RU2799049C2 - Methods for treatment of behavior changes - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to methods of treating behavioral changes. A method for treating behavioral change in a patient includes administering to the patient a therapeutically effective amount of a KDM1A inhibitor, wherein the behavioral change in the individual is social withdrawal or aggressiveness. Also the use of a KDM1A inhibitor for the treatment of behavior change and for the manufacture of a medicinal product for the treatment of behavior change is disclosed, where the behavior change in a person is social withdrawal or aggressiveness.

EFFECT: group of inventions provides treatment of behavioral changes without any sedative effect.

18 cl, 6 dwg, 5 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to methods for treating behavioral changes.

BACKGROUND OF THE INVENTION

Behavioral changes such as, for example, social withdrawal or violent behavior are common in today's society and are considered by physicians as a medical condition in their own right. However, the treatment of behavior change remains a medical challenge. There are currently no approved drugs specifically for the treatment of social withdrawal, aggressive behavior, or other behavioral changes. In addition, many of the existing drugs that are used to treat behavior changes can cause serious side effects: for example, many antipsychotics (also known as antipsychotics or major tranquilizers) that are used to treat aggressive behavior and other behavior changes cause sedation. Effect.

Thus, there is an urgent and unmet need for new and/or improved drugs for the treatment of behavioral changes, in particular for drugs acting through novel mechanisms of action that allow behavioral changes to be specifically treated and/or exhibit a more favorable side effect profile, than modern treatments. The present invention addresses these and other needs.

SUMMARY OF THE INVENTION

The invention provides new methods for treating behavioral changes using KDM1A inhibitors.

Thus, the present invention provides a KDM1A inhibitor for use in the treatment of behavior change.

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

The present invention further provides the use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of behavior change.

The present invention further provides the use of a KDM1A inhibitor for the treatment of behavior change.

In some embodiments, the change in behavior is a change in social behavior. In some embodiments, the change in behavior is aggressiveness or social withdrawal.

In preferred embodiments, the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or its pharmaceutically an acceptable salt or solvate.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effect of treatment with the KDM1A inhibitor Compound 1 (as defined below and in Example 1) on aggressive behavior in the alien resident test in male SAMP8 mice as measured by total number of attacks, as described in more detail in Example 3. Means and standard error of the mean (SEM) are presented. *p<0.05; **p<0.01.

Figure 2 shows the effect of treatment with Compound 1 on aggressive behavior in the alien-resident test on male SAMP8 mice, as measured by the number of clinch attacks, as described in more detail in Example 3. Mean values and SEM are presented. **p<0.01; ***p<0.001.

Figure 3 shows the effect of treatment with Compound 1 on social avoidance in the alien-resident test in a rat isolation model as assessed by time without social interaction (measured in seconds), as described in more detail in Example 4. Mean values and SEM are presented . *p<0.05; **p<0.01.

Figure 4 shows the effect of Compound 1 on social avoidance in the alien-resident test in a rat isolation model as measured by the number of arousals, as described in more detail in Example 4. Mean values and SEM are presented. *p<0.05; ***p<0.001.

Figure 5 shows the effect of Compound 1 on social interaction behavior in a three-chamber test (TCT) as assessed by time spent in each of the target chamber and chamber of mice (measured in seconds), as described in more detail in Example 5. Means and SEM presented. ***p<0.001.

Figure 6 shows the effect of Compound 1 on TCT social interaction behavior as measured by time spent directly on the study of new mice (measured in seconds), as described in more detail in Example 5. Mean values and SEM are presented. ***p<0.001.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that KDM1A inhibitors are useful as therapeutic agents for the treatment of behavioral changes, as explained in more detail below in the present description and illustrated in the Examples.

Accordingly, the present invention provides a KDM1A inhibitor for use in the treatment of behavior change.

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

The present invention further provides the use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of behavior change.

The present invention further provides the use of a KDM1A inhibitor for the treatment of behavior change.

In accordance with the present invention, "behavioral change" refers, in particular, to a change, disorder, dysfunction, aberration, disorder, or the like that affects the behavior of an object, including, for example, but not limited to, changes in behavior caused by or associated with genetic or epigenetic changes, behavioral changes associated with illness, behavioral changes induced by drug therapy, behavioral changes induced by acute and/or chronic drug abuse, or behavioral changes induced by adverse social environments (eg, childhood rejection or neglect, traumatic experiences such as like war or adult sexual abuse), among other things. Behavioral changes in accordance with the present invention do not include changes in cognitive function (eg, memory impairment) or mood (eg, anxiety).

In some embodiments, the change in behavior is a change in social behavior. In particular, it refers to a change, disruption, dysfunction, aberration, disorder, or the like that affects the subject's social behavior for any reason, including, for example, but not limited to, changes in social behavior (for example, changes in social interaction or aggressiveness) caused by or associated with genetic or epigenetic changes, social behavior changes (eg, changes in social interaction or aggressiveness) associated with the disease, social behavior changes (eg, changes in social interaction or aggressiveness) caused by drug therapy, social behavior changes (eg, changes in social interactions or aggressiveness) caused by acute and/or chronic drug abuse, or social behavior changes (eg, changes in social interaction or aggressiveness) caused by adverse social environments (eg, childhood rejection or neglect, traumatic experiences such as war or sexual abuse in adulthood), among others. Examples of changes in social behavior in accordance with the invention include, but are not limited to, social exclusion, aggressiveness or apathy, among others.

Thus, the present invention also relates to a KDM1A inhibitor for use in the treatment of a behavioral disorder, behavioral dysfunction, behavioral aberration or behavioral disorder, in particular social behavioral disorder, social behavioral dysfunction, social behavioral aberration or social behavioral disorder. Similarly, the invention also provides a method for treating a behavioral disorder, behavioral dysfunction, behavioral aberration, or behavioral disorder (particularly a social behavioral disorder, social behavioral dysfunction, social behavioral aberration, or social behavioral disorder) in a patient (preferably a human), the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Social behavior disorder, social behavior dysfunction, social behavior aberration or social behavior disorder may be, in particular, social withdrawal, aggressiveness or apathy. In addition, any of the above conditions may be, for example, (i) caused by or associated with genetic or epigenetic changes, (ii) associated with a disease, (iii) caused by drug therapy, (iv) caused by acute and/or chronic drug abuse, or (v) caused by an unfavorable social environment, as also described in more detail below in the present description.

"Social alienation" according to the present invention specifically refers to an abnormal, pathological or inappropriate lack of social interaction and/or a reduced degree of social interaction (including social avoidance) for members of social species such as humans, in particular the condition, in which the individual withdraws from society and individual relationships through a consistent (in different situations and over time) display of solitary behavior in the presence of others, often accompanied by indifference or indifference. In this regard, social exclusion (which can also be called passive exclusion) arises from internal factors, when an individual, for one reason or another, chooses not to interact with others. Social withdrawal in accordance with the invention does not include active social isolation, used to denote the absence of social interaction associated with external factors, for example, the process in which an individual is left alone because his/her peers do not want to interact with him/her (i.e. the individual is isolated from others). Non-limiting examples of social withdrawal to be treated in accordance with the present invention include social withdrawal caused by or associated with genetic or epigenetic changes (including, for example, COMT), social withdrawal associated with a disease (including, for example, autism spectrum disorder (ASD, such as, for example, autism or Asperger's Syndrome), anxiety disorder (TPD), schizophrenia (including, for example, schizotypal and/or delusional disorder), mood disorder (including, for example, major depressive disorder, dysthymic disorder, or bipolar disorder), drug addiction, post-traumatic stress disorder (PTSD), dementia (including, for example, Alzheimer's disease), paranoid personality disorder, depressive personality disorder, schizoaffective disorder, traumatic brain injury (TBI), or eating disorder (including, for example, bulimia), social withdrawal caused by drug therapy, social withdrawal caused by acute and/or chronic drug abuse (including, for example, dependence syndrome), or social withdrawal caused by adverse social environments (eg, childhood rejection or neglect, traumatic experiences such as war or adult sexual abuse), among others.

In accordance with the present invention, "aggressiveness" refers, in particular, to any kind of abnormal, pathological or inappropriate aggressive or violent behavior, hostility or arousal, for example, of a physical or verbal nature, including interpersonal aggressiveness (i.e. in relation to other objects ) and / or intrapersonal aggressiveness (i.e. aggressiveness towards oneself). Non-limiting examples of aggressiveness to be treated in accordance with the invention include, but are not limited to, aggressiveness induced or associated with genetic or epigenetic changes (including, for example, 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, UBE2A, SMARCA2, HCFC1, HERC2, NDP, PAK3, ATP13A2, SPAST, NSD1, STAMBP, HPRT1, DJ1, TARDBP, MAPT, or AVPR1A), disease-associated aggressiveness (including, for example, Alzheimer's disease (AD), Huntington's disease (HD), Lewy body dementia (LWB), Parkinson's disease ( PD), schizophrenia (SZ), bipolar disorder (BD), depression (DS), traumatic brain injury (TBI), REM sleep behavior disorder (RPBS), dementia, dentato-rubro-pallido-Lewis atrophy (DRLA) , Tourette syndrome (TS), conduct disorder (including, for example, unsocialized conduct disorder, socialized conduct disorder, or oppositional defiant disorder), drug addiction, stress-related disorder (including, for example, post-traumatic stress disorder), autism spectrum disorder (ASD) , borderline personality disorder or adult Attention Deficit Hyperactivity Disorder), drug-induced aggression, toxin-induced aggression (eg, trimethyltin), acute and/or chronic drug abuse-induced aggression (including, for example, withdrawal syndrome), aggressiveness caused by a dietary deficiency (eg, Zn), aggressiveness due to lack of sleep, or aggressiveness due to adverse social environments (eg, childhood rejection or neglect, traumatic experiences such as war or sexual abuse in adulthood), among others.

The diseases listed above as examples of diseases in the context of social withdrawal associated with the disease, or in the context of aggressiveness associated with the disease, are also examples of the disease in the context of behavior change associated with the disease, as well as in the context of social behavior change associated with the disease. .

In some embodiments, the behavior change is social withdrawal.

In some embodiments, the behavior change is social withdrawal associated with a disease. In some embodiments, said disease is a CNS disease. In some embodiments, said CNS disorder is an autism spectrum disorder (ASD, such as, for example, autism or Asperger's syndrome), anxiety disorder (PDD), schizophrenia (including, for example, schizotypal and/or delusional disorder), mood disorder ( including, for example, major depressive disorder, dysthymic disorder, or bipolar disorder), drug addiction, post-traumatic stress disorder (PTSD), dementia (including, for example, Alzheimer's disease), paranoid personality disorder, depressive personality disorder, schizoaffective disorder, TBI, or eating disorder (including, for example, bulimia).

In some embodiments, the change in behavior is aggressiveness.

In some embodiments, the change in behavior is aggressiveness associated with a disease. In some embodiments, said disease is a CNS disease. In some embodiments, said CNS disease is AD, HD, DTL, PD, SZ, BR, DS, TBI, RPPS, dementia, FDD, TS, conduct disorder (e.g., unsocialized conduct disorder, socialized conduct disorder, or oppositional defiant disorder) , drug addiction, stress-related disorder (including, for example, post-traumatic stress disorder), ASD, borderline personality disorder, or adult attention deficit hyperactivity disorder. In a preferred embodiment, the disease is AD. However, the disease can also differ from AD. For example, the disease may be HD, LTD, PD, SZ, BR, DS, TBI, RPPS, dementia, FAD, TS, conduct disorder (e.g., unsocialized conduct disorder, socialized conduct disorder, or oppositional defiant disorder), drug addiction, disorder, associated with stress (including, for example, post-traumatic stress disorder), ASD, borderline personality disorder, or attention deficit hyperactivity disorder in adults.

In some embodiments, the behavior change is apathy.

Any KDM1A inhibitor, including KDM1A inhibitors, can in principle be used in the methods of treatment and therapeutic applications described herein, as described in more detail below in this application. Preferably, however, the KDM1A inhibitor for use in the methods and uses of the invention is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4- oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof, and most preferably the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl) -1,3,4-oxadiazol-2-amine (in non-salt form). This compound is also referred to in the present description (including Examples and Figures) as Compound 1 or Comm. 1. The names "5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cycopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine", "Compound 1" or "Comp. 1" are used interchangeably herein.

Accordingly, the present invention provides 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof, or a solvate for use in the treatment of behavior change.

The present invention further provides a method of treating behavior change 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-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof.

The present invention further provides the use of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof, or a solvate for the manufacture of a drug for the treatment of behavior change.

The present invention further provides the use of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt thereof, or solvate to treat behavioral change.

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

In some embodiments, the behavior change is social withdrawal.

In some embodiments, the change in behavior is aggressiveness.

In some embodiments, the behavior change is apathy.

Preferably, a KDM1A inhibitor for use in the treatments and uses described herein, e.g. compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1, 3,4-oxadiazol-2-amine (or a pharmaceutically acceptable salt or solvate thereof) is administered orally. Exemplary formulations that may be administered orally are described in more detail below.

As explained 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- an amine, or a pharmaceutically acceptable salt or solvate of said compound for use in the treatment of behavior change. Accordingly, the invention relates to the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine as the free base ( in non-salt form) for use in the treatment of behavior change, and furthermore, the invention also relates to a pharmaceutically acceptable salt or solvate of 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino) methyl)-1,3,4-oxadiazol-2-amine for use in the treatment of behavior change.

As also shown in the Examples, it has surprisingly been found in the context of the present invention that KDM1A inhibitors such as, for example, Compound 1 provide strong therapeutic effects in animal models (human) of behavior change. In particular, positive effects of KDM1A inhibitors have been observed in relation to various types of behavioral changes, in particular aggressiveness, social withdrawal and other changes in social behavior.

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 aggressiveness. To test the effect of a compound of interest, such as Compound 1, on aggressiveness, an animal model (e.g., a rodent model) is selected when vehicle-treated animals are known to develop or are identified as exhibiting altered (increased) aggressive behavior compared to control animals, as assessed by using a well known method for measuring aggressive behavior and then assessing whether treatment of said aggressive animals with the compound reduces their aggressive behavior compared to vehicle-treated animals, or even restores aggressive behavior to (normal) levels of control animals. Animal aggressive behavior can be assessed using any standard method for assessing aggressive behavior parameters, such as, for example, the resident alien (RI) test, which can be performed, for example, as described in more detail in Example 3.1. As an example of a suitable animal model for aggressiveness studies, male SAMP8 mice can be used, using male SAMR1 mice as controls. As shown in Example 3 and Figures 1 and 2, vehicle-treated male SAMP8 mice exhibit significantly more aggressive behavior compared to the SAMR1 control strain, as evidenced by a significantly increased number of total attacks, especially clinch attacks. Treatment of male SAMP8 mice with a KDM1A inhibitor (particularly Compound 1) drastically reduces their aggressiveness, as shown in Figures 1 and 2, in terms of attacks (both general attacks and clinch attacks), which is recovered in SAMP8 mice treated with Compound 1 , up to SAMR1 levels. Thus, treatment with the KDM1A inhibitor Compound 1 is able to correct altered aggressive behavior in SAMP8 mice, supporting the use of KDM1A inhibitors to treat aggressiveness and associated behavioral changes.

In addition to providing a therapeutic effect on aggressiveness, KDM1A inhibitors such as Compound 1 are also useful in the treatment of other behavioral changes such as social withdrawal, as shown in Example 4 and Figures 3 and 4. While mice are jealous of their territory , rats are known to be a more sociable species and thus are the most appropriate species for assessing social interaction behavior and in particular social withdrawal. A suitable model for assessing social exclusion is the isolation nurturing model in rats. In this model, rats are isolated after weaning and deprived of the normal environment that determines their social behavior. Isolation at this developmental stage in the rat leads to behavioral changes, in particular a lack of interest in social interactions (social avoidance) in the adult animal, which can be used as a model for social withdrawal in humans. The social behavior of the animals in this model can be assessed using any standard method for such assessment known in the art, such as the alien resident test. As shown in Example 4 and Figures 3 and 4, social avoidance parameters are significantly increased in vehicle-treated isolated rats compared to vehicle-treated non-isolated rats, as reflected by time without social interaction (Figure 3) and number of arousals. (Figure 4). Treatment with the KDM1A inhibitor Compound 1 significantly reduced social avoidance in isolated rats, as shown in Figure 3 by a dose-dependent reduction in time without social interaction in isolated rats and in Figure 4 by a reduction in arousal, which was significantly increased in vehicle-treated isolated rats and was restored to normal (i.e., to levels in non-isolated rats) by treatment with the KDM1A inhibitor Compound 1. Treatment with a KDM1A inhibitor is able to improve or correct social avoidance, supporting the use of KDM1A inhibitors to treat social withdrawal and associated changes in social behavior.

The suitability of KDM1A inhibitors for the treatment of social behavior changes is further illustrated in Example 5 and in Figures 5 and 6 using another widely used social behavior test, the three chamber test (TCT). TCT is a widely used method for measuring social behavior in mice and is useful for evaluating the effects of a compound for treating changes in social interaction using animals exhibiting congenital or acquired social behavior deficits. In the TCT test, as explained in more detail in Example 5, after adapting to a three-chamber arena, the mouse is released into the middle chamber and allowed to explore the other compartments. In the adjacent "mouse" compartment, an obedient stimulus mouse is in a mesh container, while in another adjacent compartment, a similar container is located without a stimulus mouse (target compartment). The tendency to approach or avoid a compartment with a stimulus 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, is able to restore social interaction behavior/sociability in subjects that experience changes in social interaction. As described in Example 5, in contrast to the SAMR1 control strain, female SAMP8 mice do not prefer the "mouse" chamber over the "target" chamber, and also spend less time examining a new mouse, thus demonstrating deficiencies in social behavior. Treatment of female SAMP8 mice with the KDM1A inhibitor Compound 1 completely restored social interaction behavior/sociability in SAMP8 mice to SAMR1 levels, as shown by restoring both the socialization chamber (mouse chamber) preference (see Figure 5) and the time spent testing new mice (see Figure 6). It is important to note that the therapeutic effects of KDM1A inhibitors such as Compound 1 in the treatment of behavioral changes are achievable without causing sedation as shown in Examples 3 and 4 using standard assays to measure sedative or anxiolytic effects such as the Open Field and "Elevated plus maze". Sedation is a serious side effect in many drugs currently used to treat behavioral changes. For example, antipsychotic medications used to treat aggressiveness usually cause severe sedation. Thus, KDM1A inhibitors, and Compound 1 in particular, are most preferred over current therapies because they can be used to treat behavioral changes without causing sedative side effects.

KDM1A inhibitors

As used herein, a KDM1A inhibitor is a compound that inhibits KDM1A, in particular human KDM1A.

All kinds of KDM1A inhibitors can be used in the methods and uses according to the invention.

Preferably, the KDM1A inhibitor for use in the methods and uses of the invention is a small molecule. Both irreversible and reversible inhibitors of KDM1A are described and can be used in accordance with the present invention. Irreversible KDM1A inhibitors exert their inhibitory activity by becoming covalently linked to the FAD cofactor within the active site of KDM1A, and are typically based on a 2-cyclylcyclopropylamino moiety, such as a 2-(hetero)arylcyclopropylamino moiety. Reversible KDM1A inhibitors have also been disclosed.

Non-limiting examples of KDM1A inhibitors that can be used in accordance with the present invention are disclosed in, for example: WO2010/043721, WO2010/084160, WO2011/035941, WO2011/042217, WO2011/131697, WO2012/013727, WO201 2/013728, WO2012 /045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/022489, WO2011/131576, WO2012/034116, WO2012/135113, WO 2013/022047, WO2013/025805, WO2014/058071, WO2014/084298 WO2014/086790 WO2014/164867 WO2014/205213 WO2015/021128 WO2015/031564 US2015-0065434 WO2007/021839 WO2008/127734 WO2015/0 89192, CN104119280, CN103961340, CN103893163, CN103319466, CN103054869, WO2015/123408 WO2015/123424 WO2015/123437 WO2015/123465 WO2015/156417 WO2015/181380 WO2016/123387 WO2016/130952 WO2016/172496 77656, WO2017/027678, CN106045862, WO2012/071469, WO2013/033688 WO2014/085613 WO2015/120281 WO2015/134973 WO2015/168466 WO2015/200843 WO2016/003917 WO2016/004105 07727, WO2016/007731, WO2016/007736, WO2016/034946, WO2016 WO2017/116558 2017/114497, CN106432248, CN106478639, CN106831489, CN106928235, CN105985265, WO2017 /149463, WO2017/157322, WO2017/195216, WO2017/198780, WO2017/215464, WO2018/081342, WO2018/081343, US2017-0283397, as well as

including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. Any one of the above compounds containing a 1,2-substituted cyclopropyl ring can be used in the form of the corresponding trans isomer (in which two substituents on the cyclopropyl ring are in the trans configuration) or in the form of any one of the appropriate defined trans isomers (in which the two substituents on the cyclopropyl ring have the same absolute configuration, as shown in the depicted structure; or in which the two substituents on the cyclopropyl ring each have the opposite absolute configuration, as shown in the depicted structure).

Additional non-limiting examples of KDM1A inhibitors that are used in accordance with the present invention are disclosed, for example, in: 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; 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; S.L. 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 22-dec-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, doi:10.1016/j.bmcl.2015.06.054. Irreversible inhibitors of KDM1A that can be used in the methods/applications of the invention include, but are not limited to, any one of the compounds disclosed in: WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/131576, WO2012/135113, WO 2013/022047, WO2014/058071, WO2014/084298, WO2014/086790, WO2014/164867, WO2015/021128; WO2015/123408 WO2015/123424 WO2015/123437 WO2015/123465 WO2015/156417 WO2015/181380 WO2016/123387 WO2016/130952 WO2016/172 496, 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. Epub 2014 Aug 27, also as

including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. Any one of the above compounds containing a 1,2-substituted cyclopropyl ring can be used in the form of the corresponding trans isomer (in which two substituents on the cyclopropyl ring are in the trans configuration) or in the form of any one of the appropriate defined trans isomers (in which the two substituents on the cyclopropyl ring have the same absolute configuration, as shown in the depicted structure; or in which the two substituents on the cyclopropyl ring each have the opposite absolute configuration, as shown in the depicted structure).

Reversible KDM1A inhibitors that can be used in the methods/applications of the invention include, but are not limited to, any one of the compounds disclosed in WO2007/021839, WO2008/127734, WO2011/022489, WO2012/034116, WO2012/071469, WO2013/02580 5 WO2015/0065434, WO2013/033688, CN103054869, CN103319466, WO2014/085613, CN103893163A, CN103961340, WO2014/205213, WO2015/089192, WO2015/120281, WO2015/134973, WO2015/168466, WO2015/200843, WO2016 /003917, WO2016/004105, WO2016/007722, WO2016/007727, WO2016/007731, WO2016/007736, WO2016/034946, WO2016/037005, WO2016/161282, WO 2017/004519, WO2017/079670, WO2017/090756, CN106432248, CN106478639 , CN106928235, same as

including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. In some embodiments, in the methods and uses of the 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 contains a cyclopropyl ring substituted at position 1 with an amino group that is optionally substituted and substituted at position 2 an aryl or heteroaryl group (in which the aryl or heteroaryl group is optionally substituted).

The ability of a compound to inhibit KDM1A can be tested in vitro using any method for determining KDM1A inhibition known in the art, such as the method disclosed in Example 2.

The most preferred KDM1A inhibitor for use in the methods and uses of the 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.

Other KDM1A inhibitors that can be used in the methods and uses of the invention include:

(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-(thiazol-5-yl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-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)pyridin-3-yl)cyclopropyl)amino)cyclohexanol;

4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamide;

N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)acetamide;

N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)methanesulfonamide;

(R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-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-inden-1,3-diamine;

N1-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1H-inden-1,3-diamine;

N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1H-inden-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)cyclohexanamine;

N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine;

N1-((cis)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

tert-Butyl-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate;

1-ethyl-3-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)urea;

4-morpholino-N-((trans)-2-phenylcyclopropyl)cyclohexanamine;

N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-(2-(o-tolyl)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-(naphthalene-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)pyrrolidin-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-(pyridin-3-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(4-(1H-pyrazol-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)thiazol-2-yl)phenol;

3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile;

5-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-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)thiazol-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)piperazin-1-sulfonamide;

N1-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)amino)benzonitrile;

N1-((trans)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(o-tolyl)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-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

(cis)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1S,2R)-2-(pyridin-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-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

(cis)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

(cis)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

(cis)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

(trans)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

N-(4'-((1R,2S)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazin-1-sulfonamide;

N-(4'-((1S,2R)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazin-1-sulfonamide;

N-(4'-((1S,2R)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazin-1-sulfonamide;

N-(4'-((1R,2S)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)piperazin-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)pyridin-3-yl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

N-((trans)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-(thiazol-5-yl)cyclopropyl)piperidin-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)piperidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidine-3-amine;

N-((trans)-2-phenylcyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)pyrrolidin-3-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)pyrrolidin-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)azepane-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]undecan-9-amine;

N-((trans)-2-phenylcyclopropyl)-2-azaspiro[4,5]decan-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-(pyridin-3-yl)cyclopropyl)piperidine-4-amine;

N-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)piperidine-4-amine;

N-((1S,2S)-2-(thiazol-5-yl)cyclopropyl)piperidine-4-amine;

N-((1R,2R)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

N-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

N-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-phenylcyclopropyl)-7-azaspiro[3.5]nonan-2-amine;

N-(2-(o-tolyl)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-(piperidin-4-ylamino)cyclopropyl)-[1,1'-biphenyl]-3-yl)methanesulfonamide;

N-(4'-((trans)-2-(piperidin-4-ylamino)cyclopropyl)-[1,1'-biphenyl]-3-yl)propan-2-sulfonamide;

1-(methylsulfonyl)-N-((trans)-2-phenylcyclopropyl)piperidine-4-amine;

1-(4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidin-1-yl)ethanone;

4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine-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-(pyridin-4-yl)piperidin-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-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

N-((trans)-2-methyl-2-phenylcyclopropyl)piperidine-4-amine;

N-((trans)-2-(o-tolyl)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-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-2-phenyl-N-(2-(piperidin-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-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(Trans)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(Trans)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(Trans)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1S,2R)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1R,2S)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1S,2R)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1R,2S)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1S,2R)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1R,2S)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1S,2S)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1R,2R)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1S,2R)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(1R,2S)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(1S,2R)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1R,2S)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

(1S,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1R,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

(1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(1R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

(1S,2R)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(1R,2S)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

(Trans)-2-phenyl-N-(pyrrolidin-3-ylmethyl)cyclopropanamine;

(Trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-N-(azetidin-3-ylmethyl)-2-phenylcyclopropanamine;

(Trans)-2-(4-cyclopropylphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-N-(piperidin-4-ylmethyl)-2-(4-(pyridin-3-yl)phenyl)cyclopropanamine;

(Trans)-2-(4-(1H-pyrazol-5-yl)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

(Trans)-2-(naphthalene-2-yl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(trans)-2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

(trans)-2-(4-(benzyloxy)phenyl)-N-((1-methylpiperidin-4-yl)methyl)cyclopropanamine;

4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;

1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid;

N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]- 4-(1H-1,2,3-triazol-1-yl)benzamide;

4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile;

including their any optically active stereoisomer

or a pharmaceutically acceptable salt or solvate thereof.

Pharmaceutical formulations

While it is possible that a KDM1A inhibitor such as Compound 1 may be administered for use in therapy directly as such, it is usually administered in the form of a pharmaceutical composition which contains the compound as the active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients or carriers. Any reference to a KDM1A inhibitor in the present specification includes reference to the compound per se, i.e., the corresponding compound in non-salt form (e.g., free base) or in the form of any pharmaceutically acceptable salt or solvate thereof, as well as reference to a pharmaceutical composition containing said compound and one or more pharmaceutically acceptable excipients or carriers.

The KDM1A inhibitor can be administered by any means that achieve the intended purpose. Examples include oral, parenteral (including, for example, intravenous, subcutaneous or intracerebral) or topical administration.

For oral delivery, the compound may be formulated which includes pharmaceutically acceptable carriers such as binders ( eg gelatin, cellulose, gum tragacanth), excipients ( eg starch, lactose), lubricants ( eg magnesium stearate, silicon dioxide ) leavening agents ( eg alginate, primogel and corn starch) and sweeteners or flavors ( eg glucose, sucrose, saccharin, methyl salicylate and peppermint). The composition may be delivered orally, for example in the form of closed gelatin capsules or compressed tablets. Capsules and tablets may be prepared using any of the standard techniques. Capsules and tablets can also be coated with various coatings known in the art to change the flavor, taste, color and shape of the capsules and tablets. In addition, liquid carriers such as fatty oils may also be included in the capsules.

Suitable formulations for oral administration may also be in the form of a suspension, syrup, chewing gum, cachet, elixir, and the like. If desired, standard agents for modifying aromas, flavors, colors and shapes of these special shapes can also be included. In addition, for ease of administration by enteral feeding tube to patients who cannot swallow, the active compounds can be dissolved in a suitable lipophilic vegetable oil carrier such as olive oil, corn oil and safflower oil.

The compound may also be administered parenterally in the form of a solution or suspension, or in a lyophilized form capable of being converted to the form of a solution or suspension before use. Such formulations may use diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer. Other standard solvents, pH buffers, stabilizers, antibacterial agents, surfactants and antioxidants may be included. For example, suitable ingredients include sodium chloride, acetates, citrates or phosphate buffers, glycerol, dextrose, fatty oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. Parenteral formulations may be stored in any standard container such as vials and ampoules.

For topical administration, the compound may be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickeners, humectants, and stabilizing agents may be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petroleum jelly, beeswax or mineral oil, lanolin, squalene, and the like. A particular form of topical administration is delivery via a transdermal patch. Methods for making transdermal patches are disclosed in, for example , Brown, et al. (1988) Ann. Rev. Med . 39:221-229, which is incorporated herein by reference.

Subcutaneous implantation for sustained release of the compound may also be a suitable route of administration. This entails surgical procedures for implanting the active compound in any suitable formulation into the subcutaneous space, eg under the anterior abdominal wall. See, for example , Wilson et al . (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as carriers for the sustained release of active compounds. Hydrogels are generally known in the art. They are usually made by cross-linking high molecular weight biocompatible polymers into a network that swells in water to form a gel-like material. Preferably, the hydrogels are biodegradable or biosorbable. For purposes of the present invention, hydrogels derived from polyethylene glycols, collagen or a copolymer of glycol with L-lactic acid can be used. See, for example , Phillips et al . (1984) J. Pharmaceut. sci. , 73: 1718-1720.

The compound may also be conjugated with a water-soluble non-immunogenic non-peptide high molecular weight polymer to form a polymeric conjugate. For example, the compound may be covalently linked to polyethylene glycol to form a conjugate. Typically, such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the compound in the conjugate may have a longer half-life in the body and exhibit better efficacy. See usually Burnham (1994) Am. J. Hosp. Pharm . 15:210-218. PEGylated proteins are currently used in protein replacement therapy and for other therapeutic purposes. For example, pegylated interferon (PEG-INTRON A®) is used clinically to treat hepatitis B. Pegylated adenosine deaminase (ADAGEN®) is used to treat severe combined immunodeficiency (SCID). Pegylated L-asparaginase (ONCASPAR®) is used to treat acute lymphoblastic leukemia (ALL). Preferably, the covalent bond between the polymer and the active compound and/or within the polymer itself is cleaved hydrolytically under physiological conditions. Such conjugates, known as "prodrugs", can easily release the active compound within the body. Controlled release of the active compound can also be achieved by encapsulating the active ingredient in microcapsules, nanocapsules or hydrogels, as is well known in the art. Other pharmaceutically acceptable prodrugs of the compound include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, tertiary amine quaternary derivatives, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.

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

Pharmaceutical compositions such as oral and parenteral compositions may be formulated in unit dosage forms for ease of administration and dosage uniformity. As used herein, "unit dosage forms" refers to physically discrete units suitable as unit doses for administration to subjects, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in combination with one or more suitable pharmaceutical carriers. .

In therapeutic applications, pharmaceutical compositions should be administered in a manner appropriate to the disease to be treated, as determined by one of ordinary skill in the medical field. The appropriate dose and the appropriate duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the route of administration, among others. Generally, a suitable dosage and administration schedule will provide the pharmaceutical composition in an amount sufficient to provide a therapeutic effect, such as improved clinical outcome such as more frequent complete or partial remissions, or longer disease resistance and/or overall survival, or reduction in symptom severity, or any other objectively identifiable improvement as noted by the clinician. Effective doses can generally be estimated or extrapolated using experimental models such as dose-response curves derived from in vitro test systems or animal models such as those illustrated in the Examples.

The pharmaceutical compositions of the invention may be included in a container, pack or dispenser along with instructions for administration.

KDM1A inhibitors such as Compound 1 have been found to be orally active and effective in treating behavioral changes when administered orally, as also shown in Examples 3 and 4. Accordingly, it is preferred if a KDM1A inhibitor (eg Compound 1) is administered orally to treat behavior change.

The present invention also encompasses the use of KDM1A inhibitors in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses the use of a KDM1A inhibitor in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (ie ² H; also referred to as "D"). Accordingly, the invention also encompasses KDM1A inhibitors that are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture containing about 99.98 mole % hydrogen-1 ( ¹ H) and about 0.0156 mole % deuterium ( ² H or D). The deuterium content at one or more of the hydrogen positions in the KDM1A inhibitor can be increased using deuteration techniques known in the art. For example, a KDM1A inhibitor or a reagent or precursor that is used in the synthesis of a KDM1A inhibitor can be subjected to an H/D exchange reaction using, for example, heavy water (D ₂ O). Additional suitable deuteration methods are described in: Atzrodt J et al., Bioorg Med Chem , 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled 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 specifically stated otherwise, it is preferred that the KDM1A inhibitor used in accordance with the present invention is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or ¹ H hydrogen atoms in the KDM1A inhibitor is preferred. In general, it is preferred that none of the atoms in the KDM1A inhibitor to be used in accordance with the invention be replaced by certain isotopes. The KDM1A inhibitor or pharmaceutical composition containing the KDM1A inhibitor that is used in accordance with the present invention can be administered in monotherapy (for example, without the simultaneous administration of any additional therapeutic agents or without the simultaneous administration of any additional therapeutic agents in relation to the same behavioral change treated with a KDM1A inhibitor). Accordingly, a KDM1A inhibitor or a pharmaceutical composition containing a KDM1A inhibitor can be used in the monotherapeutic treatment of behavioral change (eg, without the administration of any other therapeutic agents for the same behavioral change until treatment with the KDM1A inhibitor is discontinued). However, a KDM1A inhibitor or a pharmaceutical composition containing a KDM1A inhibitor may also be administered in combination with one or more additional therapeutic agents. If a KDM1A inhibitor is used in combination with a second therapeutic agent active on the same behavioral change, the dose of each compound may be different from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of a KDM1A inhibitor with one or more additional therapeutic agents may include the simultaneous/co-administration of the KDM1A inhibitor and the additional therapeutic agent(s) (either in the same pharmaceutical formulation or in separate pharmaceutical formulations) or the sequential/separate administration of the KDM1A inhibitor and the additional therapeutic agent( ov). If the administration is sequential, either the KDM1A inhibitor or one or more additional therapeutic agents may be administered first. If the administration is simultaneous, one or more additional therapeutic agents may be included in the same pharmaceutical formulation as the KDM1A inhibitor, or they may be administered in one or more different (separate) pharmaceutical formulations (which may be administered using the same or different route of administration).

Definitions

Unless otherwise indicated, all technical and scientific terms used in this specification have the same meaning as generally understood by those skilled in the art to which this invention pertains.

The following definitions apply throughout the present description and claims, unless specifically stated otherwise.

"Patient" or "object" for the purposes of the present invention includes both humans and other animals, in particular mammals and other organisms. Thus, the methods and uses of the invention are useful in both human therapy and veterinary applications. In a preferred aspect, the subject or patient is a mammal, and in a most preferred aspect, the subject or patient is a human.

The term "abnormal" indicates a deviation from the normal, average, or expected.

The term "inappropriate" means that something is contrary to social standards and/or expectations.

The term "pathological" means that something, such as an event or condition, is a disease state or is altered or caused by or associated with a disease.

The terms "treatment", "treating" and the like are used in the present description usually to denote the achievement of the desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease (i.e., behavior change) or a symptom thereof, and/or may be therapeutic in terms of partially or completely curing or ameliorating the disease (i.e., behavior change) and/or symptom or adverse effect associated with the disease, or partial or complete arrest of the progression of the disease and/or symptom or adverse effect associated with the disease. As used herein, the term "treatment" encompasses any treatment of a disease (i.e., behavior change) in a patient and includes, but is not limited to, any one or more of the following: (a) preventing a change in behavior in a patient that may be predisposed to /is at risk of developing behavior change; (b) delaying the onset of behavior change; (c) inhibition of behavioral change, ie. stopping, delaying, or slowing down its development/progression; or (d) reducing the change in behavior, i.e. causing (total or partial) regression, correction or mitigation of behavior change. The present invention relates specifically and distinctly to each of these forms of treatment.

Used in the present description, the term "therapeutically effective amount" refers to an amount sufficient to achieve the desired biological effect (eg, therapeutic effect) in the object. Accordingly, a therapeutically effective amount of a compound may be an amount sufficient to treat a disease and/or delay the onset or progression of a disease and/or alleviate one or more symptoms of a disease when administered to a subject suffering from or susceptible to the disease.

Used in the present description, the term "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and/or bases of the specified connection and which is not biologically or otherwise undesirable. The compound may be sufficiently acidic, sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. Typical pharmaceutically acceptable salts include salts obtained by reacting a compound of the invention, for example, Compound 1 with a mineral or organic acid, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, subrates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, ethanesulfonates, propanesulfonates, benzenesulfonates, toluenesulfonates, trifluoromethanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates or salicylates. When the compound contains an acid moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, eg sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

As used herein, the term "pharmaceutically acceptable solvate" refers to a complex of variable stoichiometry formed by a solute and a pharmaceutically acceptable solvent such as water, ethanol, and the like. The complex with water is known as a hydrate. It is to be understood that the invention encompasses pharmaceutically acceptable solvates of any KDM1A inhibitors in non-salt form as well as in the form of a pharmaceutically acceptable salt thereof.

As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to non-API substances (API refers to an active pharmaceutical ingredient), such as disintegrants, binders, fillers, and lubricants used in formulating pharmaceutical products. . They are generally safe to administer to humans according to established government standards, including those issued by the US Food and Drug Administration and/or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

Used in the present description, the term "small molecule" refers to an organic compound with a molecular weight below 900 daltons, preferably below 500 daltons. Molecular weight is the mass of a molecule and is calculated as the sum of the atomic masses of each constituent element multiplied by the number of atoms of that element in the molecular formula.

As used herein, the term "comprising" (or "comprise", "comprises", or "comprising"), unless expressly stated otherwise or contrary to context, has the meaning of "including", i.e. “comprising, in addition to additional optional elements…”. Furthermore, in addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A containing B and C" has the meaning "A including B and C", in which A may contain additional optional elements (for example, "A containing B, C and D" could also be included ), but the term also includes the meaning "A consisting essentially of B and C" and the meaning "A consisting of B and C" (i.e., no components other than B and C are contained in A).

Used in the present description, unless expressly indicated otherwise or does not contradict the context, the terms "a", "an" and "the" are used interchangeably with "one or more" and "at least one". Thus, for example, a composition containing a KDM1A inhibitor can be interpreted as referring to a composition containing "one or more" KDM1A inhibitors.

EXAMPLES

The following examples illustrate various aspects of the invention. Of course, it should be understood that the examples are merely illustrative of certain embodiments of the invention, and do not limit the scope of the invention. The results are also presented and described in the Figures and legends of the Figures.

Example 1: Materials

Compound 1 (or Comp. 1) is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine , also known as (-) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, whose chemical structure is shown below .

This connection can be obtained as disclosed in WO2012/013728.

Example 2: In Vitro KDM1A Inhibition Assay

The inhibitory activity of a compound against KDM1A can be determined using the method described below. The human recombinant protein KDM1A was used (GenBank accession number NM_015013, 158 amino acid end with GST N-terminal tag, MW: 103 kDa).

Serial 3-fold dilutions of test compound ranging from 30 µl to 1 nM were pre-incubated for 15 minutes with recombinant human KDM1A enzyme (BPS Bioscience, Ref. 50100) on ice in assay buffer (50 mM sodium phosphate, pH 7.4) . Each inhibitor concentration was tested in duplicate. The enzymatic reaction was initiated by adding the dimethyl peptide substrate H3K4 (Anaspec, Ref. 63677), to appK _M KDM1A. After 30 min incubation at 37° C., Amplex Red reagent and horseradish peroxidase (HRP) solution were added to detect H ₂ O ₂ generated in the enzymatic reaction, according to the recommendations provided by the supplier (Invitrogen). The mixture was incubated for 5 minutes at room temperature in the dark and the conversion of Amplex Red reagent to highly fluorescent resorufin was analyzed using an Infinite F200 Tecan fluorescent microplate reader (λexcitation=540 nm, λemission=590 nm). The maximum demethylase activity of KDM1A was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of KDM1A. The IC ₅₀ value for each inhibitor was calculated using GraphPad Prism5 software from a minimum of two independent experiments.

Compound 1 is a KDM1A inhibitor as shown by the mean IC ₅₀ of 101 ± 40 nM obtained in the KDM1A assay described herein.

Example 3: Assessing the Effect of KDM1A Inhibitors on Aggressive Behavior

The effect of the KDM1A inhibitor Compound 1 on aggressive behavior was assessed in male SAMP8 mice using the alien resident (RI) test. The RI test is a standardized way to measure social behavior, in particular aggressive behavior in a semi-natural setting.

3.1 METHOD

The SAM mouse models were developed from the AKR/J mouse strain by Kyoto University. The progeny of SAMP8 showed severe aging and were selected for further distribution and study of these characteristics. The progeny of SAMR1 showed normal aging and was selected as an aging resistant strain.

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 for 5 weeks from 5 months of age and then subjected to the RI test. Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or Compound 1 was administered in drinking water. Vehicle treated SAMR1 mice were included as controls (n=6). All drugs were administered in drinking water and diluted in vehicle. Drug concentration was calculated weekly based on body weight and adjusted based on drinking water intake.

The resident alien test (RI) was performed as follows: the test subject (resident) was kept in its home cage without bedding change for one week. On the day of the study, a significantly younger and smaller object (stranger; 90-day-old mouse C57BL6) was introduced into the resident's home cage. The session (20 minutes) was recorded on video and social interaction (explored parameters: social interaction and nurturing) and aggressive behavior (explored parameters: lateral threats, clinch attacks, restrained behavior and general attacks as the sum of all three measured parameters of aggressive behavior) of the test subject were analyzed by an experimenter who did not participate in the treatment.

Statistical Analysis : Vehicle, SAMR1 and SAMP8 groups were compared by t-test. Among SAMP8 groups, different treatments were compared by one-way ANOVA with Dunnett's test and SNK post-Hoc analysis.

3.2 RESULTS

When the aggressive behavior of SAMP8 mice was compared with that of SAMR1 mice in the RI test, the number of general attacks and in particular clinch attacks was significantly increased in vehicle-treated SAMP8 mice compared to vehicle-treated SAMR1 mice, as shown in Figures 1 and 2 , indicating that male SAMP8 mice exhibit altered (increased) aggressive behavior compared to the SAMR1 control strain. 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. Thus, Compound 1 significantly reduced aggressiveness in SAMP8 mice, correcting the altered aggressive behavior of these animals.

Vehicle-treated SAMP8 animals showed no significant difference compared to vehicle-treated SAMR1 mice in time spent in social interaction. No significant difference was observed in the number of rearing attempts in vehicle-treated SAMP8 mice compared to SAMR1 mice, and Compound 1 treatment did not affect this in SAMP8 mice.

3.3 EFFECT OF KDM1A INHIBITORS ON AGGRESSIVE BEHAVIOR IS NOT A CONSEQUENCE OF SEDATION

To confirm that the effect of Compound 1 on the aggressive behavior of male SAMP8 mice was due to the direct effect of the compound on the aggressiveness of the animals, and not due to the potential sedative effect of the compound, the effect of Compound 1 on anxiety and locomotor activity in male SAMP8 mice was studied using Open Field tests. » (EP) and «Elevated plus maze» (EPM), as described below.

3.3.1 METHOD

Animals (n=8/group) were treated from 5 months of age with vehicle, 0.32 or 0.96 mg/kg/day of Compound 1 and by the 7th month of treatment they were sequentially subjected to OD and PCL tests at one week intervals.

Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or KDM1A inhibitor (Compound 1) was administered in drinking water. Vehicle treated SAMR1 mice were included as controls (n=8). All drugs were administered in drinking water and diluted in vehicle. Drug concentration was calculated weekly based on body weight and adjusted based on drinking water intake.

The OP and PCL tests were performed as follows:

Open field (OP) : A white plastic arena 50 × 50 cm in size with walls 25 cm high was used to analyze spontaneous exploratory behavior. The floor of the device was divided into 25 equal areas. The movements of each animal were recorded on video for 5 min. Motor activity was analyzed by video tracking of captured images using SMART® (v3.0, PanLab, SLU, Spain).

Elevated plus maze (EPM) : The EPL consisted of four arms at right angles to each other, connected to a central platform and supported 50 cm above the floor. The two opposite arms had high walls (closed arms, 30 × 5 × 15 cm), while the other two were open arms (30 × 5 × 0 cm). The animal was placed facing the closed arm and its movements were videotaped for 5 min and analyzed by video tracking using SMART® (v3.0, PanLab, SLU, Spain).

Statistical Analysis : Vehicle, SAMR1 and SAMP8 groups were compared by t-test. Among SAMP8 groups, different treatments were compared by one-way ANOVA with Dunnett's test and SNK post-Hoc analysis.

3.3.2 RESULTS

No significant differences were observed between vehicle-treated SAMR1 mice and vehicle-treated SAMP8 mice in the OD test, and Compound 1 treatment did not significantly affect locomotor activity or time spent in the central zone. SAMP8 mice spent a significantly longer period of time in the open arms of the PCL 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.

Summarizing the above, the data and results obtained in Example 3 show that the KDM1A inhibitor Compound 1, administered at doses well tolerated by mice over a long period of treatment, significantly reduces aggressiveness, but it does not act as a sedative or anxiolytic agent in mice. SAMP8. Thus, Example 3 supports the conclusion that KDM1A inhibitors, in particular Compound 1, can be used to treat behavioral changes such as aggressiveness without causing sedation.

Using the protocol described herein in Example 3, behavioral change improving effects (including, for example, aggressiveness improving effects) can be tested with other KDM1A inhibitors.

Example 4: Assessing the Impact of KDM1A Inhibitors on Social Exclusion

While mice are jealous of their territory, rats are known to be more sociable. To further characterize the therapeutic effects of KDM1A inhibitors such as Compound 1 for the treatment of behavior change, the effect of Compound 1 on social withdrawal, another type of behavior change, was evaluated in rats using a rat isolation rearing model.

In this model, rats are isolated after weaning on postnatal day 21 (PND21) and deprived of the normal environment that conditions their social behavior. Isolation at this stage of rat development can lead to behavioral changes, in particular a lack of interest in social interactions, which can be used as a model for social withdrawal in humans.

4.1 METHOD

Immediately after weaning (postnatal day 21-23), 48 male Sprague-Dawley rats were divided into two groups: control (non-isolated; n=12) contained 3-4 animals per cage; isolated (n=36) 1 animal in a cage. Beginning on postnatal day 61 (PND), isolated adult male rats were treated with vehicle, Compound 1 at 0.16 mg/kg/day or Compound 1 at 0.48 mg/kg/day (n=12/group) in within 5 weeks. Control (non-isolated) animals were treated with vehicle. The route of administration was drinking water and vehicle 1.8% 2-hydroxypropyl-β-cyclodextrin. The drug concentration was adjusted weekly for body weight and water intake. During the last week of treatment, all animals were examined in RI (PND94) to assess social behavior and on another day in the PCL test (PND87-88) to assess anxiety behavior.

The resident alien test (RI) was performed following a protocol similar to that described for mice in Example 3 above, as follows: Briefly, the test subject (resident) was kept in its home cage without changing bedding for one week. On the day of the study (PND94), a significantly younger and smaller object (outsider; a 50-day-old Sprague-Dawley rat) was introduced into the resident's home cage. The session was videotaped for 15 min, and social interaction (measured parameters: active and passive social interaction, avoidance and time without social interaction) and aggressive behavior of the test subject were analyzed by the experimenter, who did not participate in the treatment.

The Elevated Plus Maze (EPM) test was performed following a protocol similar to that described for mice in Example 3 above, as follows: The EPL consisted of four arms at right angles to each other, connected to a central platform and supported on 50 cm above the floor. The two opposite arms had high walls (closed arms, 46.5 × 12 × 42 cm), while the other two were open arms (46.5 × 12 × 0.3 cm). The animal was placed facing the closed arm and its movements were video recorded for 5 min and analyzed by video tracking using SMART® (v2.5.21, PanLab, SLU, Spain).

Statistical analysis : Non-isolated and vehicle isolated groups were compared by t-test. Among isolated groups, different drug therapies were compared by one-way ANOVA with Dunnett's test and SNK post-Hoc analysis.

4.2 RESULTS

The conducted RI test did not reveal aggressive behavior in rats and did not significantly affect active or passive social interaction. However, social avoidance parameters were significantly increased in isolated vehicle-treated rats compared to non-isolated vehicle-treated rats as measured by time without social interaction (Figure 3) and number of arousals (Figure 4). The time without social interaction in isolated rats decreased in a dose-dependent manner with Compound 1 treatment, and the number of arousals, which had been significantly increased in isolated rats, was restored to normal levels (i.e., levels in non-isolated rats) by treatment with Compound 1 (see .Figure 3 and 4).

In the PCL test, no differences were found between isolated vehicle-treated rats and non-isolated vehicle-treated rats. Compound 1 did not have any significant effect on anxiety or locomotor activity in rats as assessed in PCL, indicating that the beneficial effects produced by Compound 1 on social avoidance parameters measured in the RI test are not due to sedation. medicinal product.

Summarizing the above, the data and results obtained in Example 4 show that the KDM1A inhibitor, Compound 1, administered at doses well tolerated by rats over a long period of treatment, corrected behavioral changes, in particular social avoidance, in weaned rats. without causing a sedative effect. Thus, Example 4 further confirms the fact that KDM1A inhibitors, in particular Compound 1, can be used for the (non-sedative) treatment of behavioral changes, including social withdrawal.

Using the protocol described herein in Example 4, behavioral change improvement effects (including, for example, social withdrawal) can be tested with other KDM1A inhibitors.

Example 5: Evaluation of the effect of KDM1A inhibitors using a three-chamber test (TCT) in mice

The KDM1A inhibitor, Compound 1, was also tested in an additional animal model for changes in social behavior, the three-chamber test (TCT). TCT is a widely used method for measuring social behavior in mice and can be used to assess the effects of a compound to treat changes in social interaction using animals exhibiting congenital or acquired social behavior deficits.

In this test, after adapting to a three-chamber arena, the mouse is released into the middle chamber and allowed to explore other compartments. In the adjacent "mouse" compartment, an obedient stimulus mouse is in a mesh container, while in another adjacent compartment, a similar container is located without a stimulus mouse (target compartment). The propensity to approach or avoid a compartment with a stimulus mouse provides a measure of social interaction/sociability behavior. Wild-type mice prefer social interaction and spend more time in the mouse compartment compared to the target compartment.

5.1 METHOD

In this study, 8-month-old female SAMP8 mice were treated with either vehicle (n=9) or 0.96 mg/kg/day of Compound 1 (n=12) for 4 months and then subjected to TCT. Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or Compound 1 (diluted in vehicle) was administered in drinking water. Vehicle treated SAMR1 mice were included as controls (n=11). Drug concentration was calculated weekly based on body weight and adjusted based on drinking water intake.

TCT was performed in a transparent Plexiglas box with three identical serial chambers (15 × 15 × 20 cm) with two identical small metal cages placed in both side chambers. Neighboring chambers were communicated and the animals were free to move from one to the other. The test subject (female SAMR1 or SAMP8 mice) was allowed to explore the device for 5 minutes. This habituation time was controlled so that the animals did not give preference to one of the chambers. Then a new female mouse was introduced into one of the metal cages (mouse chamber) while the other cage was left empty (target chamber). The time spent in each chamber and the time of direct examination of new mice were measured over a total observation time of 10 minutes.

Statistical analysis: The t-test was used to assess the significance of differences in the study of new mice for SAMP8 mice relative to SAMR1 mice and for Compound 1 treated SAMP8 mice relative to vehicle treated SAMP8 mice. 2 ANOVA method was used to evaluate the significance of camera preference. ⃰⃰⃰: р˂0.001.

5.2 RESULTS

The results obtained in this study 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 target chamber. In contrast to SAMR1 control animals, vehicle-treated female SAMP8 mice did not show a preference for the mouse chamber over the target chamber (see Figure 5) and also spent less time testing a new mouse compared to SAMR1 mice (see Figure 6) thus showing shortcomings in social behavior. Treatment of female SAMP8 mice with the KDM1A inhibitor Compound 1 restored both the socialization chamber preference (mouse chamber) (Figure 5) and the time spent on novel mouse testing (Figure 6) in SAMP8 mice to SAMR1 levels. Thus, Compound 1 completely corrected the changes in social interaction/lack of sociability in SAMP8 mice.

The results obtained in Example 5 also show that KDM1A inhibitors such as Compound 1 can be used for the (non-sedative) treatment of social behavior changes.

Using the protocol described herein in Example 5, social behavior change improvement effects can be tested with other KDM1A inhibitors.

All publications, patents and patent applications cited in this specification are hereby incorporated herein by reference in their entirety.

The publications, patents and patent applications referred to in the description are provided solely for their disclosure prior to the filing date of this application. Nothing in this specification should be construed as an admission that they are prior art to the present application.

Although the invention has been described in connection with its specific embodiments, it should be understood that it is capable of further modifications, and this application is intended to cover any variations, uses or adaptations of the invention, following, in general, the principles of the invention and including such departures from the present disclosure. , which are in accordance with known or accepted practice in the technical field to which the invention pertains, and which can be applied to the essential features set forth above and as follows in the appended claims.

Claims (18)

1. A method of treating behavioral change in a patient, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor, wherein the behavioral change in the individual is social withdrawal or aggressiveness. 2. The method of claim 1, wherein the behavior change is social withdrawal. 3. The method of claim 1 wherein the change in behavior is aggressiveness. 4. The method according to any one of paragraphs. 1-3, wherein the patient to be treated is a human. 5. The method according to any one of paragraphs. 1-4, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. 6. The method of any one of claims 1 to 5, wherein the method comprises oral administration of a KDM1A inhibitor. 7. The use of a KDM1A inhibitor for the manufacture of a drug for the treatment of behavior change, where the behavior change in a person is social withdrawal or aggressiveness. 8. The use of claim 7 wherein the change in behavior constitutes social exclusion. 9. Use according to claim 7, wherein the change in behavior is aggressiveness. 10. Use according to any one of claims 7 to 9, wherein the patient to be treated is a human. 11. Use according to any one of claims 7-10, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3 ,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. 12. Use according to any one of claims 7 to 11, wherein the drug is for oral administration. 13. The use of a KDM1A inhibitor for the treatment of behavior change, where the behavior change in a person is social withdrawal or aggressiveness. 14. The use of claim 13 wherein the change in behavior constitutes social exclusion. 15. Use according to claim 13, wherein the change in behavior is aggressiveness. 16. Use according to any one of claims 13 to 15, wherein the patient to be treated is a human. 17. Use according to any one of claims 13-16, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3 ,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. 18. Use according to any one of claims 13-17, wherein the KDM1A inhibitor is administered orally.

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