Treatment methods for behavioral change

Abstract

To provide novel and / or improved drugs for treating behavior alterations, particularly drugs acting via novel mechanisms of action that allow specifically treating behavior alterations and / or exhibiting a more favorable side effect profile than current treatments.SOLUTION: Provided herein are methods for treating behavior alterations using KDM1A inhibitors, particularly 5-((((1R,2S)- 2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for treating behavioral changes.

Background Art

[0002] Behavioral changes such as social withdrawal and aggressive behavior are very common in today's society, and clinicians consider them as medical conditions in themselves. Nevertheless, the treatment of behavioral changes remains a medical challenge. Currently, there are no approved drugs specifically aimed at treating social withdrawal, aggressive behavior or other behavioral changes. Moreover, many of the existing drugs used in the treatment of behavioral changes can cause severe side effects; for example, many antipsychotics (also known as neuroleptics or major tranquilizers) used to treat aggressive behavior and other behavioral changes cause sedation.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Therefore, there is a strong and unmet need for new and / or improved drugs for treating behavioral changes, particularly drugs that act via a novel mechanism of action that enables specific treatment of behavioral changes and / or exhibit a more favorable side effect profile than current treatments. The present invention addresses these and other needs.

Means for Solving the Problems

[0004] Outline of the invention The present invention provides a novel method for treating behavioral changes by using a KDM1A inhibitor.

[0005] Therefore, the present invention provides a KDM1A inhibitor for use in the treatment of behavioral changes.

[0006] The present invention further provides a method for treating behavioral changes in a patient (preferably a human), comprising administering a therapeutically effective amount of a KDM1A inhibitor to the patient.

[0007] The present invention further provides the use of KDM1A inhibitors for the manufacture of therapeutic agents for behavioral changes.

[0008] The present invention further provides the use of KDM1A inhibitors for the treatment of behavioral changes.

[0009] In some embodiments, the behavioral change is a change in social behavior. In some embodiments, the behavioral change is aggression or social withdrawal.

[0010] In a preferred embodiment, the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof. [Brief explanation of the drawing]

[0011] [Figure 1] As described in more detail in Example 3, the effect of treatment with compound 1 (defined below and in Example 1), a KDM1A inhibitor, on aggressive behavior in the resident intruder test in male SAMP8 mice, as evaluated by the total number of attacks, is shown. The mean and standard error (SEM) are shown. * p < 0.05; ** p < 0.01. [Figure 2] As described in more detail in Example 3, the effect of treatment with compound 1 on aggressive behavior in the resident intruder test in male SAMP8 mice, evaluated by the number of clinch attacks, is shown. Mean and SEM are shown. ** p < 0.01; *** p < 0.001. [Figure 3]As described in more detail in Example 4, the effect of treatment with compound 1 on social avoidance in the resident intruder test of a rat isolation model, assessed by time without social interaction (measured in seconds), is shown. Mean and SEM are shown. * p < 0.05; ** p < 0.01. [Figure 4] The effect of compound 1 on social avoidance in the resident intruder test of a rat isolation model, evaluated by the number of avoidances, is shown, as described in more detail in Example 4. Mean and SEM are shown. * p < 0.05; *** p < 0.001. [Figure 5] The effect of compound 1 on social interaction behavior in the three-chamber test, evaluated by the time spent (measured in seconds) in each of the object chamber and mouse chamber, is shown. Mean and SEM results are shown. *** p < 0.001. [Figure 6] The effect of compound 1 on social interaction behavior in TCT, as evaluated by the time (measured in seconds) spent on direct exploration of novel mice, is shown. Mean and SEM results are shown. *** p < 0.001. [Modes for carrying out the invention]

[0012] Detailed description of the invention The present invention is based on the discovery that KDM1A inhibitors are useful as therapeutic agents for treating behavioral changes, as described in more detail below herein and in the examples.

[0013] Therefore, the present invention provides a KDM1A inhibitor for use in treating behavioral changes.

[0014] The present invention further provides a method for treating behavioral changes in a patient (preferably a human), comprising administering a therapeutically effective amount of a KDM1A inhibitor to the patient.

[0015] The present invention further provides the use of KDM1A inhibitors for the manufacture of therapeutic agents for behavioral changes.

[0016] The present invention further provides the use of KDM1A inhibitors for the treatment of behavioral changes.

[0017] According to the present invention, “behavioral changes” particularly relate to changes, disturbances, dysfunctions, abnormalities, and disorders affecting the behavior of an individual, including, but not limited to, behavioral changes induced by or associated with genetic or epigenetic mutations, behavioral changes associated with disease, behavioral changes induced by pharmacotherapy, behavioral changes induced by acute and / or chronic drug abuse, or behavioral changes induced by unfortunate social circumstances (e.g., neglect or omission in childhood, war, or traumatic experiences such as sexual assault in adulthood). Behavioral changes according to the present invention do not include changes in cognitive function (e.g., memory impairment) or mood (e.g., anxiety).

[0018] In some embodiments, behavioral changes are social behavioral changes. In particular, this relates to changes, disturbances, dysfunctions, abnormalities, disorders, etc., that affect the social behavior of an individual due to any cause, such as, for example, changes in social behavior induced by or associated with genetic or epigenetic mutation (e.g., changes in social interaction or aggression), changes in social behavior associated with disease (e.g., changes in social interaction or aggression), changes in social behavior induced by pharmacotherapy (e.g., changes in social interaction or aggression), changes in social behavior induced by acute and / or chronic substance abuse (e.g., changes in social interaction or aggression), or changes in social behavior induced by unfortunate social environments (e.g., childhood neglect or ostracism, war or traumatic experiences such as sexual assault in adulthood). Examples of social behavioral changes according to the present invention include, for example, social withdrawal, aggression, or emotional blunting.

[0019] Thus, the present invention also relates to a KDM1A inhibitor for use in the treatment of behavior disturbance, behavioral dysfunction, behavioral abnormality, or behavior disorder, particularly social behavior disturbance, social behavioral dysfunction, social behavioral abnormality or social behavior disorder. Similarly, the present invention provides a method for treating behavior disturbance, behavioral dysfunction, behavioral abnormality, or behavior disorder (particularly social behavior disturbance, social behavioral dysfunction, social behavioral abnormality, or social behavior disorder) in a patient (preferably a human), the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Social behavior disturbance, social behavioral dysfunction, social behavioral abnormality, or social behavior disorder can particularly be social withdrawal, aggression, or emotional blunting. Further, any of the aforementioned conditions can be induced or associated with, for example, (i) genetic or epigenetic mutations, (ii) associated with a disease, (iii) induced by drug therapy, (iv) acute and / or chronic drug abuse, or (v) an adverse social environment, as will be described in more detail below.

[0020] "Social withdrawal" according to the present invention refers to the abnormal, pathological or inappropriate lack and / or decrease in the degree of social interaction (including social avoidance), often accompanied by indifference or arrogance, especially for members of social species such as humans, by consistently (through situations and time) exhibiting solitary behavior in the presence of others. In particular, it relates to a state where an individual withdraws from society and interpersonal relationships. In this regard, social withdrawal (which can also be called passive withdrawal) is considered to be caused by internal factors where, for some reason, an individual chooses not to interact with others. Social withdrawal according to the present invention does not include active social isolation and is used to indicate a lack of social interaction due to external factors, for example, the process where an individual is alone because his / her colleagues do not want to interact with him / her (i.e., the individual is isolated from others). Non-limiting examples of social withdrawal treated according to the present invention include social withdrawal induced or associated with genetic or epigenetic mutations (e.g., COMT, etc.), social withdrawal associated with diseases (e.g., autism spectrum disorder (ASD, such as autism or Asperger's syndrome, etc.), avoidant personality disorder (AvPD), schizophrenia (e.g., schizophrenia type and / or delusional disorder), mood disorders (e.g., major depressive disorder, cyclothymic disorder, or bipolar disorder), drug intoxication, post-traumatic stress disorder (PTSD), dementia (such as Alzheimer's disease, etc.), paranoid personality disorder, depressive personality disorder, schizoaffective disorder, traumatic brain injury (TBI), or eating disorders (such as bulimia nervosa, etc.)), drug therapy-induced social withdrawal, social withdrawal induced by acute and / or chronic drug abuse (e.g., dependence syndrome), or social withdrawal induced by an unfortunate social environment (e.g., childhood neglect or abuse, psychological trauma experiences such as war or adult sexual assault, etc.).

[0021] According to the present invention, "aggression" includes, in particular, any abnormal, pathological or inappropriate aggressive or violent behavior of any kind, such as physical or verbal hostility or incitement, including interpersonal aggression (i.e., towards other individuals) and / or intrapersonal aggression (i.e., self-aggression). Non-limiting examples of aggression treated according to the present invention include genetic or epigenetic mutations (e.g., trisomy 21, GABRA2, MAOA, SLC6A4, CHMP2B, VPS13A, PLA2G6, TBP, HTT, ANK3, EHMT1, MYCN, CASK, HDAC4, MLL / KMT2A, TCF4, CNTNAP2, NRXN1, ATN1, CTNNB1, MED12, KDM5C / JARID1C, CUL4B, SYN1, UB). Aggression, disease (e.g., Alzheimer's disease (AD), Huntington's disease (HD), Lewy body dementia (DLB), Parkinson's disease (PD), schizophrenia (SZ), bipolar disorder (BPD), depression () that is triggered by or associated with E2A, SMARCA2, HCFC1, HERC2, NDP, PAK3, ATP13A2, SPAST, NSD1, STAMBP, HPRT1, DJ1, TARDBP, MAPT, or AVPR1A) Aggression can be associated with conditions such as dementia (DS), traumatic brain injury (TBI), REM sleep behavior disorder (RBD), dementia, dentatorubral-pallidoluysian atrophy (DRPLA), Tourette syndrome (GTS), conduct disorder (e.g., antisocial conduct disorder, social conduct disorder, or oppositional conduct disorder), drug addiction, stress-related disorders (e.g., post-traumatic stress disorder), autism spectrum disorder (ASD), borderline personality disorder, or adult attention deficit hyperactivity disorder), drug-induced aggression, toxin-induced aggression (e.g., trimethyltin), acute and / or chronic drug abuse (e.g., withdrawal), food deprivation (e.g., zinc), sleep deprivation, or unfortunate social circumstances (e.g., childhood neglect or neglect, war, or traumatic experiences in adulthood such as sexual assault).

[0022] The above-mentioned diseases are examples of diseases from the perspective of disease-related social withdrawal, or from the perspective of disease-related aggression, and similarly, examples of diseases from the perspective of disease-related behavioral changes, as well as examples of diseases from the perspective of disease-related social behavioral changes.

[0023] In some embodiments, the behavioral change is social withdrawal.

[0024] In some embodiments, the behavioral change is a disorder-related social withdrawal. In some embodiments, the disorder is a CNS disorder. In some embodiments, a CNS disorder is an autism spectrum disorder (ASD, e.g., autism or Asperger's syndrome), avoidant personality disorder (AvPD), schizophrenia (e.g., schizotypal and / or paranoid disorder), mood disorder (e.g., major depressive disorder, dysthymic disorder, or bipolar disorder), substance addiction, post-traumatic stress disorder (PTSD), dementia (e.g., Alzheimer's disease), paranoid personality disorder, depressive personality disorder, schizoaffective disorder, TBI, or eating disorder (e.g., bulimia nervosa).

[0025] In some embodiments, the change in behavior is aggression.

[0026] In some embodiments, the behavioral change is disorder-related aggression. In some embodiments, the disorder is a CNS disorder. In some embodiments, the CNS disorder is AD, HD, DLB, PD, SZ, BPD, DS, TBI, RBD, dementia, DRPLA, GTS, conduct disorder (e.g., antisocial conduct disorder, social conduct disorder, or oppositional conduct disorder), drug addiction, stress-related disorder (e.g., post-traumatic stress disorder), ASD, borderline personality disorder, or adult attention deficit hyperactivity disorder. In a preferred embodiment, the disorder is AD. However, the disorder may be different from AD. For example, the disorders may be HD, DLB, PD, SZ, BPD, DS, TBI, RBD, dementia, DRPLA, GTS, conduct disorder (e.g., antisocial conduct disorder, social conduct disorder, or oppositional conduct disorder), substance addiction, stress-related disorders (e.g., post-traumatic stress disorder), ASD, borderline personality disorder, or adult attention deficit hyperactivity disorder.

[0027] In some embodiments, the change in behavior is emotional blunting.

[0028] In principle, any DM1A inhibitor, such as the KDM1A inhibitors described in this specification in more detail below, may be used in the therapeutic methods and uses described herein. However, it is preferable that the KDM1A inhibitor used in the methods and uses of the present invention is compound:5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, and it is particularly preferable that the KDM1A inhibitor is compound:5 ((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine (unsalted form). This compound is referred to as Compound 1 or by its abbreviation (Comp.1) in this specification (including the examples and drawings). The names "5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine", "Compound 1", or "Comp.1" are used interchangeably herein.

[0029] Accordingly, the present invention provides 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of behavioral changes.

[0030] The present invention further provides a method for treating behavioral changes in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof.

[0031] The present invention further provides the use of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of therapeutic agents for behavioral changes.

[0032] The present invention further provides the use of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of behavioral changes.

[0033] In some embodiments, the change in behavior is a change in social behavior.

[0034] In some embodiments, the behavioral change is social withdrawal.

[0035] In some embodiments, the change in behavior is aggression.

[0036] In some embodiments, the change in behavior is emotional blunting.

[0037] For use in the therapeutic methods and applications described herein, it is preferable that a KDM1A inhibitor, such as 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine (or a pharmaceutically acceptable salt or solvate thereof) be administered orally. Exemplary formulations that may be administered orally are described in more detail below.

[0038] As described above, in preferred embodiments, the present invention provides the compound:5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate of the compound, for use in the treatment of behavioral changes. Accordingly, the present invention relates to the compound:5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine as a free base (non-salt form) for use in the treatment of behavioral changes, and further, the present invention also relates to a pharmaceutically acceptable salt or solvate of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine for use in the treatment of behavioral changes.

[0039] As illustrated in the examples, surprisingly, from the perspective of the present invention, it has been found that KDM1A inhibitors, such as Compound 1, provide potent therapeutic effects in animal models of (human) behavioral changes. In particular, beneficial effects of KDM1A inhibitors have been observed on various types of behavioral changes, especially aggression, social withdrawal, and other social behavioral changes.

[0040] As shown in more detail in Example 3 and Figures 1 and 2, KDM1A inhibitors such as compound 1 have been found to be effective in treating aggression. To test the effect of a target compound such as compound 1 on aggression, an animal model (e.g., a rodent model) is selected in which vehicle-treated animals are known to exhibit or exhibit modified (increased) aggression compared to control animals, and is evaluated by measuring aggression behavior using established methods. Then, it is evaluated whether treatment of the aggressive animals with the compound reduces their aggression compared to vehicle-treated animals, or restores their aggression to the (normal) level of the control animals. The aggressive behavior of the animals can be evaluated using standard methods for evaluating aggression behavior parameters, such as the resident intruder (RI) test, which can be performed as described in detail in Example 3.1. As an example of an animal model suitable for testing aggression, male SAMP8 mice can be used with male SAMR1 mice as controls. As shown in Example 3 and Figures 1 and 2, vehicle-treated male SAMP8 mice exhibit significantly increased aggressive behavior compared to the control strain SAMR1, as indicated by the significantly increased number of total attacks and especially clinch attacks. As shown in Figures 1 and 2 by the number of attacks (total attacks and clinch attacks), treatment of female SAMP8 mice with a KDM1A inhibitor (particularly compound 1) dramatically reduces their aggression, restoring it to SAMR1 levels in compound 1-treated SAMP8 mice. Therefore, treatment with the KDM1A inhibitor compound 1 can correct the altered aggressive behavior in SAMP8 mice, which supports the use of KDM1A inhibitors to treat changes in aggression and related behaviors.

[0041] In addition to exhibiting therapeutic effects against aggression, KDM1A inhibitors such as Compound 1 are also useful in treating other behavioral changes such as social abstinence, as shown in Example 4 and Figures 3 and 4. While mice are highly territorial, rats are known to be a more gregarious species and are therefore particularly well-suited for evaluating social interaction behavior, especially social abstinence. A suitable model for evaluating social abstinence is the rat isolation housing model. In this model, rats are isolated after weaning and deprived of the normal environment that pre-calibrates social behavior. Isolation at this stage of rat development results in behavioral changes, particularly a lack of interest in social interaction (social avoidance) in adult animals, which can be used as a model for social abstinence in humans. The social behavior of animals in this model can then be evaluated using standard methods of such evaluation known in the art, such as the resident intruder test. As shown in Example 4 and Figures 3 and 4, the social avoidance parameter is significantly increased in vehicle-treated isolated rats compared to vehicle-treated non-isolated rats, as reflected in the time without social interaction (Figure 3) and the number of avoidances (Figure 4). Treatment with KDM1A inhibitor compound 1 significantly reduced social avoidance in isolated rats, as shown in Figure 3 by dose-dependent reduction and in Figure 4 by reduction in the number of avoidances. Avoidance was significantly increased in vehicle-treated isolated rats and returned to normal with treatment with KDM1A inhibitor compound 1. Treatment with KDM1A inhibitors can improve or correct social avoidance and supports the use of KDM1A inhibitors to treat social withdrawal and associated social behavioral changes.

[0042] The usefulness of KDM1A inhibitors for treating changes in social behavior is further illustrated in Example 5 and Figures 5 and 6 using the Three Chamber Test (TCT), another widely used social behavior test. The TCT is a commonly used method for measuring the social behavior of mice and is useful for evaluating the effects of compounds that treat changes in social interaction using animals exhibiting congenital or acquired deficiencies in social behavior. In the TCT test, as described in detail in Example 5, mice are released into the central chamber after being adapted to a three-chamber arena, allowing them to explore the other compartments. In an adjacent “mouse” compartment, a compliant stimulated mouse is placed in a mesh wire container, while in the other adjacent compartment, a similar container (object compartment) without a stimulated mouse is placed. The tendency to approach or avoid the compartment containing the stimulated mouse provides a measure of sociability. As shown in Example 5 and Figures 5 and 6, treatment with a KDM1A inhibitor such as compound 1 can restore the social interaction behavior / sociability of subjects, indicating changes in social interaction. As described in Example 5, in contrast to the control strain SAMR1, female SAMP8 mice did not show preference for the “mouse” chamber compared to the “object” chamber, had a short time to explore new mice, and therefore exhibited defects in social behavior. Treatment of female SAMP8 mice with KDM1A inhibitor compound 1 completely restored the social interaction behavior / sociability of SAMP8 mice to SAMR1 levels, as demonstrated by the restoration of both preference for the sociability chamber (mouse chamber) (see Figure 5) and the time spent exploring new mice (see Figure 6).

[0043] As shown in Examples 3 and 4, which use standard assays to measure sedative or anxiolytic effects such as the open-field and elevated cruciform maze tests, it is important that the therapeutic effect of KDM1A inhibitors such as compound 1 in the treatment of behavioral changes can be achieved without causing sedation. Sedation is a serious side effect of many drugs currently used to treat behavioral changes. For example, antipsychotic drugs used to treat aggression generally cause strong sedation. Therefore, KDM1A inhibitors, particularly compound 1, are highly advantageous over current treatments in that they can be used to treat behavioral changes without causing sedative side effects.

[0044] KDM1A inhibitors As used herein, a KDM1A inhibitor is a compound that inhibits KDM1A, particularly human KDM1A.

[0045] Any type of KDM1A inhibitor can be used in the method and use according to the present invention.

[0046] The KDM1A inhibitor used in the method and use according to the present invention is preferably a small molecule. Both irreversible and reversible KDM1A inhibitors have been reported and can be used according to the present invention. Irreversible KDM1A inhibitors exert inhibitory activity by covalently binding to the FAD cofactor within the KDM1A active site and are generally based on a 2-cyclyl-cyclopropylamino moiety, such as a 2-(hetero)arylcyclopropylamino moiety. Reversible inhibitors of KDM1A have also been disclosed.

[0047] Non-limiting examples of KDM1A inhibitors that can be used in the present invention include, for example, WO2010 / 043721, WO2010 / 084160, WO2011 / 035941, WO2011 / 042217, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2013 / 057320, WO2013 / 057322, WO2010 / 143582, US2010-0324147, WO2011 / 022489, WO2011 / 131576, WO2012 / 034116, W O2012 / 135113, WO2013 / 022047, WO2013 / 025805, WO2014 / 058071, WO2014 / 084298, WO2014 / 086790, WO2014 / 164867, WO2014 / 205213, WO2015 / 021128 , WO2015 / 031564, US2015-0065434, WO2007 / 021839, WO2008 / 127734, WO2015 / 089192, CN104119280, CN103961340, CN103893163, CN103319466, CN10 3054869, WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 123465, WO2015 / 156417, WO2015 / 181380, WO2016 / 123387, WO2016 / 130952, WO20 16 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2012 / 071469, WO2013 / 033688, WO2014 / 085613, WO2015 / 120281, WO2015 / 134973, WO20 15 / 168466, WO2015 / 200843, WO2016 / 003917, WO2016 / 004105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 007736, WO2016 / 034946, WO 2016 / 037005, WO2016 / 161282, WO2017 / 004519, WO2017 / 027678, WO2017 / 079476, WO2017 / 079670, WO2017 / 090756, WO2017 / 109061, WO2017 / 116558,Compounds disclosed in WO2017 / 114497, CN106432248, CN106478639, CN106831489, CN106928235, CN105985265, WO2017 / 149463, WO2017 / 157322, WO2017 / 195216, WO2017 / 198780, WO2017 / 215464, WO2018 / 081342, WO2018 / 081343, US2017-0283397, and, [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] (GSK-LSD1); [ka] (T-3775440); [ka] ; [ka] (Seclidemstat); [ka] ; [ka] ; [ka] ;or [ka] ; and any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof.

[0048] Any one of the above compounds comprising a 1,2-substituted cyclopropyl ring can be used in the form of the corresponding trans isomer (where the two substituents on the cyclopropyl ring are in a trans configuration) or in the form of any one of the respective specific trans isomers (where the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the depicted structure; or where the two substituents on the cyclopropyl ring have the opposite absolute configuration as shown in the depicted structure).

[0049] The results of the KDM1A cross-sectional analysis were published by KDM Chem et al. Lett 2015、25(9):1925-8. doi:10.1016 / j.bmcl.2015.03.030. Epub 2015 Mar 20、PMID:25827526;S Valente et al、Eur J Med Chem. 2015、94:163-74. doi:10.1016 / j.ejmech.2015.02.060. Epub 2015 Mar 3、PMID:25768700;MN Ahmed Khan et al Med. Chem. Commun.、2015,6、407-412、DOI:10.1039 / C4MD00330F epub 29 Sep 2014;M Pieroni et al、Eur J Med Chem. 2015;92:377-386. doi:10.1016 / j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID:25585008;V Rodriguez et al、Med. Chem. Commun.、2015、6、665-670 DOI:10.1039 / C4MD00507D、Epub 23 Dec 2014;P Vianello et al、Eur J Med Chem. 2014、86:352-63. doi:10.1016 / j.ejmech.2014.08.068. Epub 2014 Aug 27;DP Mold et al、Med. Res. Rev.、2015、35:586-618. doi:10.1002 / med.21334、epub 24-Nov-2014;LY Ma et al、2015、58(4):1705-16. doi:10.1021 / acs.jmedchem.5b00037. Epub 2015 Feb 6;SL Nowotarski et al、2015、23(7):1601-12. doi:10.1016 / j.bmc.2015.01.049. Epub 2015 Feb 7. PMID:25725609;CJ Kutz et al Medchemcomm.2014, 5(12):1863-1870 PMID:25580204;C Zhou et al, Chemical Biology & Drug Design, 2015, 85(6):659-671. doi:10.1111 / cbdd.12461;epub Dec 22, 2014;P Prusevich et al;ACS Chem Biol. 2014. 9(6):1284-93. doi:10.1021 / cb500018s. Epub 2014 Apr 7;B Dulla et al;Org Biomol Chem 2013,11;3103–3107;doi:10.1039 / c3ob40217g;JR Hitchin et al;MedChemCommun,2013;4,1513–1522 DOI:10.1039 / c3md00226h;and Y Zhou et al, Biorg Med Chem Lett, 2015, online publication 20-Jun-2015; Thanks for watching.

[0050] Irreversible KDM1A inhibitors that may be used in the method / use of the present invention include, but are not limited to, WO2010 / 043721, WO2010 / 084160, WO2011 / 035941, WO2011 / 042217, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2013 / 057320, WO2013 / 057322, WO2010 / 143582, US2010-0324147, WO2011 / 131576, WO2012 / 135113, and WO2013 / 02204. 7, WO2014 / 058071, WO2014 / 084298, WO2014 / 086790, WO2014 / 164867, WO2015 / 021128; WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 1234 65, WO2015 / 156417, WO2015 / 181380, WO2016 / 123387, WO2016 / 130952, WO2016 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2014 / 164867 WO2017 / 027678, WO2017 / 079476, WO2017 / 109061, WO2017 / 116558, WO2017 / 114497, CN106831489;K Taeko et al, Bioorg Med Chem Lett. 2015, 25(9):1925-8. doi:10.1016 / j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID:25827526;S Valente et al, Eur J Med Chem. 2015, 94:163-74. doi:10.1016 / j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID:25768700;MN Ahmed Khan et al Med. Chem. Commun., 2015,6, 407-412, DOI:10.1039 / C4MD00330F epub 29 Sep 2014;M Pieroni et al, Eur J Med Chem. 2015;92:377-386. doi:10.1016 / j.ejmech.2014.12.032.Epub 2015 Jan 7. PMID:25585008;V Rodriguez et al, Med. Chem. Commun., 2015, 6, 665-670 DOI:10.1039 / C4MD00507D, Epub 23 Dec 2014;or P Vianello et al, Eur J Med Chem. 2014, 86:352-63. doi:10.1016 / j.ejmech.2014.08.068. Any one of the compounds disclosed in Epub 2014 Aug 27, as well as... [ka] ; [ka] ; [ka] ; [ka] ; [ka] (GSK-LSD1); [ka] (T-3775440); [ka] ; [ka] ; [ka] ; [ka] ;or [ka] ; This includes any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof.

[0051] Any one of the above compounds comprising a 1,2-substituted cyclopropyl ring can be used in the form of the corresponding trans isomer (where the two substituents on the cyclopropyl ring are in a trans configuration) or in the form of any one of the respective specific trans isomers (where the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the depicted structure; or where the two substituents on the cyclopropyl ring have the opposite absolute configuration as shown in the depicted structure).

[0052] Reversible KDM1A inhibitors that can be used in the method / use of the present invention include, but are not limited to, WO2007 / 021839, WO2008 / 127734, WO2011 / 022489, WO2012 / 034116, WO2012 / 071469, WO2013 / 025805, US2015 / 0065434, WO2013 / 033688, CN103054869, CN103319466, WO2014 / 085613, CN103893163A, CN103961340, WO2014 / 205213, WO2015 / 031564, WO2015 / 089192, WO2015 / 120 281, WO2015 / 134973, WO2015 / 168466, WO2015 / 200843, WO2016 / 003917, WO2016 / 0 04105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 007736, WO2016 Any one of the compounds disclosed in / 034946, WO2016 / 037005, WO2016 / 161282, WO2017 / 004519, WO2017 / 079670, WO2017 / 090756, CN106432248, CN106478639, CN106928235, and, [ka] ; [ka] (Secridemstat); This includes any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof.

[0053] In some embodiments, in the methods and uses according to the present invention, the KDM1A inhibitor is an irreversible KDM1A inhibitor, preferably a 2-(hetero)arylcyclopropylamino KDM1A inhibitor. As used herein, “2-(hetero)arylcyclopropylamino KDM1A inhibitor” or “2-(hetero)arylcyclopropylamino compound” means a KDM1A inhibitor whose chemical structure comprises a cyclopropyl ring substituted at position 1 with an optionally substituted amino group, and a cyclopropyl ring substituted at position 2 with an aryl or heteroaryl group (where the aryl or heteroaryl group is optionally substituted).

[0054] The ability of a compound to inhibit KDM1A can be tested in vitro using any method known in the art to determine KDM1A inhibition, for example, the method disclosed in Example 2.

[0055] A particularly preferred KDM1A inhibitor for use in the method and use according to the present invention is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof.

[0056] Other KDM1A inhibitors that can be used in the method and use of the present invention include the following: (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(thiazole-5-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; 4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)amino)cyclohexanol; 4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)amino)cyclohexanecarboxamide; N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)amino)cyclohexyl)acetamide; N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)amino)cyclohexyl)methanesulfonamide; (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidine-3-amine; N1-((trans)-2-(4'-chloro-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(3'-chloro-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; 4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-ol; N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)methanesulfonamide; N1-((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; N1-methyl-N4-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-N4-methylcyclohexane-1,4-diamine; N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine; N1-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclobutan-1,3-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclobutane-1,3-diamine; N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-idden-1,3-diamine; N1-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1H-idene-1,3-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine; N1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine; N1-((1S,2S)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine; N1-((1R,2R)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine; 1-Methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexaneamine; N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine; N1-((cis)-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl) tert-butyl carbamate; 1-Ethyl-3-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)urea; 4-Morphorino-N-((trans)-2-phenylcyclopropyl)cyclohexaneamine; N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-(o-toluyl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine; 4-(2-((4-aminocyclohexyl)amino)cyclopropyl)phenol; N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-(-2-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-(2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (R)-1-(4-(((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)pyrrolidine-3-amine; (Cis)-N1-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; (Trans)-N1-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; (Cis)-N1-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; (Trans)-N1-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(pyridine-3-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(1H-indazole-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(1H-pyrazole-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol; 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazole-2-yl)phenol; 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridine-2-yl)-5-methoxybenzonitrile; 5-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridine-2-yl)-2-methylphenol; N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-6-methoxy-[1,1'-biphenyl]-3-yl)methanesulfonamide; N-(3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazole-2-yl)phenyl)-2-cyanobenzenesulfonamide; N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)-2-cyanobenzenesulfonamide; 6-amino-N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)pyridine-3-sulfonamide; N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; N1-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-((3-(piperazine-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(pyridine-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(6-((3-methylbenzyl)amino)pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; 3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridine-2-yl)amino)benzonitrile; N1-((trans)-2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(o-toluyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; N1-((trans)-2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1S,2R)-2-(pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1R,2S)-2-(pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-(pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-(pyridine-3-yl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine; (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine; (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine; (trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine; (cis)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1S,2R)-2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1R,2S)-2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-(naphthalene-2-yl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1S,2R)-2-(4-(1H-pyrazole-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1R,2S)-2-(4-(1H-pyrazole-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-(4-(1H-pyrazole-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-(4-(1H-pyrazole-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N-(4'-((1R,2S)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; N-(4'-((1S,2R)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; N-(4'-((1S,2R)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; N-(4'-((1R,2S)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazine-1-sulfonamide; (cis)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (cis)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; (trans)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine; N-((trans)-2-phenylcyclopropyl)piperidine-4-amine; N-((1S,2R)-2-phenylcyclopropyl)piperidine-4-amine; N-((1R,2S)-2-phenylcyclopropyl)piperidine-4-amine; N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridine-3-yl)cyclopropyl)tetrahydro-2H-pyran-4-amine; N-((trans)-2-(pyridine-3-yl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(thiazole-5-yl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidine-4-amine; N-((trans)-2-phenylcyclopropyl)piperidine-3-amine; N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidine-3-amine; N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidine-3-amine; N-((trans)-2-phenylcyclopropyl)pyrrolidine-3-amine; N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)pyrrolidine-3-amine; N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)pyrrolidine-3-amine; N-((trans)-2-phenylcyclopropyl)azetidine-3-amine; N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)azetidine-3-amine; N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)azetidine-3-amine; N-((trans)-2-phenylcyclopropyl)azepan-3-amine; N-((trans)-2-phenylcyclopropyl)-8-azabicyclo[3.2.1]octane-3-amine; N-((trans)-2-phenylcyclopropyl)-3-azabicyclo[3.2.1]octane-8-amine; N-((trans)-2-phenylcyclopropyl)decahydroquinoline-4-amine; N-((trans)-2-phenylcyclopropyl)-1,2,3,4-tetrahydroquinoline-4-amine; N-((trans)-2-phenylcyclopropyl)-3-azaspiro[5.5]undecane-9-amine; N-((trans)-2-phenylcyclopropyl)-2-azaspiro[4.5]decane-8-amine; N-((trans)-2-phenylcyclopropyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-amine; N-((1S,2R)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidine-4-amine; N-((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidine-4-amine; N-((1S,2R)-2-(pyridine-3-yl)cyclopropyl)piperidine-4-amine; N-((1R,2S)-2-(pyridine-3-yl)cyclopropyl)piperidine-4-amine; N-((1S,2S)-2-(thiazole-5-yl)cyclopropyl)piperidine-4-amine; N-((1R,2R)-2-(thiazole-5-yl)cyclopropyl)piperidine-4-amine; N-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidine-4-amine; N-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidine-4-amine; N-((trans)-2-phenylcyclopropyl)-7-azaspiro[3.5]nonane-2-amine; N-(2-(o-toluyl)cyclopropyl)piperidine-4-amine; N-(2-(2-fluorophenyl)cyclopropyl)piperidine-4-amine; N-(2-(3,4-difluorophenyl)cyclopropyl)piperidine-4-amine; N-(2-(4-methoxyphenyl)cyclopropyl)piperidine-4-amine; N-(2-(naphthalene-2-yl)cyclopropyl)piperidine-4-amine; N-(2-methyl-2-phenylcyclopropyl)piperidine-4-amine; N-(6-methoxy-4'-((trans)-2-(piperidine-4-ylamino)cyclopropyl)-[1,1'-biphenyl]-3-yl)methanesulfonamide; N-(4'-((trans)-2-(piperidine-4-ylamino)cyclopropyl)-[1,1'-biphenyl]-3-yl)propane-2-sulfonamide; 1-(methylsulfonyl)-N-((trans)-2-phenylcyclopropyl)piperidine-4-amine; 1-(4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine-1-yl)ethanone; 4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine e-1-carboxamide; N-((trans)-2-(4-bromophenyl)cyclopropyl)tetrahydro-2H-pyran-4-amine; 2,2,6,6-Tetramethyl-N-((trans)-2-phenylcyclopropyl)piperidine-4-amine; 1-Methyl-N-((trans)-2-phenylcyclopropyl)piperidine-4-amine; 1-Isopropyl-N-((trans)-2-phenylcyclopropyl)piperidine-4-amine; N-((trans)-2-phenylcyclopropyl)-1-(2,2,2-trifluoroethyl)piperidine-4-amine; N-((trans)-2-phenylcyclopropyl)-1-(pyridine-4-yl)piperidine-4-amine; 4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide; N-((trans)-2-fluoro-2-phenylcyclopropyl)piperidine-4-amine; N-((1S,2S)-2-fluoro-2-phenylcyclopropyl)piperidine-4-amine; N-((1R,2R)-2-fluoro-2-phenylcyclopropyl)piperidine-4-amine; N-((trans)-2-(naphthalene-2-yl)cyclopropyl)piperidine-4-amine; N-((trans)-2-methyl-2-phenylcyclopropyl)piperidine-4-amine; N-((trans)-2-(o-toluyl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(2-fluorophenyl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(3,4-difluorophenyl)cyclopropyl)piperidine-4-amine; N-((trans)-2-(4-methoxyphenyl)cyclopropyl)piperidine-4-amine; (Trans)-2-phenyl-N-(piperidine-4-ylmethyl)cyclopropanamine; (Trans)-2-phenyl-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (Trans)-2-phenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine; (Trans)-2-(4'-chloro-[1,1'-biphenyl]-4-yl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine; (Trans)-N-(piperidine-4-ylmethyl)-2-(pyridine-3-yl)cyclopropanamine; (Trans)-N-(piperidine-4-ylmethyl)-2-(thiazole-5-yl)cyclopropanamine; (Trans)-N-(piperidine-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (Trans)-2-(4-(benzyloxy)phenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (Trans)-N-(2-(piperidine-4-yl)ethyl)-2-(pyridine-3-yl)cyclopropanamine; (Trans)-N-(2-(piperidine-4-yl)ethyl)-2-(thiazole-5-yl)cyclopropanamine; (Trans)-N-(2-(piperidine-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (Trans)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (1S,2R)-2-phenyl-N-(piperidine-4-ylmethyl)cyclopropanamine; (1R,2S)-2-phenyl-N-(piperidine-4-ylmethyl)cyclopropanamine; (1S,2R)-2-phenyl-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (1R,2S)-2-phenyl-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (1S,2R)-N-(piperidine-4-ylmethyl)-2-(pyridine-3-yl)cyclopropanamine; (1R,2S)-N-(piperidine-4-ylmethyl)-2-(pyridine-3-yl)cyclopropanamine; (1S,2S)-N-(piperidine-4-ylmethyl)-2-(thiazole-5-yl)cyclopropanamine; (1R,2R)-N-(piperidine-4-ylmethyl)-2-(thiazole-5-yl)cyclopropanamine; (1S,2R)-N-(piperidine-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (1R,2S)-N-(piperidine-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (1S,2R)-2-(4-(benzyloxy)phenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (1R,2S)-2-(4-(benzyloxy)phenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (1S,2R)-N-(2-(piperidine-4-yl)ethyl)-2-(pyridine-3-yl)cyclopropanamine; (1R,2S)-N-(2-(piperidine-4-yl)ethyl)-2-(pyridine-3-yl)cyclopropanamine; (1S,2S)-N-(2-(piperidine-4-yl)ethyl)-2-(thiazole-5-yl)cyclopropanamine; (1R,2R)-N-(2-(piperidine-4-yl)ethyl)-2-(thiazole-5-yl)cyclopropanamine; (1S,2R)-N-(2-(piperidine-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (1R,2S)-N-(2-(piperidine-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine; (1S,2R)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (1R,2S)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidine-4-yl)ethyl)cyclopropanamine; (Trans)-2-phenyl-N-(pyrrolidine-3-ylmethyl)cyclopropanamine; (Trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (Trans)-N-(azetidine-3-ylmethyl)-2-phenylcyclopropanamine; (Trans)-2-(4-cyclopropylphenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (Trans)-N-(piperidine-4-ylmethyl)-2-(4-(pyridine-3-yl)phenyl)cyclopropanamine; (Trans)-2-(4-(1H-pyrazole-5-yl)phenyl)-N-(piperidine-4-ylmethyl)cyclopropanamine; (Trans)-2-(naphthalene-2-yl)-N-(piperidine-4-ylmethyl)cyclopropanamine; 2-methyl-2-phenyl-N-(piperidine-4-ylmethyl)cyclopropanamine; (trans)-2-methyl-2-phenyl-N-(piperidine-4-ylmethyl)cyclopropanamine; (trans)-2-(4-(benzyloxy)phenyl)-N-((1-methylpiperidine-4-yl)methyl)cyclopropanamine; 4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidine-1-yl)methyl)benzoic acid; 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidine-1-yl)methyl)cyclobutanecarboxylic acid; N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazole-1-yl)benzamide; 4-[2-(4-amino-piperidine-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-yl]-2-fluorobenzonitrile; [ka] (T-3775440); [ka] (Secridemstat); [ka] ; [ka] ; [ka] ;or [ka] ; and any optically active stereoisomer thereof or pharmaceutically acceptable salts or solvates thereof.

[0057] Pharmaceutical preparations A KDM1A inhibitor, for example, compound 1, may be administered for direct therapeutic use, but is more commonly administered in the form of a pharmaceutical composition containing the compound as an active pharmaceutical ingredient along with one or more pharmaceutically acceptable excipients or carriers. References to KDM1A inhibitors herein include references to the compound itself, i.e., the compound in its non-salt form (e.g., as a free base) or in the form of its pharmaceutically acceptable salt or solvate, as well as references to a pharmaceutical composition containing the compound and one or more pharmaceutically acceptable excipients or carriers.

[0058] KDM1A inhibitors can be administered by any means necessary to achieve the intended purpose. Examples include oral, parenteral (intravenous, subcutaneous, or intracerebral, etc.), or local routes of administration.

[0059] For oral delivery, the compound can be formulated into a formulation containing a pharmaceutically acceptable carrier such as a binder (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginates, Primogel, and corn starch), and sweeteners or flavorings (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be delivered orally, for example, in the form of encapsulated gelatin capsules or compressed tablets. Capsules and tablets can be prepared by any prior art. Capsules and tablets can also be coated with various coatings known in the art to alter the flavor, taste, color, and shape of the capsules and tablets. Liquid carriers, such as fatty oils, may also be contained in the capsules.

[0060] Appropriate oral formulations may also be in the form of suspensions, syrups, chewing gums, wafers, elixirs, etc. If necessary, conventional agents may also be included to modify the flavor, taste, color, and shape in special forms. Furthermore, for convenient administration via enteral feeding tubes in patients unable to swallow, the active compound can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil, and safflower oil.

[0061] The compounds can also be administered parenterally in the form of a solution or suspension, or in a lyophilized form that can be converted to a solution or suspension before use. Such formulations may use diluents or pharmaceutically acceptable carriers, such as sterile water and saline buffer. Other conventional solvents, pH buffers, stabilizers, antimicrobial agents, surfactants, and antioxidants may all be included. For example, useful components include sodium chloride, acetate, citrate or phosphate buffers, glycerin, dextrose, fixative oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, and ascorbic acid. Parenteral formulations can be stored in conventional containers such as vials and ampoules.

[0062] For topical administration, the compound may be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, infusions, and aerosols. Therefore, one or more thickeners, humectants, and stabilizers may be included in the formulation. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, and squalene. A special form of topical administration is delivery by transdermal patch. Methods for manufacturing transdermal patches are disclosed, for example, in Brown, et al. (1988) Ann. Rev. Med. 39:221-229, which are incorporated herein by reference.

[0063] Subcutaneous implantation for sustained release of compounds can also be a suitable route of administration. This requires a surgical procedure to implant the active compound in any suitable formulation into a subcutaneous space, for example, beneath the anterior abdominal wall. See, for example, Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for sustained release of active compounds. Hydrogels are commonly known in the art. They are usually made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel-like material. It is preferable that the hydrogel is biodegradable or bioabsorbable. For the purposes of the present invention, hydrogels made of polyethylene glycol, collagen, or poly(glycolic acid-co-L-lactic acid) may be useful. See, for example, Phillips et al. (1984) J. Pharmaceut. Sci., 73:1718-1720.

[0064] The compound can also be combined with water-soluble, non-immunogenic, non-peptide high molecular weight polymers to form polymer complexes. For example, the compound can be covalently bonded to polyethylene glycol to form a complex. Typically, such complexes exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Therefore, when administered to a patient, the half-life of the compound in the complex is longer, resulting in a better effect. See Burnham (1994) Am. J. Hosp. Pharm. 15:210-218 for general information. PEGylated proteins are currently used in protein replacement therapies and other therapeutic applications. For example, PEGylated interferon (PEG-INTRON A®) is clinically used in the treatment of hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is used in the treatment of severe combined immunodeficiency (SCIDS). PEGylated L-asparaginase (ONCAPSPAR®) is used in the treatment of acute lymphoblastic leukemia (ALL). The covalent bond between the polymer and the active compound and / or the polymer itself is preferably hydrolytically degradable under physiological conditions. Such complexes, known as “prodrugs,” can readily release the active compound in the body. Controlled release of the active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels, which are commonly known in the art. Other pharmaceutically acceptable prodrugs of compounds include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid complexes, phosphate esters, metal salts, and sulfonic acid esters.

[0065] Liposomes can also be used as carriers for active compounds. Liposomes are micelles made of various lipids, such as cholesterol, phospholipids, fatty acids, and their derivatives. Various modified lipids can also be used. Liposomes can reduce the toxicity and increase the stability of active compounds. Methods for preparing liposome suspensions containing active ingredients are generally known in the art. See U.S. Patent No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976).

[0066] Pharmaceutical compositions, such as oral and parenteral compositions, can be formulated in unit dosage forms to facilitate administration and ensure uniformity of dose. As used herein, “unit dosage form” means a physically distinct unit appropriate as a unit dose to be administered to a subject, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with one or more appropriate pharmaceutical carriers.

[0067] For therapeutic use, pharmaceutical compositions should be administered in a manner appropriate to the disease being treated, as determined by those skilled in the medical field. Appropriate doses, durations, and frequencies of administration are determined by factors such as the patient's condition, the type and severity of the disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and administration plan provides a sufficient amount of the pharmaceutical composition to deliver therapeutic benefits, such as improved clinical outcomes including more frequent complete or partial remission, longer disease-free and / or overall survival, reduced symptom severity, or other improvements that can identify the objectives pointed out by the clinician. Effective doses can generally be evaluated or estimated using experimental models, such as dose-response curves obtained from in vitro studies, or test systems of animal models, as shown in the examples.

[0068] The pharmaceutical composition of the present invention may be contained in a container, pack, or dispenser along with instructions for administration.

[0069] KDM1A inhibitors, such as Compound 1, are orally active and have been found to be effective in treating behavioral changes when administered orally, as shown in Examples 3 and 4. Therefore, it is preferable that KDM1A inhibitors (e.g., Compound 1) be administered orally for the treatment of behavioral changes.

[0070] The present invention also encompasses the use of KDM1A inhibitors in which one or more atoms are substituted with specific isotopes of the corresponding atoms. For example, the present invention may involve replacing one or more hydrogen atoms (or, for example, all hydrogen atoms) with deuterium atoms (i.e., 2 This includes the use of KDM1A inhibitors substituted with H (also called "D"). Therefore, the present invention also includes deuterium-rich KDM1A inhibitors. Natural hydrogen contains about 99.98 mol% hydrogen ( 1 H) and approximately 0.0156 mol% deuterium ( 2 It is an isotopic mixture containing H or D. The deuterium content at one or more hydrogen positions in a KDM1A inhibitor can be increased using deuterating techniques known in the art. For example, a KDM1A inhibitor, or a reactant or precursor used in the synthesis of a KDM1A inhibitor, can undergo an H / D exchange reaction using heavy water (D2O), for example. More suitable deuterating techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The deuterium content can be determined, for example, by mass spectrometry or NMR spectroscopy. Unless otherwise specified, KDM1A inhibitors used in accordance with the present invention are preferably deuterium-free. Therefore, KDM1A inhibitors should contain naturally occurring hydrogen atoms or 1It is preferable that a hydrogen atom of H is present. Generally, it is preferable that the atoms in the KDM1A inhibitor used according to the present invention are not substituted with a specific isotope.

[0071] KDM1A inhibitors or pharmaceutical compositions containing KDM1A inhibitors used in accordance with the present invention can be administered as monotherapy (for example, without the simultaneous administration of any further therapeutic agents or any further therapeutic agents for the same behavioral change to be treated with the KDM1A inhibitor). Therefore, KDM1A inhibitors or pharmaceutical compositions containing KDM1A inhibitors can be used in monotherapy for behavioral changes (for example, without the administration of any other therapeutic agents for the same behavioral change until treatment with the KDM1A inhibitor is completed). However, KDM1A inhibitors or pharmaceutical compositions containing KDM1A inhibitors can also be administered in combination with one or more further therapeutic agents. When a KDM1A inhibitor is used in combination with a second therapeutic agent that is active for the same behavioral change, the dose of each compound may differ from that when the corresponding compound is used alone, and in particular, each compound may be used in a low dose. The combination of a KDM1A inhibitor and one or more further therapeutic agents may include simultaneous / accompanying administration of the KDM1A inhibitor and the further therapeutic agents (either as a single pharmaceutical formulation or separate pharmaceutical formulations), or sequential / individual administration of the KDM1A inhibitor and the further therapeutic agents. If administration is sequential, either a KDM1A inhibitor or one or more additional therapeutic agents may be administered first. If administered concurrently, one or more additional therapeutic agents may be contained in the same pharmaceutical formulation as the KDM1A inhibitor, or administered in one or more different (separate) pharmaceutical formulations (which may be the same or different routes of administration).

[0072] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to whom this invention relates.

[0073] The following definitions apply throughout this specification and the claims unless otherwise indicated.

[0074] For the purposes of this invention, the term "patient" or "subject" encompasses both humans and other animals, particularly mammals, as well as other living organisms. Therefore, the methods and uses of this invention are applicable to both human therapeutic and veterinary applications. In preferred embodiments, the subject or patient is a mammal, and in most preferred embodiments, the subject or patient is a human.

[0075] The term "abnormal" indicates a deviation from normal, average, or expected.

[0076] The term "inappropriate" indicates that something does not conform to social standards and / or expectations.

[0077] The term "pathological" indicates that something, such as a phenomenon or state, constitutes a diseased state, is altered by or caused by a disease, or is associated with a disease.

[0078] In this specification, terms such as “treatment” and “to treat” are used generally to mean obtaining a desired pharmacological and / or physiological effect. An effect is preventive in that it completely or partially prevents a disease (i.e., a behavioral change) or its symptoms, and / or therapeutic in that it partially or completely cures or improves a disease (i.e., a behavioral change) and / or symptoms or side effects caused by the disease, or partially or completely halts the progression of a disease and / or symptoms or side effects caused by the disease. As used herein, the term “treatment” is broad to encompass any treatment of a disease (i.e., a behavioral change) in a patient and includes, but is not limited to, one or more of the following: (a) preventing a behavioral change in a patient who is predisposed to / at risk of developing a behavioral change; (b) delaying the onset of a behavioral change; (c) inhibiting a behavioral change, i.e., blocking, delaying or slowing its onset / progression; or mitigating a behavioral change, i.e., causing regression, correction or reduction of the behavioral change. The present invention relates specifically and distinctly to each of these forms of treatment.

[0079] As used herein, the term “therapeutic dose” means an amount sufficient to produce a desired biological effect (e.g., therapeutic effect) in a subject. Therefore, a therapeutic dose of a compound may be sufficient to treat a disease and / or delay the onset or progression of the disease and / or alleviate one or more symptoms of the disease when administered to a subject suffering from or susceptible to the disease.

[0080] As used herein, “pharmaceutically acceptable salt” means a salt of a particular compound that retains the biological efficacy of the free acid and / or base and is not biologically or otherwise undesirable. Compounds may have functional groups that are sufficiently acidic, sufficiently basic, or both, and therefore may react with a number of inorganic or organic bases, and either inorganic or organic acids, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the present invention include hydrochlorides, hydrobromites, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, capronates, heptanoates, propionates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, hexin-1,6-diates, benzoates, chlorobenzoates, methylbenzoates, and dinitrobenzoates. Examples of salts prepared by the reaction of compound 1 with a mineral acid or organic acid include salts such as acid salts, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenyl acetate, phenylpropionate, phenyl butyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelates, pyruvates, stearates, ascorbicates, or salicylates. If the compound has an acidic moiety, suitable pharmaceutically acceptable salts include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, and procaine. Pharmaceutically acceptable salts are well known in the art.

[0081] As used herein, “pharmaceutically acceptable solvate” means a variable stoichiometric complex formed by a solute with a pharmaceutically acceptable solvent such as water or ethanol. The complex with water is known as a hydrate. It should be understood that the present invention encompasses pharmaceutically acceptable solvates of any KDM1A inhibitor, both in their non-salt and pharmaceutically acceptable salt forms.

[0082] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means non-API (API meaning active pharmaceutical ingredient) substances such as disintegrants, binders, fillers, and lubricants used in the formulation of pharmaceuticals. They are generally safe for administration to humans in accordance with established government standards, such as those published by the U.S. Food and Drug Administration and / or the European Medicines Agency. pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0083] As used herein, “small molecule” means an organic compound with a molecular weight of less than 900 daltons, preferably less than 500 daltons. Molecular weight is the mass of a molecule and is calculated by multiplying the sum of the atomic weights of each component by the number of atoms of that element in the molecular formula.

[0084] As used herein, the terms “comprising” (or “comprise,” “comprises,” “contain,” “contains,” or “containing”) mean, in particular, “comprising,” that is, “comprising, among any further elements, of which.” In addition, the term also encompasses the narrower meanings of “essentially consisting of” and “consisting of.” For example, the term “A containing B and C” means “A containing B and C in particular,” where A can contain any further elements (for example, “A containing B, C, and D” is also included), but the term also means “essentially consisting of B and C” (i.e., elements other than B and C are not included in A).

[0085] Unless otherwise indicated or inconsistent with the context, the terms “a,” “an,” and “the” as used herein are interchangeable with “one or more” and “at least one.” Therefore, for example, a composition containing “a” a KDM1A inhibitor can be interpreted as meaning a composition containing “one or more” KDM1A inhibitors.

[0086] Examples The following examples illustrate various aspects of the present invention. It should be understood that these examples are, of course, only illustrative of specific embodiments of the present invention and do not limit the scope of the invention. The results are also shown and explained in the drawings and the legend of the drawings. [Examples]

[0087] material Compound 1 (or its abbreviation (Comp.1)) is compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, also known as (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, and its chemical structure is shown below. [ka]

[0088] This compound can be obtained as disclosed in International Publication No. 2012 / 013728. [Examples]

[0089] In vitro KDM1A inhibition assay The inhibitory activity of a compound against KDM1A can be determined using the method described below.

[0090] Human recombinant KDM1A protein (GenBank accession number NM_015013, N-terminal GST tagged, amino acid 158, MW: 103 kDa) was used.

[0091] Serial 3-fold dilutions of test compounds in the range of 30 μM to 1 nM were pre-incubated on ice in assay buffer (50 mM sodium phosphate, pH 7.4) with human recombinant KDM1A enzyme (BPS Bioscience, Ref. 50100). Each inhibitor concentration was tested repeatedly. The enzymatic reaction was initiated by adding dimethyl H3K4 peptide substrate (Anaspec, Ref. 63677) to appKM of KDM1A. After incubation at 37°C for 30 minutes, Amplex Red reagent and horseradish peroxidase (HRP) solution were added as recommended by the supplier (Invitrogen) to detect H2O2 formed during the enzymatic reaction. The mixture was incubated in the dark at room temperature for 5 minutes, and the conversion of Amplex Red reagent to highly fluorescent resorphines was analyzed using an Infinite F200 Tecan fluorescence microplate reader (λ excitation = 540 nm, λ emission = 590 nm). The maximum demethylase activity of KDM1A was obtained in the absence of the inhibitor, and correction was made for background fluorescence in the absence of KDM1A. The IC50 values ​​of each inhibitor were calculated using GraphPad Prism5 software from at least two independent experiments.

[0092] The mean IC10¹±40 nM obtained in the KDM1A assay described herein 50 As indicated by the values, compound 1 is a KDM1A inhibitor. [Examples]

[0093] Evaluation of the effects of KDM1A inhibitors on aggressive behavior The effect of KDM1A inhibitor compound 1 on aggressive behavior was evaluated in SAMP8 male mice using the resident intruder (RI) test. The RI test is a standardized method for measuring social behavior, particularly aggressive behavior in semi-natural environments.

[0094] 3.1 Method The SAM mouse model was developed by Kyoto University from the AKR / J mouse strain. The SAMP8 litter exhibited severe aging and was selected to further inherit and test these traits. The SAMR1 litter exhibited normal aging and was selected as an aging-resistant strain.

[0095] In this study, male SAMP8 animals were treated with either vehicle (n=5), 0.32 (n=8), or 0.96 (n=8) mg / kg / day of compound 1 from 5 weeks to 5 months of age, and then subjected to RI testing. Vehicle (1.8% 2-hydroxypropyl-α-cyclodextrin, Sigma-Aldrich, Spain) or compound 1 was administered via drinking water. Vehicle-treated SAMR1 mice were included as controls (n=6). All drugs were administered via drinking water and diluted with vehicle. Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

[0096] The Resident Intruder (RI) test was conducted as follows: Subjects (residents) were kept in their home cages for one week without changing their bedding. On the test day, a fairly young, small subject (intruder; a 90-day-old C57BL6 mouse) was introduced into the resident home cage. The session (20 minutes) was videotaped, and the experimenter, blinded to the procedure, analyzed the test subject's social interactions (parameters tested: social interaction and hind leg standing) and aggressive behavior (parameters tested: lateral threat, clinch attack, keep-down behavior, and total aggression as the sum of the three aggressive behavior parameters).

[0097] Statistical analysis: The SAMR1 and SAMP8 vehicle groups were compared using t-tests. Within the SAMP8 group, different treatments were compared using one-way ANOVA, Dunnet, and SNK post-hoc analyses.

[0098] 3.2 Results When comparing the aggressive behavior of SAMP8 mice in the RI test with that of SAMR1 mice, as shown in Figures 1 and 2, the total number of attacks, particularly clinch attacks, was significantly increased in vehicle-treated SAMP8 mice compared to vehicle-treated SAMR1 mice. This indicates that male SAMP8 mice exhibit altered (increased) aggressive behavior compared to the control strain SAMR1. Treatment of SAMP8 mice with compound 1 reduced the number of attacks in SAMP8 mice to SAMR1 levels, as shown in Figures 1 and 2. Therefore, compound 1 significantly reduced the aggression of SAMP8 mice and corrected the altered aggressive behavior of the animals.

[0099] Vehicle-treated SAMP8 animals did not show a significant difference in the time spent on social interaction compared to vehicle-treated SAMR1 mice. There was no significant difference in the number of hind-leg standings between vehicle-treated SAMP8 mice and vehicle-treated SAMR1 mice, and treatment with compound 1 did not affect this reading in SAMP8 mice.

[0100] 3.3 The effect of KDM1A inhibitors on aggressive behavior is not due to sedation. The effect of compound 1 on aggressive behavior in male SAMP8 mice was due to the compound's direct effect on animal aggression and not to the compound's potential sedative effect. Anxiety and spontaneous movement in male SAMP8 mice were investigated using open-field (OF) and elevated cross maze (EPM) tests, as described below.

[0101] 3.3.1 Method Animals (n=8 / group) were treated with vehicle, compound 1 at 0.32 or 0.96 mg / kg / day from 5 months of age and were subjected to OF and EPM tests consecutively at 1-week intervals until 7 months of treatment.

[0102] A vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or a KDM1A inhibitor (compound 1) was administered in drinking water. Vehicle-treated SAMR1 mice were included as controls (n=8). All drugs were administered via drinking water and diluted with the vehicle. Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

[0103] OF and EPM tests were performed as follows: Open field: To analyze spontaneous exploratory behavior, a 50 x 50 cm white plastic arena with 25 cm high walls was used. The floor of the apparatus was divided into 25 equal squares. The movements of each animal were video recorded for 5 minutes. Spontaneous movements were analyzed by video tracking the captured images using SMART® (v3.0, PanLab, SLU, Spain).

[0104] Elevated Plus Maze (EPM): The EPM consisted of four arms perpendicular to each other, connected to a central square, and was maintained at a height of 50 cm above the floor. Two of the opposite arms had high walls (closed arms, 30 x 5 x 15 cm), while the other two were open arms (30 x 5 x 0 cm). Animals were placed facing the closed arms, and their movements were recorded for 5 minutes and analyzed by video tracking using SMART® (v3.0, PanLab, SLU, Spain).

[0105] Statistical analysis: The SAMR1 and SAMP8 vehicle groups were compared using t-tests. Within the SAMP8 group, different treatments were compared using one-way ANOVA, Dunnet, and SNK post-hoc analyses.

[0106] 3.3.2 Results In the OF test, no significant difference was observed between vehicle-treated SAMR1 mice and vehicle-treated SAMP8 mice, and treatment with compound 1 did not significantly affect the time spent in spontaneous movement or the central zone. SAMP8 mice spent significantly longer with open arms in the EPM compared to SAMR1 mice, but this behavior was not significantly altered by compound 1. Therefore, compound 1 did not have anxiolytic or sedative effects in SAMP8 mice.

[0107] In summary, the data and results obtained in Example 3 indicate that compound 1, a KDM1A inhibitor administered to SAMP8 mice at a dose well tolerable to the mice for long-term treatment, dramatically reduced aggression but did not function as a sedative or anxiolytic. Therefore, Example 3 supports the finding that KDM1A inhibitors, particularly compound 1, can be used to treat behavioral changes such as aggression without causing sedation.

[0108] The protocol described in Example 3 of this specification can be used to verify the effect of improving behavioral changes (e.g., improvement in aggression) using other KDM1A inhibitors. [Examples]

[0109] Evaluation of the effects of KDM1A inhibitors on social withdrawal While mice are highly territorial, rats are known to be a more gregarious species. To further characterize the therapeutic effects of KDM1A inhibitors such as compound 1 for treating behavioral changes, we used a rat isolation housing model to evaluate the effect of compound 1 on social withdrawal, another type of behavioral change, in rats.

[0110] In this model, rats are isolated after weaning at 21 days postnatal (PND21), depriving them of their normal environment that presupposes social behavior. Isolation at this stage of rat development may result in behavioral changes, particularly a lack of interest in social interaction, which could be used as a model for human social withdrawal.

[0111] 4.1 Method Immediately after weaning (21-23 days postnatal), 48 Sprague-Dolly male rats were divided into two groups: control (non-isolated; n=12), maintaining 3-4 animals per cage; isolation (n=36), 1 animal per cage. Starting at 61 days postnatal (PND61), adult isolation male rats were treated with a vehicle at 0.16 mg / kg / day of compound 1 or 0.48 mg / kg / day of compound 1 for 15 weeks (n=12 / group). Control (non-isolated) animals were treated with a vehicle. The route of administration was drinking water, and the vehicle was 1.8% 2-hydroxypropyl-β-cyclodextrin. Drug concentrations were adjusted weekly according to body weight and water consumption. In the last week of treatment, all animals were tested with RI (PND94) to assess social behavior, and on a different day, anxiety behavior was assessed with the EPM test (PND87-88).

[0112] The Resident Intruder (RI) test was performed following a protocol similar to that described for mice in Example 3 above: Briefly, the test subjects (residents) were kept in their home cages for one week without changing their bedding. On the test day, a fairly young, small subject (intruder; a 50-day-old Sprague-Dolly rat) was introduced into the resident home cage. The session was videotaped for 15 minutes, and the experimenter, blinded to the procedure, analyzed the test subjects' social interactions (measured parameters: active and passive social interactions, avoidance, and time without social interaction) and aggressive behavior.

[0113] The elevated cross maze (EPM) test was performed according to the same protocol as described for the mice in Example 3 above: The EPM consisted of four arms perpendicular to each other connected to a central square, and was maintained at a height of 50 cm above the floor. Two of the opposite arms had high walls (closed arms, 46.5 x 12 x 42 cm), while the other two arms were open arms (46.5 x 12 x 0.3 cm). The animals were placed facing the closed arms, and their movements were recorded for 5 minutes and analyzed by video tracking using SMART® (v2.5.21, PanLab, SLU, Spain).

[0114] Statistical analysis: Non-isolated and isolated vehicle groups were compared using t-tests. Within the isolated group, different drug treatments were compared using one-way ANOVA, Dunnet, and SNK post-hoc analyses.

[0115] 4.2 Results The radioisotope (RI) studies conducted did not reveal aggressive behavior in rats, and isolation did not significantly affect active or passive social interactions. However, social avoidance parameters, as assessed by time without social interaction (Figure 3) and the number of avoidances (Figure 4), were significantly increased in vehicle-treated rats compared to vehicle-treated, non-isolated rats. Time without social interaction in isolated rats decreased in a dose-dependent manner with treatment with compound 1, and the significantly increased number of avoidances in isolated rats was restored to normal (i.e., at the level of non-isolated rats) with treatment with compound 1 (see Figures 3 and 4).

[0116] No differences were observed between vehicle-treated and isolation-vehicle-treated rats in the EPM test. Compound 1 did not produce a significant effect on anxiety or spontaneous movement in rats assessed by the EPM, indicating that the beneficial effect of Compound 1 on social avoidance parameters measured in the RI test is not due to the drug's sedative effect.

[0117] In summary, the data and results obtained in Example 4 demonstrate that compound 1, a KDM1A inhibitor administered at a dose well tolerable to rats for long-term treatment, corrected behavioral changes, particularly social avoidance, in rats isolated after weaning without causing sedation. Thus, Example 4 further supports the finding that KDM1A inhibitors, particularly compound 1, can be used for the (non-sedating) treatment of behavioral changes (including social withdrawal).

[0118] The protocol described in Example 4 of this specification can be used to verify the effect of other KDM1A inhibitors on improving behavioral changes (e.g., on social withdrawal). [Examples]

[0119] Evaluation of the efficacy of KDM1A inhibitors using the three-chamber test (TCT) in mice. Compound 1, a KDM1A inhibitor, was further tested in additional animal models for changes in social behavior and the Three Chamber Test (TCT). The TCT is a commonly used method for measuring social behavior in mice and can be used to evaluate the effects of compounds on treating changes in social interaction using animals that exhibit congenital or acquired impairments in social behavior.

[0120] In this test, after adapting the mice to a three-chamber arena, they are released into the central chamber to explore the other compartments. In one adjacent “mouse” compartment, a docile stimulus mouse is placed in a mesh wire container, while in the other adjacent compartment, a similar container (object compartment) without a stimulus mouse is placed. The tendency to approach or avoid the compartment containing the stimulus mouse provides a measure of social interaction behavior / sociability. Wild-type mice prefer social interaction and spend more time in the mouse compartment compared to the object compartment.

[0121] 5.1 Method In this study, 8-month-old female SAMP8 mice were treated with either a vehicle (n=9) or compound 1 (n=12) at 0.96 mg / kg / day for 4 months, followed by TCT. The vehicle (1.8% 2-hydroxypropyl-α-cyclodextrin, Sigma-Aldrich, Spain) or compound 1 (diluted with vehicle) was administered in drinking water. Vehicle-treated SAMR1 mice were included as controls (n=11). Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

[0122] The TCT was performed in a transparent plexiglass box with three identical, consecutive chambers (15x15x20 cm), with two identical small metal cages placed in each of the outer chambers. The adjacent chambers were connected, allowing animals to move freely from one to the other. Test subjects (SAMR1 or SAMP8 female mice) were allowed to explore the apparatus for 5 minutes. This habituation was monitored to prevent the animals from showing preference for one of the chambers. Subsequently, a new female mouse was introduced into one of the metal cages (mouse chamber), while the other cage was left empty (object chamber). The time spent in each chamber and the time spent directly exploring the new mouse were measured during a total observation time of 10 minutes.

[0123] Statistical analysis: The significance of differences in novel mouse exploration for SAMP8 compared to SAMR1 mice, and for compound 1-treated mice compared to vehicle-treated SAMP8 mice, was assessed using t-tests. The significance of chamber preference was assessed using two-way ANOVA. ***: p < 0.001.

[0124] 5.2 Results The results obtained from this test are shown in Figures 5 and 6. As shown in Figure 5, vehicle-treated female SAMR1 mice spent more time in the mouse chamber compared to the object chamber. In contrast to control SAMR1 animals, vehicle-treated female SAMP8 mice did not show a preference for the mouse chamber over the object chamber (see Figure 5), and also spent less time exploring novel mice compared to SAMR1 mice (see Figure 6), thus indicating a deficit in social behavior. Treatment of female SAMP8 mice with compound 1, a KDM1A inhibitor, restored both the preference for the socialization chamber (mouse chamber) (Figure 5) and the time spent exploring novel mice (Figure 6) to SAMR1 levels. Therefore, compound 1 completely corrected the altered social interaction / lack of sociability in SAMP8 mice.

[0125] The results obtained in Example 5 further demonstrate that KDM1A inhibitors, such as Compound 1, can be used for the (non-sedative) treatment of changes in social behavior.

[0126] The protocol described in Example 5 of this specification can be used to verify the effect of other KDM1A inhibitors on improving social behavior.

[0127] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

[0128] The publications, patents, and patent applications referenced herein are provided solely for prior disclosure purposes prior to the filing date of this application. Nothing herein should be construed as acknowledging that they constitute prior art to this application.

[0129] While the present invention has been described in relation to its specific embodiments, further modifications are possible, and it should be understood that this application is intended to cover any variations, uses, or adaptations of the present invention, generally in accordance with the principles of the invention and within the known or customary scope of the art to which the invention relates, including deviations from the disclosure applicable to the essential features described in the above and below claims.

Claims

1. A pharmaceutical composition for use in the treatment of behavioral changes, wherein the behavioral changes are social withdrawal or aggressive behavior, and the pharmaceutical composition comprises 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.

2. The pharmaceutical composition according to claim 1, wherein the change in behavior is social withdrawal.

3. The pharmaceutical composition according to claim 1, wherein the change in behavior is aggressive behavior.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient being treated is a human being.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine.

6. A pharmaceutical composition according to any one of claims 1 to 5, which is administered orally.

7. Use of a KDM1A inhibitor, which is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a therapeutic agent for behavioral change, wherein the behavioral change is social withdrawal or aggressive behavior.

8. The use according to claim 7, wherein the change in behavior is social withdrawal.

9. The use according to claim 7, wherein the change in behavior is aggressive behavior.

10. The use according to any one of claims 7 to 9, wherein the patient being treated is a human being.

11. The use according to any one of claims 7 to 10, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine.

12. The use according to any one of claims 7 to 11, wherein the drug is for oral administration.

Images