2 -thiophenyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br; ℝ 3 \mathbb{R}^3 is H; R 4 R^4 is H; or R 3 and R 4 together are forming a CH 2 -CH 2 group.

5. The use of claim 1 wherein in the compound of formula 1: Α is CH 2 , O or NMe; R 1 R^1 is selected from • 𝖭 𝖧 𝖱 1.1 \mathsf{NHR}^{1.1} N H R 1.2 NHR^{1.2} , R 1.1 R^{1.1} is phenyl, optionally substituted with one or two residues selected from the group consisting of Me, Et, Bu, CF 3 , CH 2 CONMe 2 , CH 2 NHCONH-cyclohexyl, CN, CONR 1.1.1 R 1.1.2 , COOMe, COOEt, OMe, SO 2 Me, SO 2 CH 2 CH 2 OH, SO 2 Et, SO 2 -cyclopropyl, SO 2 -piperidinyl, SO 2 NHEt, SO 2 NMeEt, F, Cl, CO-morpholinyl, CH 2 -pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, and pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, and =O; R 1.1 .1 R^{1.1.1} H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH 2 -i-Pr, CH 2 -t-Bu, CH(CH 3 )CH 2 CH 3 , CH 2 CHF 2 , CH 2 CONMe 2 , CH 2 CO-azetindinyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -pyranyl, CH 2 -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 OH or thiadiazolyl, optionally substituted with Me; R 1.1 .2 R^{1.1.2} H, Me, Et, SO 2 Me, SO 2 Et or R 1.1.1 and R 1.1.2 together are forming a four-, five- or six-membered carbocyclic ring, optionally containing one O, replacing a carbon atom of the ring, optionally substituted with one or two residues selected from the group consisting of CH 2 OH R 1.2 R^{1.2} is selected from 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 1.2.1 R 1.2.2 , COOMe, COOEt, CONH 2 , OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and oxadiazolyl, each optionally substituted with Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe 2 , CONHMe, and =O; 4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe, R 1.2 .1 R^{1.2.1} H, Me; R 1.2 .2 R^{1.2.2} H, Me; R 2 R^2 is selected from CH 2 -phenyl or CH 2 -naphthyl, both optionally substituted with one or two residues selected from the group consisting of CH 3 , CF 3 , OCF 3 , F, Cl, Br, and Et R 3 R^3 is H; R 4 R^4 is H.

6. The use of claim 1 wherein in the compound of formula 1: Α is CH 2 , O or NMe; R 1 R^1 is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , wherein X 1 X_1 is the point of attachment of 𝖱 1 \mathsf{R}^1 to formula 1; R 2 R^2 is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] 1 attachment of R 2 to formula 1; ℝ 3 \mathbb{R}^3 is H; R 4 R^4 is H; or R 3 and R 4 together are forming a CH 2 -CH 2 group.

7. The use of claim 1 wherein the compound is a co-crystal of formula 2, or a salt thereof, wherein the compound of formula 2 has the following structure: [Image disponible dans le document PDF, Image available in the PDF document] wherein R 1 R^1 is C 1-6 -alkyl, C 1-6 -haloalkyl, O-C 1-6 -haloalkyl, halogen; m is 1, 2 or 3; R 2 a R^{2a} and R 2 b R^{2b} are each independently selected from H, C 1 − 6 C_{1-6} -alkyl, C 1 − 6 C_{1-6} -alkenyl, C 1 − 6 C_{1-6} -alkynyl, C 3-6 -cycloalkyl, COO-C 1-6 -alkyl, O-C 1-6 -alkyl, CONR 2b.1 R 2b.2 , halogen; R 2b.1 is H, C 1-6 -alkyl, C 0-4 -alkyl-C 3-6 -cycloalkyl, C 1-6 -haloalkyl; R 2b.2 is H, C 1-6 -alkyl; or R 2 b .1 R^{2b.1} and R 2 b .2 R^{2b.2} are together a C 3 - 6 C_{3\text{-}6} -alkylene group forming with the nitrogen atom a heterocyclic ring, wherein optionally one carbon atom of the ring is replaced by an oxygen atom; R 3 R^3 is H, or Me; X is an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p-toluenesulphonate; j is 0, 0.5, 1, 1.5 or 2; with a co-crystal 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-hydroxy-2-naphtoic acid, mucic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, and glycine.

8. The use of claim 1 wherein the compound is a crystalline salt of the formula below, [Image disponible dans le document PDF, Image available in the PDF document] .

9. The use of claim 7, comprising use of a pharmaceutical composition comprising the at least one co-crystal of the compound of formula 2 and a pharmaceutically acceptable carrier.

10. The use of claim 1 wherein the compound of formula 1 is for use in the form of the individual optical isomers, a mixture of the individual enantiomers, a racemate or in the form of the enantiomerically pure compounds.

11. The use of claim 1 comprising use of a pharmaceutical composition comprising as an active ingredient one or more compounds of formula 3, or a co-crystal or a salt thereof, wherein the compound of formula 3 has the following structure: [Image disponible dans le document PDF, Image available in the PDF document] wherein R 1 R^1 is H, C 1 − 6 C_{1-6} -alkyl, C 0 − 4 C_{0-4} -alkyl- C 3 − 6 C_{3-6} -cycloalkyl, C 1 − 6 C_{1-6} -haloalkyl; R 2 R^2 is H, C 1 − 6 C_{1-6} -alkyl; X is an anion selected from the group consisting of chloride or ½ dibenzoyltartrate is 1 or 2, a first diluent, a second diluent, a binder, a disintegrant and a lubricant.

12. The use of claim 11 wherein the pharmaceutical composition further comprises an additional disintegrant.

13. The use of claim 11 or 12 wherein the pharmaceutical composition further comprises a glidant.

14. The use of claim 11, 12 or 13 wherein the diluent of the pharmaceutical composition further comprises cellulose powder, dibasic calciumphosphatae anhydrous, dibasic calciumphosphate dehydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelantinized starch, or xylitol.

15. The use of claim 1, comprising treating aging-associated-neuronal loss.

16. The use of claim 1, comprising treating aging-associated-memory impairment.

17. The use of claim 1, comprising treating aging-associated-loss of motor coordination.