Methods of treating marginal personality disorders

Abstract

Provided herein are methods of treating marginal personality disorders using a KDM1A inhibitor, in particular vafidinostat.

Description

[0001] This application is a divisional application of International Application No. PCT / EP2020 / 057803, filed on March 20, 2020, entitled “Methods of treating borderline personality disorder”, which entered the Chinese national phase on September 18, 2021, and has application number 202080022896.7. TECHNICAL FIELD

[0002] The present invention relates to methods of treating borderline personality disorder. BACKGROUND

[0003] Borderline personality disorder (BPD) is one of the most complex, functionally debilitating, and costly mental illnesses currently facing the mental health system. BPD is characterized by impairment in personality functioning and the presence of pathological personality traits. Individuals with BPD typically experience emotional instability, impulsivity, irrational beliefs, and distorted perceptions, as well as intense but unstable relationships with others. Up to 10% of those affected die by suicide. Diagnosed women are about three times more likely than men.

[0004] Treatment of BPD remains a medical challenge. There are currently no FDA-approved medications that specifically treat BPD. Medications such as mood stabilizers and atypical antipsychotics are used off-label for the treatment of BPD, but their efficacy is questionable and they have unwanted side effects such as sedation and weight gain.

[0005] Accordingly, there is a strong and unmet medical need for new and / or improved medications for the treatment of BPD, particularly medications that act through new mechanisms of action and treat core features of BPD, and that have a more favorable side effect profile than current off-label use of non-specific medications. The present invention addresses these and other needs. SUMMARY

[0006] The present invention provides new methods of treating borderline personality disorder using KDM1A inhibitors.

[0007] Accordingly, the present invention provides KDM1A inhibitors for use in the treatment of borderline personality disorder.

[0008] The present invention further provides methods of treating borderline personality disorder in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0009] The present invention further provides the use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of borderline personality disorder.

[0010] The present application further provides the use of a KDM1A inhibitor in the treatment of borderline personality disorder.

[0011] In preferred embodiments, the KDM1A inhibitor is vafidemstat, or a pharmaceutically acceptable salt or solvate thereof. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 Effect of treatment with the KDM1A inhibitor vafidemstat (as defined herein and in Example 1) on aggression in human BPD patients is shown as statistically significant reduction in the aggression-related BPDCL domain summary score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with vafidemstat), as described in more detail in Example 3. Data are expressed as mean ± standard error of the mean (SEM); p = 0.0029.

[0013] Figure 2 Efficacy of the KDM1A inhibitor vafidemstat treatment of BPD is shown as statistically significant reduction in the BPD Checklist (BPDCL) total score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with vafidemstat), as described in more detail in Example 3. Data are expressed as mean ± SEM; p = 0.0048.

[0014] Figure 3 Treatment with vafidemstat resulted in statistically significant reduction in the non-aggression-related BPDCL domain summary score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of treatment with vafidemstat), as described in more detail in Example 3. Data are expressed as mean ± SEM; p = 0.0234. DETAILED DESCRIPTION

[0015] The present application is based on the unexpected finding that KDM1A inhibitors are useful as therapeutic agents for the treatment of BPD. KDM1A inhibitors, including vafidemstat, have been reported to be useful for reducing aggression, e.g. disease-related aggression, without sedation. Vafidemstat is currently in a phase Ila clinical trial for the treatment of aggression in Alzheimer’s disease, Lewy body dementia, autism spectrum disorder, attention deficit hyperactivity disorder, and BPD patients (REIMAGINE trial). The results of this clinical trial unexpectedly demonstrated that vafidemstat is not only effective for the treatment of aggression in BPD patients, but also exhibits additional therapeutic effects on BPD, as detailed below and in the examples. KDM1A inhibitors, in particular vafidemstat, are useful for the treatment of BPD, including the treatment of the (non-aggressive) core features of BPD, as defined below.

[0016] Accordingly, the present application provides KDM1A inhibitors for use in the treatment of BPD.

[0017] The present application further provides a method of treating BPD in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0018] The present application further provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of BPD.

[0019] The present application further provides the use of a KDM1A inhibitor in the treatment of BPD.

[0020] In some embodiments, the present application provides KDM1A inhibitors for use in the treatment of BPD by treating one or more core features of BPD.

[0021] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or ameliorating) one or more core features of BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0022] In some embodiments, the present application provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or ameliorating) one or more core features of BPD.

[0023] In some embodiments, the present application provides the use of a KDM1A inhibitor in the treatment of BPD by treating (e.g., reducing or ameliorating) one or more core features of BPD.

[0024] According to the present application, "core features of BPD" refer to the essential features of BPD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association, which include impairment in personality (self and interpersonal) functioning and presence of pathological personality traits.

[0025] In some embodiments, the present application provides KDM1A inhibitors for use in the treatment of BPD by treating (e.g., reducing or ameliorating) one or more non-aggressive symptoms of BPD.

[0026] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or ameliorating) one or more non-aggressive symptoms of BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0027] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0028] In some embodiments, the present application provides use of a KDM1A inhibitor in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0029] According to the present application, "non-aggressive" as used, for example, in the context of symptoms of BPD, means that the symptoms of BPD are not directly related to aggression or aggressive behavior, or are not related to aggression or aggressive behavior. As used herein, "aggression," "aggressive," and related terms refer to any kind of abnormal, pathological, or inappropriate aggressive or violent behavior, hostility, or agitation, for example, physical or verbal, including interpersonal aggression (i.e., toward other individuals) and / or self-aggression (i.e., self-aggression).

[0030] Examples of non-aggressive symptoms of BPD include mood swings, irrational beliefs, intense but unstable relationships with others, abandonment, identity disturbance, emptiness, and dissociation.

[0031] In some embodiments, the present application provides a KDM1A inhibitor for use in treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0032] In some embodiments, the present application provides a method of treating BPD in a patient (preferably a human) by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0033] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0034] In some embodiments, the present application provides use of a KDM1A inhibitor in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0035] In some embodiments, the present application provides a KDM1A inhibitor for use in treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0036] In some embodiments, the present application provides a method of treating BPD in a patient (preferably a human) by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0037] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0038] In some embodiments, the present application provides use of a KDM1A inhibitor in treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0039] In some embodiments, the present application provides a KDM1A inhibitor for use in treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0040] In some embodiments, the present application provides a method of treating BPD in a patient (preferably a human) by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0041] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0042] In some embodiments, the present application provides use of a KDM1A inhibitor in treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0043] In some embodiments, the present application provides a KDM1A inhibitor for use in treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0044] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0045] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0046] In some embodiments, the present application provides use of a KDM1A inhibitor in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0047] In some embodiments, the present application provides a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0048] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0049] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0050] In some embodiments, the present application provides use of a KDM1A inhibitor in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0051] In some embodiments, the present application provides a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0052] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0053] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0054] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0055] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0056] In some embodiments, the present application provides a method of treating a patient (preferably a human) with BPD by treating (e.g., reducing or improving) one or more core features of BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0057] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0058] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0059] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0060] In some embodiments, the present application provides a method of treating a patient (preferably a human) with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0061] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0062] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0063] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0064] In some embodiments, the present application provides a method of treating a patient (preferably a human) with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0065] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0066] In some embodiments, the present application provides use of a KDM1A inhibitor in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0067] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0068] In some embodiments, the present application provides a method of treating a patient (preferably a human) with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression, the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0069] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0070] In some embodiments, the present application provides use of a KDM1A inhibitor in treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0071] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0072] In some embodiments, the present application provides a method of treating a patient, preferably a human, with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0073] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0074] In some embodiments, the present application provides use of a KDM1A inhibitor in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0075] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0076] In some embodiments, the present application provides a method of treating a patient, preferably a human, with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0077] In some embodiments, the present application provides use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0078] In some embodiments, the present application provides use of a KDM1A inhibitor in treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0079] In some embodiments, the present application provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0080] In some embodiments, the present application provides a method of treating a patient, preferably a human, with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0081] In some embodiments, the present application provides a use of a KDM1A inhibitor in the manufacture of a medicament for treating a BPD patient by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0082] In some embodiments, the present application provides a use of a KDM1A inhibitor in treating a BPD patient by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0083] In some embodiments, the present application provides a KDM1A inhibitor for treating a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0084] In some embodiments, the present application provides a method of treating a BPD patient (preferably a human) by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0085] In some embodiments, the present application provides a use of a KDM1A inhibitor in the manufacture of a medicament for treating a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0086] In some embodiments, the present application provides a use of a KDM1A inhibitor in treating a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0087] In some embodiments, the present application provides a KDM1A inhibitor for use in treating one or more core features of BPD.

[0088] In some embodiments, the present application provides a method of treating one or more core features of BPD in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0089] In some embodiments, the present application provides a use of a KDM1A inhibitor in the manufacture of a medicament for treating one or more core features of BPD.

[0090] In some embodiments, the present application provides a use of a KDM1A inhibitor in treating one or more core features of BPD.

[0091] In some embodiments, the present application provides a KDM1A inhibitor for use in the treatment of one or more non-aggressive symptoms of BPD.

[0092] In some embodiments, the present application provides a method for the treatment of one or more non-aggressive symptoms of BPD in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0093] In some embodiments, the present application provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of one or more non-aggressive symptoms of BPD.

[0094] In some embodiments, the present application provides the use of a KDM1A inhibitor in the treatment of one or more non-aggressive symptoms of BPD.

[0095] In some embodiments, the present application provides a KDM1A inhibitor for use in the treatment of one or more core features of BPD, as well as agitation and / or aggression.

[0096] In some embodiments, the present application provides a method for the treatment of one or more core features of BPD, as well as agitation and / or aggression in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0097] In some embodiments, the present application provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of one or more core features of BPD, as well as agitation and / or aggression.

[0098] In some embodiments, the present application provides the use of a KDM1A inhibitor in the treatment of one or more core features of BPD, as well as agitation and / or aggression.

[0099] In some embodiments, the present application provides a KDM1A inhibitor for use in the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression.

[0100] In some embodiments, the present application provides a method for the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

[0101] In some embodiments, the present application provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression.

[0102] In some embodiments, the present application provides the use of a KDM1A inhibitor in the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression.

[0103] Also provided herein are KDM1A inhibitors for use in treating (e.g., reducing) agitation in BPD. Also, provided herein are KDM1A inhibitors for use in treating (e.g., reducing) agitation in a patient with BPD. Also provided herein are KDM1A inhibitors for use in treating a patient with BPD by treating (e.g., reducing) agitation. Also provided herein are methods of treating (e.g., reducing) agitation in a patient (preferably a human) with BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Also, provided herein is the use of a KDM1A inhibitor in the preparation of a medicament for treating (e.g., reducing) agitation in BPD. Also provided herein is the use of a KDM1A inhibitor in the treatment (e.g., reduction) of agitation in BPD.

[0104] Further, provided herein are KDM1A inhibitors for use in treating (e.g., reducing) aggression in BPD. Also, provided herein are KDM1A inhibitors for use in treating (e.g., reducing) aggressive behavior in a patient with BPD. Also provided herein are KDM1A inhibitors for use in treating a patient with BPD by treating (e.g., reducing) aggression. Also provided herein are methods of treating (e.g., reducing) aggression in a patient (preferably a human) with BPD, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Also, provided herein is the use of a KDM1A inhibitor in the preparation of a medicament for treating (e.g., reducing) aggression in BPD. Also provided herein is the use of a KDM1A inhibitor in the treatment (e.g., reduction) of aggression in BPD.

[0105] In the therapeutic methods and therapeutic uses described herein, in principle any KDM1A inhibitor can be used, including the KDM1A inhibitors described in more detail below. However, the KDM1A inhibitor that is preferred for use in the methods and uses of the application is the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine, also known as (41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine, valifibrostar (INN) or ORY-2001, or a pharmaceutically acceptable salt or solvate thereof, and particularly preferred the KDM1A inhibitor is the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine (non-salt form). The names “5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine”, “(41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine”, “valifibrostar” or “ORY-2001” are used interchangeably herein.

[0106] Thus, the present application provides valifibrostar or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of BPD.

[0107] The present application further provides a method of treating BPD in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of valifibrostar or a pharmaceutically acceptable salt or solvate thereof.

[0108] The present application further provides the use of valifibrostar or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of BPD.

[0109] The present application further provides the use of valifibrostar or a pharmaceutically acceptable salt or solvate thereof in the treatment of BPD.

[0110] In some embodiments, the present application provides valifibrostar or a pharmaceutically acceptable salt or solvate thereof for use in treating BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0111] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more core features of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0112] In some embodiments, the present application provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0113] In some embodiments, the present application provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0114] In some embodiments, the present application provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0115] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0116] In some embodiments, the present application provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0117] In some embodiments, the present application provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0118] In some embodiments, the present application provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0119] In some embodiments, the present application provides a method of treating BPD in a patient, preferably a human, by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments, the application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0121] In some embodiments, the application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0122] In some embodiments, the application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0123] In some embodiments, the application provides a method of treating BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0124] In some embodiments, the application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0125] In some embodiments, the application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0126] In some embodiments, the application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0127] In some embodiments, the application provides a method of treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0129] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0130] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0131] In some embodiments, the present application provides a method of treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0133] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0134] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0135] In some embodiments, the present application provides a method of treating BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0136] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0137] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0138] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0139] In some embodiments, the present application provides a method of treating BPD in a patient (preferably a human) by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0141] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0142] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a BPD patient by treating (e.g., reducing or improving) one or more core features of BPD.

[0143] In some embodiments, the present application provides a method of treating a BPD patient (preferably a human) by treating (e.g., reducing or improving) one or more core features of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0145] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD.

[0146] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0147] In some embodiments, the present application provides a method for treating a patient, preferably a human, with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0148] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0149] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD.

[0150] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0151] In some embodiments, the present application provides a method for treating a patient, preferably a human, with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

[0153] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0154] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0155] In some embodiments, the present application provides a method of treating (preferably a human) patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression, said method comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0156] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0157] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of a BPD patient by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

[0158] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a BPD patient by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0159] In some embodiments, the present application provides a method of treating (preferably a human) patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation, said method comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0160] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a BPD patient by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0161] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

[0162] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0163] In some embodiments, the present application provides a method of treating (preferably a human) patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation, said method comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0164] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0165] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

[0166] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0167] In some embodiments, the present application provides a method of treating (preferably a human) patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression, said method comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0168] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a patient with BPD by treating (e.g., reducing or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

[0169] In some embodiments, the present invention provides the use of valfedestator or a pharmaceutically acceptable salt or solvate thereof in treating patients with BPD by treating (e.g., alleviating or improving) one or more core characteristics of BPD and by treating (e.g., reducing) agitation and aggression.

[0170] In some embodiments, the present invention provides valfedestatin or a pharmaceutically acceptable salt or solvate thereof, which treats patients with BPD by treating (e.g., reducing or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0171] In some embodiments, the present invention provides a method for treating a patient with BPD (preferred) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, the method comprising administering to the patient a therapeutically effective amount of valfedatestat or a pharmaceutically acceptable salt or solvate thereof.

[0172] In some embodiments, the present invention provides the use of valfedestatin or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating patients with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0173] In some embodiments, the present invention provides the use of valfedestatin or a pharmaceutically acceptable salt or solvate thereof in treating patients with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

[0174] In some embodiments, the present invention provides valfedestatin or a pharmaceutically acceptable salt or solvate thereof, which has one or more core features for the treatment of BPD.

[0175] In some embodiments, the present invention provides a method for treating BPD in a patient (preferred person) with one or more core features, the method comprising administering to the patient a therapeutically effective amount of valfedestatin or a pharmaceutically acceptable salt or solvate thereof.

[0176] In some embodiments, the present invention provides the use of valfedestatin or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating one or more core features of BPD.

[0177] In some embodiments, the present invention provides the use of valfedestatin or a pharmaceutically acceptable salt or solvate thereof in one or more core features of the treatment of BPD.

[0178] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of one or more non-aggressive symptoms of BPD.

[0179] In some embodiments, the present application provides a method for the treatment of one or more non-aggressive symptoms of BPD in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0180] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more non-aggressive symptoms of BPD.

[0181] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of one or more non-aggressive symptoms of BPD.

[0182] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of one or more core features of BPD, together with agitation and / or aggression.

[0183] In some embodiments, the present application provides a method for the treatment of one or more core features of BPD, together with agitation and / or aggression, in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0184] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of one or more core features of BPD, together with agitation and / or aggression.

[0185] In some embodiments, the present application provides the use of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of one or more core features of BPD, together with agitation and / or aggression.

[0186] In some embodiments, the present application provides vafidemstat, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of one or more non-aggressive symptoms of BPD, together with agitation and / or aggression.

[0187] In some embodiments, the present application provides a method for the treatment of one or more non-aggressive symptoms of BPD, together with agitation and / or aggression, in a patient, preferably a human, comprising administering to the patient a therapeutically effective amount of vafidemstat, or a pharmaceutically acceptable salt or solvate thereof.

[0188] In some embodiments, the present application provides the use of a KDM1A inhibitor, e.g., vecameritaset, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression.

[0189] In some embodiments, the present application provides the use of a KDM1A inhibitor, e.g., vecameritaset, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and / or aggression.

[0190] Preferably, the KDM1A inhibitor, e.g., vecameritaset, or a pharmaceutically acceptable salt or solvate thereof, for use in the therapeutic methods and uses described herein is administered orally. Exemplary formulations for oral administration can be described in further detail below.

[0191] As mentioned above, in preferred embodiments the present application provides the compound vecameritaset, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of BPD. Thus, the present application relates to the compound vecameritaset as a free base (non-salt form) for use in the treatment of BPD, and in addition, the present application relates to a pharmaceutically acceptable salt or solvate of vecameritaset for use in the treatment of BPD.

[0192] As shown in the Examples, it was unexpectedly found in the context of the present application that KDM1A inhibitors, such as vecameritaset, can be used in the treatment of BPD. As part of a Phase Ila clinical trial, the KDM1A inhibitor vecameritaset was evaluated as a treatment for aggression in human patients with a range of CNS disorders, and it has been shown that vecameritaset significantly reduces aggressive behavior in patients with BPD, as shown in Examples 3 and Figure 1 As shown in Examples 3 and Figure 1 As shown in Examples 3 and Figure 2 and 3As shown in the Examples, it has surprisingly been found that in addition to a therapeutic effect on aggression, treatment with a KDM1A inhibitor valifepate has a significant improvement on total BPD and non-aggressive BPD features, as shown by statistically significant reductions in the BPDCL total score (as shown in Figure 2 Example 4) and the non-aggressive composite score (as shown in Figure 3 Example 4) after 8 weeks of treatment. These results demonstrate that KDM1A inhibitors, including valifepate, have a broad therapeutic effect in BPD, which goes beyond the therapeutic effect on aggression in BPD patients, and thus can be used to treat BPD, including the core features of BPD as defined above.

[0193] KDM1A inhibitors

[0194] A KDM1A inhibitor as used herein is a compound which inhibits KDM1A, in particular human KDM1A.

[0195] All types of KDM1A inhibitors can be used in the methods and uses of the present application.

[0196] Preferably, the KDM1A inhibitor used in the methods and uses according to the present application is a small molecule. Irreversible and reversible KDM1A inhibitors have been reported and can be used according to the present application. Irreversible KDM1A inhibitors exert their inhibitory activity by covalently binding to the FAD co-factor within the active site of KDM1A and are typically based on a 2-cycloalkyl-cyclopropylamino moiety, such as a 2-(hetero)aryl cyclopropylamino group. Reversible inhibitors of KDM1A have also been disclosed.

[0197] Non-limiting examples of KDM1A inhibitors that can be used in accordance with the present application have been disclosed, 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, WO2012 / 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, CN103054869, WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 123465, WO2015 / 156417, WO2015 / 181380, WO2016 / 123387, WO2016 / 130952, WO2016 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2012 / 071469, WO2013 / 033688, WO2014 / 085613, 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, WO2017 / 004519, WO2017 / 027678, WO2017 / 079476, WO2017 / 079670, WO2017 / 090756, WO2017 / 109061, WO2017 / 116558, WO2017 / 114497,CN106432248, CN106478639, CN106831489, CN106928235, CN105985265, WO2017 / 149463, WO2017 / 157322, WO2017 / 195216, WO2017 / 198780, WO2017 / 215464, WO2018 / 081342, WO2018 / 081343, US2017-0283397, WO2019 / 009412, WO2018 / 234978, WO2018 / 226053, WO2018 / 216800, WO2018 / 213211, WO2018 / 137644, and,

[0198]

[0199]

[0200]

[0201] 5-{(1R,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl}-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide (TAK-418);

[0202] 3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide (T-448); or

[0203] 3-((1S,2R)-2-(cyclopropylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide;

[0204] This includes any of its optically active stereoisomers, or any pharmaceutically acceptable salts or solvates thereof. Any of the above compounds comprising a 1,2-substituted cyclopropyl ring may be used in the form of the corresponding trans isomer (where the two substituents on the cyclopropyl ring are in the trans configuration), or in the form of any corresponding particular trans isomer (where the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the figure; or where the two substituents on the cyclopropyl ring each have opposite absolute configurations as shown in the figure).

[0205] Other non-limiting examples of KDM1A inhibitors for use according to the present application 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 29Sep 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 23Dec 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 Mould 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 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, Web Release 20-Jun-2015, doi: 10.1016 / j.bmcl.2015.06.054.

[0206] WO2010 / 143582, US2010-0324147, WO2011 / 131576, WO2012 / 135113, WO2013 / 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 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2014 / 164867 WO2017 / 027678, WO2017 / 079476, WO2017 / 109061, WO2017 / 116558, WO2017 / 114497, CN106831489; WO2018 / 137644, WO2018 / 226053, WO2019 / 009412, 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; VRodriguez et al., Med. Chem. Commun., 2015, 6, 665-670 DOI: 10.1039 / C4MD00507D, Epub 23 Dec 2014; or PVianello et al., Eur J Med Chem. 2014, 86:352-63. doi: 10.1016 / j.ejmech.2014.08.068. Epub 2014 Aug 27, and.

[0207]

[0208]

[0209]

[0210] 5-{(1R,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl}-N-(tetrahydro-2H-pyran-4- yl)thiophene-3-carboxamide (TAK-418);

[0211] 3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2- yl)benzamide (T-448); or

[0212] 3-((1S,2R)-2-(cyclopropylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2- yl)benzamide;

[0213] including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. Any of the above compounds comprising a 1,2-substituted cyclopropyl ring can be used in the form of the corresponding trans isomer (wherein the two substituents on the cyclopropyl ring are in the trans configuration), or in the form of any one of the corresponding specific trans isomers (wherein the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the structure; or wherein the two substituents on the cyclopropyl ring each have the opposite absolute configuration as shown in the structure).

[0214] Reversible KDM1A inhibitors useful in the methods / uses of the application include, but are not limited to, any of the compounds disclosed in 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 / 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, WO2017 / 004519, WO2017 / 079670, WO2017 / 090756, CN106432248, CN106478639, CN106928235, WO2018 / 234978, WO2018 / 216800, WO2018 / 213211, and

[0215]

[0216] including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof.

[0217] In some embodiments, in the methods and uses according to the application, the KDM1A inhibitor is a non-reversible KDM1A inhibitor, preferably a 2-(hetero)arylcyclopropylamino KDM1A inhibitor. As used herein, a "2-(hetero)arylcyclopropylamino KDM1A inhibitor" or "2-(hetero)arylcyclopropylamino compound" refers to a KDM1A inhibitor whose chemical structure includes a cyclopropyl ring substituted at position 1 with an amino group, which is optionally substituted, and at position 2 with an aryl or heteroaryl group (wherein the aryl or heteroaryl group is optionally substituted).

[0218] 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.

[0219] A particularly preferred KDM1A inhibitor for use in the methods and uses of the application is vafidemstat (i.e. 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine) or a pharmaceutically acceptable salt or solvate thereof.

[0220] Other KDM1A inhibitors that can be used in the methods and uses of the application include:

[0221] 5-{(1R,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl}-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide (TAK-418);

[0222] 3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide (T-448);

[0223] 3-((1S,2R)-2-(cyclopropylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide;

[0224] (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine (iadademstat);

[0225] (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0226] (trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0227] (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0228] N1-((trans)-2-(thiazol-5-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0229] N1-((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0230] N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0231] N1-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0232] N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0233] 4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanol;

[0234] 4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamide;

[0235] 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;

[0236] N1-((trans)-2-(4'-chloro-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0237] N1-((trans)-2-(3'-chloro-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0238] 4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-ol;

[0239] N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1'-biphenyl]-3-yl)methanesulfonamide;

[0240] N1-((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0241] N1-((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0242] N1-((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0243] N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0244] 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;

[0245] N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;

[0246] N1-((trans)-2-(3'-(trifluoromethyl)-[1,1 '-biphenyl]-4-yl)cyclopropyl)cyclobutane-1,3-diamine;

[0247] N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0248] N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1 H-indene-1,3-diamine;

[0249] N1-((trans)-2-(3'-(trifluoromethyl)-[1,1 '-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1 H-indene-1,3-diamine; N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1 H-indene-1,3-diamine;

[0250] N1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0251] N1-((1 S,2S)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0252] N1-((1 R,2R)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0253] 1 -methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0254] 4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexanamine;

[0255] N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine;

[0256] N1-((cis)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0257] (4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)carbamic acid tert-butyl ester;

[0258] 1 -ethyl-3-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)urea;

[0259] 4-morpholino-N-((trans)-2-phenylcyclopropyl)cyclohexanamine;

[0260] N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0261] N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine;

[0262] N1-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0263] N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0264] 4-(2-((4-aminocyclohexyl)amino)cyclopropyl)phenol;

[0265] N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0266] N1-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0267] N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0268] N1-(2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0269] (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;

[0270] (trans)-N1-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0271] (cis)-N1-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0272] (trans)-N1-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0273] N1-((trans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0274] N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0275] N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0276] N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0277] 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol;

[0278] 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenol;

[0279] 3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5- methoxybenzonitrile;

[0280] 5-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-2- methylphenol;

[0281] N-(4'-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-6-methoxy-[1,1'- biphenyl]-3-yl)methanesulfonamide;

[0282] N-(3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)- 2-cyanobenzenesulfonamide;

[0283] 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;

[0284] N1-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0285] N1-((trans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane- 1,4-diamine;

[0286] N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0287] N1-((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0288] 3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)amino)benzonitrile;

[0289] N1-((trans)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0290] N1-((trans)-2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine;

[0291] N1-((trans)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0292] N1-((trans)-2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0293] N1-((trans)-2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0294] N1-((trans)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0295] N1-((trans)-2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine;

[0296] (cis)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0297] (trans)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0298] (cis)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0299] (trans)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0300] (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;

[0301] (trans)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0302] (cis)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0303] (trans)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0304] (cis)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0305] (trans)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0306] (cis)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0307] (trans)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclobutane-1,3-diamine;

[0308] (cis)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0309] (trans)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0310] (cis)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0311] (trans)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;

[0312] (cis)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0313] (trans)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0314] (cis)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0315] (trans)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0316] 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;

[0317] (trans)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0318] (cis)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0319] (trans)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;

[0320] N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

[0321] N-((1S,2R)-2-phenylcyclopropyl)piperidin-4-amine;

[0322] N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine;

[0323] N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

[0324] N-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

[0325] N-((trans)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

[0326] N-((trans)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

[0327] N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4- amine;

[0328] N-((trans)-2-phenylcyclopropyl)piperidin-3-amine;

[0329] N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-3- amine;

[0330] N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-3-amine;

[0331] N-((trans)-2-phenylcyclopropyl)pyrrolidin-3-amine;

[0332] N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)pyrrolidin-3- amine;

[0333] N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)pyrrolidin-3-amine;

[0334] N-((trans)-2-phenylcyclopropyl)azetidin-3-amine;

[0335] N-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)azetidin-3- amine;

[0336] N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)azetidin-3-amine;

[0337] N-((trans)-2-phenylcyclopropyl)azepan-3-amine;

[0338] N-((trans)-2-phenylcyclopropyl)-8-azabicyclo[3.2.1]octan-3-amine;

[0339] N-((trans)-2-phenylcyclopropyl)-3-azabicyclo[3.2.1]octan-8-amine;

[0340] N-((trans)-2-phenylcyclopropyl)decahydroquinolin-4-amine;

[0341] N-((trans)-2-phenylcyclopropyl)-1,2,3,4-tetrahydroquinolin-4-amine;

[0342] N-((trans)-2-phenylcyclopropyl)-3-azaspiro[5.5]undecan-9-amine;

[0343] N-((trans)-2-phenylcyclopropyl)-2-azaspiro[4.5]decane-8-amine;

[0344] N-((trans)-2-phenylcyclopropyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-amine;

[0345] N-((1S,2R)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

[0346] N-((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)piperidin-4-amine;

[0347] N-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

[0348] N-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)piperidin-4-amine;

[0349] N-((1S,2S)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

[0350] N-((1R,2R)-2-(thiazol-5-yl)cyclopropyl)piperidin-4-amine;

[0351] N-((1S,2R)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

[0352] N-((1R,2S)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)piperidin-4-amine;

[0353] N-((trans)-2-phenylcyclopropyl)-7-azaspiro[3.5]nonan-2-amine;

[0354] N-(2-(o-tolyl)cyclopropyl)piperidin-4-amine;

[0355] N-(2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

[0356] N-(2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine;

[0357] N-(2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

[0358] N-(2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

[0359] N-(2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

[0360] 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)propane-2-sulfonamide; 1-(methylsulfonyl)-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

[0361] 1-(4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidin-1-yl)ethanone;

[0362] 4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)piperidine-1-carboxamide;

[0363] N-((trans)-2-(4-bromophenyl)cyclopropyl)tetrahydro-2H-pyran-4-amine;

[0364] 2,2,6,6-tetramethyl-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

[0365] 1-methyl-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

[0366] 1-isopropyl-N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

[0367] N-((trans)-2-phenylcyclopropyl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine;

[0368] N-((trans)-2-phenylcyclopropyl)-1-(pyridin-4-yl)piperidin-4-amine;

[0369] 4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide;

[0370] N-((trans)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

[0371] N-((1S,2S)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

[0372] N-((1R,2R)-2-fluoro-2-phenylcyclopropyl)piperidin-4-amine;

[0373] N-((trans)-2-(naphthalen-2-yl)cyclopropyl)piperidin-4-amine;

[0374] N-((trans)-2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

[0375] N-((trans)-2-(o-tolyl)cyclopropyl)piperidin-4-amine;

[0376] N-((trans)-2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

[0377] N-((trans)-2-(3,4-difluorophenyl)cyclopropyl)piperidin-4-amine;

[0378] N-((trans)-2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

[0379] (trans)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0380] (trans)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

[0381] (trans)-2-phenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine;

[0382] (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;

[0383] (trans)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0384] (trans)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

[0385] (trans)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0386] (trans)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

[0387] (trans)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0388] (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;

[0389] (1S,2R)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0390] (1R,2S)-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0391] (1S,2R)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

[0392] (1R,2S)-2-phenyl-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

[0393] (1S,2R)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

[0394] (1R,2S)-N-(piperidin-4-ylmethyl)-2-(pyridin-3-yl)cyclopropanamine;

[0395] (1S,2S)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0396] (1R,2R)-N-(piperidin-4-ylmethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0397] (1S,2R)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

[0398] (1R,2S)-N-(piperidin-4-ylmethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

[0399] (1S,2R)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0400] (1R,2S)-2-(4-(benzyloxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0401] (1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

[0402] (1R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(pyridin-3-yl)cyclopropanamine;

[0403] (1S,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0404] (1R,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(thiazol-5-yl)cyclopropanamine;

[0405] (1S,2R)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

[0406] (1R,2S)-N-(2-(piperidin-4-yl)ethyl)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropanamine;

[0407] (1S,2R)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

[0408] (1R,2S)-2-(4-(benzyloxy)phenyl)-N-(2-(piperidin-4-yl)ethyl)cyclopropanamine;

[0409] (trans)-2-phenyl-N-(pyrrolidin-3-ylmethyl)cyclopropanamine;

[0410] (trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0411] (trans)-N-(azetidin-3-ylmethyl)-2-phenylcyclopropanamine;

[0412] (trans)-2-(4-cyclopropylphenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0413] (trans)-N-(piperidin-4-ylmethyl)-2-(4-(pyridin-3-yl)phenyl)cyclopropanamine;

[0414] (trans)-2-(4-(1H-pyrazol-5-yl)phenyl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0415] (trans)-2-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0416] 2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0417] (trans)-2-methyl-2-phenyl-N-(piperidin-4-ylmethyl)cyclopropanamine;

[0418] (trans)-2-(4-(benzyloxy)phenyl)-N-((1-methylpiperidin-4-yl)methyl)cyclopropanamine;

[0419] 4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (GSK2879552);

[0420] 1 -((4-(methoxymethyl)-4-(((1 R,2S)-2-phenylcyclopropylamino)methyl)piperidin- 1 - yl)methyl)cyclobutanecarboxylic acid;

[0421] N-[(2S)-5-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1 -(4-methylpiperazin- 1 -yl)-1 -oxopentan-2-yl]-4-(1 H-1,2,3-triazol-1 -yl)benzamide;

[0422] 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6- dihydro-pyrimidin-4-yl]-2-fluorobenzonitrile;

[0423]

[0424] including any optically active stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0425] Pharmaceutical formulations

[0426] While it is possible for KDM1A inhibitors, such as valifibrosta, to be administered directly as such for treatment, it is common to administer as a pharmaceutical composition comprising the compound as an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients or carriers.

[0427] In this specification, any reference to a KDM1A inhibitor includes reference to the compound itself, i.e. in non-salt form (e.g. as a free base) or to the corresponding compound in any pharmaceutically acceptable salt or solvate form, as well as to a pharmaceutical composition comprising said compound and one or more pharmaceutically acceptable excipients or carriers.

[0428] A KDM1A inhibitor can be administered by any method that achieves the intended purpose. Examples include by oral, parenteral (including, for example, intravenous, subcutaneous or intracerebral) or topical routes.

[0429] For oral delivery, the compounds can be incorporated into formulations which include pharmaceutically acceptable carriers, such as binding agents (e.g., gelatin, cellulose, tragacanth, excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrants (e.g., alginates, gum, corn starch), sweetening or flavoring agents (e.g., dextrose, sucrose, saccharin, methyl salicylate, peppermint). The formulations can be delivered orally, for example, in the form of a sealed gelatin capsule or compressed tablet. The capsules and tablets can be prepared by any conventional technique. The 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. Additionally, a liquid carrier such as a fatty oil can be included in the capsule.

[0430] Suitable oral formulations can also be in the form of suspensions, syrups, chewing gum, wafer, elixirs, and the like. If desired, conventional agents for altering the flavor, taste, color and shape of the particular form can also be included. Additionally, to facilitate administration by enteral feeding tubes in patients who are unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil carrier such as olive oil, corn oil and safflower oil.

[0431] The compounds can also be administered parenterally, in the form of a solution or suspension, or in a lyophilized form for reconstitution with a suitable diluent or pharmaceutical carrier vehicle prior to use. In such formulations, diluents or pharmaceutically acceptable carriers can be used, such as sterile water and physiological saline buffer. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surface active agents and antioxidants can also be included. For example, useful components include sodium chloride, acetate, citrate or phosphate buffers, glycerol, dextrose, fixed oils, methyl paraben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid and the like. The parenteral formulations can be stored in any conventional container, such as vials and ampules.

[0432] For topical administration, the compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants and stabilizers can be included in the formulation. Examples of these agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax or mineral oil, lanolin, squalene and the like. One particular form of topical administration is through a transdermal patch. Methods for preparing transdermal patches are disclosed, for example, in (1986) Ann. in Brown et al. (1988) Ann. Rev. Med. 39:221-229, which are incorporated herein by reference.

[0433] Subcutaneous implantation of sustained-release compounds can also be a suitable route of administration. This requires surgical implantation of the active compound in any suitable formulation into a subcutaneous space, such as 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 sustained release of active compounds. Hydrogels are generally known in the art. They are typically prepared by crosslinking a high molecular weight biocompatible polymer into a network that expands in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of this invention, hydrogels made of polyethylene glycol, collagen, or poly(glycosyl-co-L-lactic acid) may be useful. See, for example, Phillips et al. (1984) J. Pharmaceut. Sci., 73:1718-1720.

[0434] This compound can also be conjugated with water-soluble, non-immunogenic, non-peptide high molecular weight polymers to form polymeric conjugates. For example, the compound can be covalently linked with polyethylene glycol to form a conjugate. Typically, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Therefore, when administered to patients, the compound in the conjugate has a longer half-life in vivo and shows better efficacy. See Burnham (1994) Am. J. Hosp. Pharm. 15:210-218. PEGylated proteins are currently used for protein replacement therapy and other therapeutic applications. For example, PEGylated interferon (PEG-INTRON). Clinically used to treat hepatitis B. Polyethylene glycol-modified adenosine deaminase. Used to treat severe combined immunodeficiency disease (SCIDS). Polyethylene glycol-modified L-asparaginase This compound is intended for the treatment of acute lymphoblastic leukemia (ALL). Preferably, the covalent bonds between the polymer and the active compound and / or the polymer itself are hydrolyzable under physiological conditions. This conjugate, known as a "prodrug," readily releases the active compound in vivo. Controlled release of the active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels known in the art. Other pharmaceutically acceptable prodrugs of this compound 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 conjugates, phosphate esters, metal salts, and sulfonates.

[0435] 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 derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compound and increase its stability. Methods of preparing liposomal suspensions containing active ingredients are well known in the art. See, e.g., U.S. Patent No. 4,522,811; Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y. (1976).

[0436] The pharmaceutical compositions, such as oral and parenteral compositions, can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, “unit dosage form” refers to physically discrete units suitable for unitary dosing to a subject, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.

[0437] In therapeutic applications, the pharmaceutical compositions are administered in a manner appropriate to the disease to be treated, as determined by one of ordinary skill in the art. Suitable dosages and suitable durations and frequencies of administration will be determined by factors such as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the method of administration, and the like. Generally, an appropriate dosage and administration regimen provides the pharmaceutical composition in an amount sufficient to provide a therapeutic benefit, such as an improved clinical outcome, e.g., more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity, or any other objectively identifiable improvement noted by a clinician. Effective dosages can often be evaluated using experimental models, such as dose-response curves obtained from in vitro or animal model test systems, or from clinical trials.

[0438] The pharmaceutical compositions of the present application can be included in a container, pack, or dispenser together with instructions for administration.

[0439] As also described in Example 3, it has been found that KDM1A inhibitors, such as vafidemstat, are orally effective and effective in the treatment of BPD when administered orally. Therefore, it is preferred to administer KDM1A inhibitors (e.g. vafidemstat) by the oral route for the treatment of BPD.

[0440] The present application also includes the use of KDM1A inhibitors wherein one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the present application includes the use of KDM1A inhibitors wherein one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e.2H; also known as “D”). Thus, the present application also includes deuterium-enriched KDM1A inhibitors. Naturally occurring hydrogen is comprised of about 99.98 mol-% hydrogen-1 1H) and about 0.0156 mol-% deuterium (D) 2 H or D) can be increased using deuteriation techniques known in the art. For example, the KDM1A inhibitor or a reactant or precursor used in the synthesis of the KDM1A inhibitor can be subjected to an H / D exchange reaction using, for example, heavy water (D2O). Other suitable deuteration 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 content of deuterium can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless specifically stated otherwise, it is preferred that the KDM1A inhibitors used according to the present application are not enriched in deuterium. Thus, it is preferred that naturally occurring hydrogen atoms or 1 H hydrogen atoms. Generally, it is preferred that the KDM1A inhibitors used according to the present application are not free of atoms being substituted by a specific isotope.

[0441] Definitions

[0442] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs.

[0443] The following definitions are applicable to the present specification and claims unless otherwise indicated.

[0444] A "patient" or "subject" for the purposes of the present application includes humans and other animals, particularly mammals. Thus, the methods and uses of the present application can be applied to in 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 (e.g., a male or female; who can be an adult, e.g., a person 18 years of age or older, or a child, e.g., a person 17 years of age or younger).

[0445] The terms "treat," "treatment," and the like, as used herein, generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease (referred to herein as BPD) or symptom thereof and / or can be therapeutic in terms of a partial or complete cure for a disease (i.e., BPD) and / or adverse effect attributable to the disease (i.e., BPD) or symptom(s) thereof, or in terms of a partial or complete halting of disease progression and / or adverse effect attributable to the disease (i.e., BPD) or symptom(s) thereof. The term "treatment" as used herein covers any treatment of a disease (i.e., BPD) in a patient and includes, but is not limited to, any one or more of: (a) preventing the disease (i.e., BPD) in a patient that can be predisposed to / at risk of the disease but does not yet experience or show symptoms of the disease; (b) delaying the onset of the disease; (c) inhibiting the disease, i.e., arresting, reducing, or slowing its development / progression; or (d) relieving the disease, i.e., causing the (complete or partial) regression, correction, or mitigation of the disease. The present application specifically and expressly relates to each of these forms of treatment.

[0446] The term "therapeutically effective amount," as used herein, refers to an amount that is sufficient to result in a desired biological effect (e.g., a therapeutic effect) in a subject. Thus, a therapeutically effective amount of a compound can be an amount that is sufficient, when administered to a subject suffering from or susceptible to the disease, to treat the disease (i.e., BPD) and / or to delay onset or progression of the disease and / or to alleviate one or more symptoms of the disease.

[0447] As used herein, the abbreviation "BPD" refers to borderline personality disorder.

[0448] As used herein, "pharmaceutically acceptable salt" means a salt that retains the biological effectiveness of the free acids and / or bases of the particular compound and that is not biologically or otherwise undesirable. Compounds can be sufficiently acidic, sufficiently basic, or both, to form a pharmaceutically acceptable salt with any of a wide variety of inorganic and organic acids and bases. Exemplary pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases, by reaction of a compound of the present application, e.g., vafidemstat, with inorganic or organic acids, such as hydrochloric, hydrobromic, sulfuric, bisulfuric, sulfamic, sulfurous, bisulfurous, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, metaphosphoric, pyrophosphoric, chloric, bromic, iodic, nitric, acetic, propionic, decanoic, octanoic, propiolic, formic, isobutyric, hexanoic, heptanoic, propynoic, oxalic, malonic, succinic, suberic, sebacic, fumaric, maleic, butyno-1,4-dioic, hexyno-1,6-dioic, benzoic, chlorobenzoic, methylbenzoate, dinitrobenzoic, hydroxybenzoic, methoxybenzoic, phthalic, sulfonic, xylene sulfonic, phenylacetic, phenylpropionic, phenylbutyric, citric, lactic, gamma-hydroxybutyric, glycolic, tartaric, methanesulfonic, ethanesulfonic, propanesulfonic, benzenesulfonic, toluenesulfonic, trifluoromethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, mandelic, pyruvic, stearic, ascorbic, or salicylic acids. Where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts can include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, such as amines, alkylamines, hydroxylalkylamines, lysine, arginine, N-methylglucosamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

[0449] As used herein, "pharmaceutically acceptable solvate" means a complex of variable stoichiometry formed from a solute and a pharmaceutically acceptable solvent, such as water, ethanol, or the like. Complexes with water are known as hydrates. It should be understood that the application encompasses pharmaceutically acceptable solvates of any non-salt form of a KDM1A inhibitor and of its pharmaceutically acceptable salt forms.

[0450] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a non-API (API refers to active pharmaceutical ingredient) substance, such as disintegrants, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe, i.e., meet the standards set by regulatory bodies including those promulgated by the U.S. Food and Drug Administration and / or the European Medicines Agency, for administration to humans. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0451] As used herein, "small molecule" refers to an organic compound having a molecular weight of less than 900 Daltons, preferably less than 500 Daltons. Molecular weight is the mass of a molecule and is calculated as the sum of the atomic weights of each constituent element in the molecular formula multiplied by the number of atoms of that element.

[0452] As used herein, the term "comprising" (or "comprise", "contain" or "contain") has the meaning "containing at least, in particular including, in addition to other optional ingredients". In addition to this, the term also includes the narrower meanings of "consisting essentially of and "consisting of". For example, the term "A comprises B and C" has the meaning "A includes B and C, in particular", where A can include other optional ingredients (e.g. "A comprises B, C and D" would also be covered), but the term also includes the meaning of "A consists essentially of B and C" and the meaning of "A consists of B and C" (i.e. A does not include other ingredients than B and C).

[0453] As used herein, the singular forms "a", "an" and "the" are used interchangeably with "one or more" and "at least one", unless explicitly stated otherwise or contradicted by context. Thus, for example, a composition comprising a KDM1A inhibitor can be interpreted to mean a composition comprising "one or more" KDM1A inhibitors. Examples

[0454] The following examples illustrate various aspects of the present application. Of course, these examples should not be construed as being limiting of the scope of the present application. Results are also presented and described in the figures and legends.

[0455] Example 1 : KDM1 A inhibitors

[0456] Vafidemstat is the compound 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, (41R,42S)-6-oxa-3-aza-1(2)-[1,3,4]oxadiazola-5(1,4),8(1)-dibenzena-4(1,2)-cyclopropanaoctaphan-15-amine or ORY-2001, and its chemical structure is shown below.

[0457]

[0458] The compound can be obtained as disclosed in WO2012 / 013728.

[0459] Example 2: In vitro KDM1 A inhibition assay

[0460] The inhibitory activity of the compounds on KDM1A can be determined using the following method.

[0461] Human recombinant KDM1A protein (GenBank Accession Number NM_015013, amino acids 158-end, with N-terminal GST tag, MW: 103 kDa) is used.

[0462] Test compounds at 30 mM to 1 nM in a series of 3-fold dilutions are pre-incubated with human recombinant KDM1A enzyme (BPS Bioscience, ref. 50100) in assay buffer (50 mM sodium phosphate pH 7.4) on ice for 15 min. Each concentration of inhibitor is tested in duplicate. The enzymatic reaction is initiated by the addition of dimethyl H3K4 peptide substrate (Anaspec, ref. 63677). After 30 min incubation at 37°C, Amplex Red reagent and horseradish peroxidase (HRP) solution are added to detect the H2O2 formed in the enzymatic reaction, following the recommendations provided by the supplier (Invitrogen). The mixture is incubated for 5 min at room temperature and in the dark and the conversion of Amplex Red reagent to high-fluorescent resorufin is analyzed using an Infinite F200 Tecan fluorescence microplate reader (l excitation = 540 nm, l emission = 590 nm). The maximum demethylase activity of KDM1A is obtained in the absence of inhibitor and the background fluorescence is corrected for in the absence of KDM1A. IC50 values for each inhibitor are calculated from a minimum of two independent experiments with GraphPad Prisms software. M The addition of dimethyl H3K4 peptide substrate (Anaspec, ref. 63677) initiates the reaction. After 30 min incubation at 37°C, Amplex Red reagent and horseradish peroxidase (HRP) solution are added to detect the H2O2 formed in the enzymatic reaction, following the recommendations provided by the supplier (Invitrogen). The mixture is incubated for 5 min at room temperature and in the dark and the conversion of Amplex Red reagent to high-fluorescent resorufin is analyzed using an Infinite F200 Tecan fluorescence microplate reader (l excitation = 540 nm, l emission = 590 nm). The maximum demethylase activity of KDM1A is obtained in the absence of inhibitor and the background fluorescence is corrected for in the absence of KDM1A. IC50 values for each inhibitor are calculated from a minimum of two independent experiments with GraphPad Prisms software.

[0463] Valifibrodesib is a KDM1A inhibitor with an average IC50 of 101 ± 40 nM obtained in the KDM1A assay as described herein. 50

[0464] Example 3: Evaluation of the effect of KDM1 A inhibitors treatment in human BPD

[0465] As part of a phase IIa clinical trial (REIMAGINE trial, EudraCT number 2018-002140-88), the safety, tolerability and efficacy of the KDM1A inhibitor valifibrodesib in the treatment of aggression in an adult population of patients with different CNS disorders was evaluated, a cohort of patients with BPD was recruited and treated with valifibrodesib for 8 weeks. A summary of the clinical trial protocol and the results obtained in the BPD cohort are provided below.

[0466] 3.1 Clinical trial design

[0467] ​Reigmaine is a single center, open-label, 1 -arm, 8-week clinical study to evaluate the efficacy, safety and tolerability of vafidemstat in the management of aggression in adult populations with Alzheimer's Disease (AD), Lewy Body Dementia (LBD), Adult Attention-Deficit Hyperactivity Disorder (ADHD), Borderline Personality Disorder (BPD) and Autism Spectrum Disorder (ASD). Six patients are to be enrolled for each disease.

[0468] Primary objective of the trial: To evaluate the safety and tolerability of vafidemstat in adult populations with Alzheimer's Disease (AD), Lewy Body Dementia (LBD), Adult Attention-Deficit Hyperactivity Disorder (ADHD), Borderline Personality Disorder (BPD), Autism Spectrum Disorder (ASD)

[0469] Secondary objectives of the trial: To study the efficacy of vafidemstat in the management of aggression in adult populations with Alzheimer's Disease (AD), Lewy Body Dementia (LBD), Adult Attention-Deficit Hyperactivity Disorder (ADHD), Borderline Personality Disorder (BPD), Autism Spectrum Disorder (ASD)

[0470] Main inclusion criteria:

[0471] - Age 18-85

[0472] - Current diagnosis of AD, LBD, ADHD, BPD or ASD according to DSM-5 criteria

[0473] - Significant or persistent agitation or aggression (which disrupts the patient's daily life, or puts the patient at risk) for at least 4 weeks prior to the screening visit, at least 3 days per week

[0474] Treatment: All patients receive vafidemstat (as free base), at a dose of 1.2 mg / day, administered orally as a single capsule, in a 5 days on / 2 days off schedule over 8 weeks.

[0475] 3.2 BPD cohort

[0476] Six patients with BPD were enrolled, but one withdrew, so the results described herein correspond to 5 BPD subjects suitable for analysis. A summary of the patients enrolled in this BPD cohort (demographics at baseline) can be found in Table 1.

[0477] Table 1:

[0478]

[0479] 3.3 Evaluation of efficacy in the BPD cohort

[0480] The evaluation of treatment effects in patients with BPD is performed using a validated scale specifically for BPD (Borderline Personality Disorder Checklist (BPDCL)). The BPDCL is a tool specifically designed to evaluate the subjective burden of BPD in the previous month and also to evaluate changes in BPD after therapeutic interventions. The BPDCL was originally developed in the Netherlands and subsequently translated into English, Spanish and other languages and has been applied in clinical and non-clinical samples. The BPDCL has shown to have adequate psychometric properties and is currently considered the most reliable scale to evaluate the effectiveness of treatments for BPD.

[0481] The BPDCL is a 47-item self-report questionnaire; the items are based on the DSM-IV BPD criteria, the literature describing BPD manifestations and clinical observations. The items are rated on a 5-point Likert scale, ranging from "not at all" to "extremely", indicating the degree to which the respondent has been troubled by 47 different BPD problems in the last month. The 47 items in the BPDCL can be clustered together into the following 9 BPD domains:

[0482] 1) Abandonment

[0483] 2) Relationships

[0484] 3) Identity disturbance

[0485] 4) Impulsivity

[0486] 5) (Para)suicide

[0487] 6) Emotional instability

[0488] 7) Emptiness

[0489] 8) Anger control

[0490] 9) Dissociation

[0491] The sum score of the BPDCL (BPDCL total score) can be used as an overall indicator of the subjective burden caused by BPD symptoms or one or more of the total scores of the individual BPD domains can be used.

[0492] The BPDCL is performed on Day 1 (Visit 1), which corresponds to baseline (i.e. before starting treatment with vafidemstat), and on Week 8 of treatment with vafidemstat (Visit 7). On the respective visit day, the effectiveness evaluation is always determined prior to treatment administration.

[0493] The efficacy evaluation was performed by evaluating the change from baseline (visit 1) to week 8 (visit 7) in the aggression-related BPDCL domain composite score (i.e., the score resulting from the composite of the scores of the BPDCL domains related to aggressive behavior, i.e., anger control, impulsivity, and (para)suicide), in the total BPDCL score, and in the non-aggression-related BPDCL domain composite score (i.e., the score resulting from the composite of the scores of all other BPDCL domains, i.e., abandonment, relationships, identity disturbance, emotional instability, emptiness, and dissociation).

[0494] Statistical analysis was performed using paired one-tailed t-tests for the comparison of visit 1 and visit 7 values.

[0495] 3.4 Results

[0496] Treatment of BPD patients with Vafidemstat was safe, well tolerated, and without apparent adverse events.

[0497] Treatment of BPD patients with Vafidemstat for 8 weeks resulted in a significant improvement in aggression, as shown by a statistically significant reduction in the aggression-related BPDCL domain composite score (as detailed in Example 3.3 above) from visit 1 to visit 7, as shown by Figure 1 (p = 0.0029).

[0498] Unexpectedly, not only the aggression-related composite score, but also the total BPDCL score and the non-aggression-related BPDCL domain composite score showed statistically significant reductions after 2 months of treatment with Vafidemstat, as shown by Figure 2 (total BPDCL score, p = 0.0048) and Figure 3 (non-aggression-related BPDCL domain composite score, p = 0.0234).

[0499] The significant improvements observed in the total BPDCL score and in the non-aggression composite score by treatment of BPD patients with Vafidemstat indicate that KDM1A inhibitors, such as Vafidemstat, have additional therapeutic effects in BPD patients beyond the treatment of aggression.

[0500] In summary, the data and results obtained in Example 3 support the finding that KDM1A inhibitors, in particular Vafidemstat, can be useful for the treatment of BPD, including the treatment of BPD core features or BPD symptoms not related to aggression.

[0501] Using the protocol described in Example 3 herein, other KDM1A inhibitors can be able to demonstrate therapeutic effects as treatments for BPD.

[0502] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0503] The publications, patents, and patent applications referred to in this specification are provided solely for their disclosure prior to the filing date of this application. Nothing herein is to be construed as an admission that the present application is not entitled to antedate such publication, patent, or patent application by virtue of prior application.

[0504] While the application has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains and as can be applied to the essential features herein set forth and fall within the scope of the application and the limitations thereof as set forth in the appended claims.

Claims

1. A KDM1A inhibitor for use in the treatment of borderline personality disorder.

2. A pharmaceutical composition for use in the treatment of borderline personality disorder, wherein the pharmaceutical composition comprises a KDM1A inhibitor and one or more pharmaceutically acceptable excipients or carriers.

3. A compound for use according to claim 1 or a pharmaceutical composition for use according to claim 2, wherein the patient to be treated is a human.

4. A compound for use according to any one of claims 1 or 3 or a pharmaceutical composition for use according to any one of claims 2 or 3, 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.

5. A compound for use according to any one of claims 1 or 3 or a pharmaceutical composition for use according to any one of claims 2 or 3, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.

6. A compound for use according to any one of claims 1 or 3 to 5 or a pharmaceutical composition for use according to any one of claims 2 to 5, wherein the KDM1A inhibitor or the pharmaceutical composition is for oral administration.

7. A method of treating borderline personality disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

8. The method according to claim 7, wherein the patient to be treated is a human.

9. The method according to claim 7 or 8, 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.

10. The method according to claim 7 or 8, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.

11. The method according to any one of claims 7 to 10, wherein the method comprises oral administration of the KDM1A inhibitor.

12. Use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of borderline personality disorder.

13. The use according to claim 12, wherein the patient to be treated is a human.

14. The use according to claim 12 or 13, 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.

15. The use according to claim 12 or 13, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.

16. The use according to any one of claims 12 to 15, wherein the medicament is for oral administration.

17. Use of a KDM1A inhibitor in the treatment of borderline personality disorder.

18. Use according to claim 17, wherein the patient to be treated is a human.

19. Use according to claim 17 or 18, 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.

20. Use according to claim 17 or 18, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4- (benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.

21. Use according to any one of claims 17 to 20, wherein the KDM1A inhibitor is administered orally.

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