RU2833298C2 - Methods of treating borderline personality disorder - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to the treatment of borderline personality disorder. Disclosed is a method of treating borderline personality disorder in a patient by treating one or more non-aggressive symptoms of borderline personality disorder, which involves administering to the patient a therapeutically effective amount of a KDM1A inhibitor, which is 5-(((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2-amine or a pharmaceutically acceptable salt or solvate thereof. Also described is the use of said KDM1A inhibitor for treating borderline personality disorder, as well as for preparing a medicinal agent based thereon.

EFFECT: invention provides treating one or more non-aggressive symptoms of borderline personality disorder.

12 cl, 3 dwg, 1 tbl, 3 ex

Description

FIELD OF INVENTION

The present invention relates to methods for treating borderline personality disorder.

BACKGROUND OF THE INVENTION

Borderline personality disorder (BPD) is one of the most complex, functionally debilitating, and costly psychiatric conditions currently facing mental health systems. The essential features of BPD are disturbances in personal (personal and interpersonal) functioning and the presence of pathological personality traits. Patients with BPD typically experience emotional instability, impulsivity, irrational beliefs and distorted perceptions, and intense but unstable relationships with others. Up to 10% of people die by suicide. Women are diagnosed approximately three times more often than men.

Treatment of BPD remains a challenging medical issue. There are currently no FDA-approved medications for the treatment of BPD. Medications such as mood stabilizers and atypical antipsychotics are used off-label to treat BPD, but with questionable effectiveness and unwanted side effects such as sedation and weight gain.

Thus, there is an urgent and unmet medical need for new and/or improved drugs for the treatment of BPD, particularly drugs that act through novel mechanisms of action and treat the core features of BPD, and with a more favorable side effect profile than currently available non-specific off-label therapeutic agents. The present invention satisfies these and other needs.

ESSENCE OF THE INVENTION

The invention provides new methods for treating borderline personality disorder by using KDM1A inhibitors.

Thus, the present invention provides a KDM1A inhibitor for use in the treatment of borderline personality disorder.

The present invention further provides a method of treating borderline personality disorder in a patient (preferably a human), comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

The present invention also provides the use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of borderline personality disorder.

The present invention also provides the use of a KDM1A inhibitor for the treatment of borderline personality disorder.

In preferred embodiments of the invention, the KDM1A inhibitor is vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the effect of treatment with the KDM1A inhibitor vafidemstat (defined herein and in Example 1) for the treatment of aggression in patients with BPD, as demonstrated by a statistically significant reduction in the composite score of the aggression-related domains of the BPDCL from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of vafidemstat treatment), as described in more detail in Example 3. Data are presented as mean±SEM; p=0.0029.

Figure 2 shows the efficacy of the KDM1A inhibitor vafidemstat for the treatment of BPD, as demonstrated by statistically significant reductions in the BPD Checklist (BPDCL) total score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of vafidemstat treatment), as described in more detail in Example 3. Data are presented as mean±SEM; p=0.0048.

Figure 3 shows that treatment with vafidemstat resulted in a statistically significant reduction in the BPDCL non-aggressive domain composite score from Visit 1 (baseline, pre-treatment) to Visit 7 (8 weeks of vafidemstat treatment), as described in more detail in Example 3. Data are presented as mean±SEM; p=0.0234.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based on the unexpected discovery that KDM1A inhibitors can be used as therapeutic agents for the treatment of BPD. It has been reported that KDM1A inhibitors, including vafidemstat, can be used to reduce aggression, such as disease-related aggression, without sedative effects. Vafidemstat is currently in a phase IIa clinical trial for the treatment of aggression in patients with Alzheimer's disease, dementia with Lewy bodies, autism spectrum disorder, attention deficit hyperactivity disorder and BPD (REIMAGINE study). The results of this clinical trial unexpectedly demonstrated that vafidemstat is not only effective for the treatment of aggression in patients with BPD, but also has additional therapeutic effects on BPD, as described in detail below and in the examples. KDM1A inhibitors and especially vafidemstat may be used as treatment for BPD, including treatment of the (non-aggressive) core features of BPD defined below.

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

The present invention 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.

The present invention also provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of BPD.

The present invention also provides the use of a KDM1A inhibitor for the treatment of BPD.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD, the method comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

In accordance with the present invention, "core features of BPD" means 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, and which include disturbances in personal (personal and interpersonal) functioning and the presence of pathological personality traits.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD.

According to the present invention, the term "non-aggressive" as used, for example, in the context of a BPD symptom means that said BPD symptom is not directly related to or associated with aggression or aggressive behavior. "Aggression," "aggressive," and related terms as used herein refer to any kind of abnormal, pathological, or inappropriate aggressive or violent behavior, hostility, or agitation, such as physical or verbal, including interpersonal aggression (i.e., toward other subjects) and/or intrapersonal aggression (i.e., self-aggression).

Examples of non-aggressive BPD symptoms include emotional instability, irrational beliefs, intense but unstable relationships with others, abandonment, identity disorder, emptiness, and dissociation.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of 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.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of 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.

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of 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.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

In some embodiments, the present invention provides the use of a KDM1A inhibitor for treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

In some embodiments, the present invention provides the use of a KDM1A inhibitor to treat a patient with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

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

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in treating a patient 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.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression, wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention provides the use of a KDM1A inhibitor in the manufacture of a medicament for treating a patient 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.

In some embodiments, the present invention provides the use of a KDM1A inhibitor for treating a patient 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.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of one or more core features of BPD.

In some embodiments, the present invention relates to a method of treating one or more core features of BPD in a patient (preferably a human), wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention provides the use of a KDM1A inhibitor in the manufacture of a medicament for the treatment of one or more major features of BPD.

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of one or more core features of BPD.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention relates to a method of treating 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.

In some embodiments, the present invention 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.

In some embodiments, the present invention provides the use of a KDM1A inhibitor for the treatment of one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of one or more core features of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention relates to a method of treating one or more core features of BPD, as well as agitation and/or aggression in a patient (preferably a human), wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention 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.

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

In some embodiments, the present invention relates to a KDM1A inhibitor for use in the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention relates to a method of treating one or more non-aggressive symptoms of BPD, as well as agitation and/or aggression in a patient (preferably a human), wherein the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor.

In some embodiments, the present invention 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.

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

The present document also provides a KDM1A inhibitor for use in treating (e.g., reducing) agitation in BPD. Similarly, the present document provides a KDM1A inhibitor for use in treating (e.g., reducing) agitation in a patient with BPD. Furthermore, the present document provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing) agitation. Furthermore, the present document provides a method of treating (e.g., reducing) agitation in a patient with BPD (preferably a human), comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Similarly, the present document provides the use of a KDM1A inhibitor in the manufacture of a medicament for treating (e.g., reducing) agitation in BPD. Furthermore, the present document provides the use of a KDM1A inhibitor for treating (e.g., reducing) agitation in BPD.

Moreover, the present document also provides a KDM1A inhibitor for use in treating (e.g., reducing) aggression in a patient with BPD. Similarly, the present document provides a KDM1A inhibitor for use in treating (e.g., reducing) aggression in a patient with BPD. Furthermore, the present document provides a KDM1A inhibitor for use in treating a patient with BPD by treating (e.g., reducing) aggression. Furthermore, the present document provides a method of treating (e.g., reducing) aggression in a patient with BPD (preferably a human), comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Similarly, the present document provides the use of a KDM1A inhibitor in the manufacture of a medicament for treating (e.g., reducing) aggression in BPD. The present document further provides the use of a KDM1A inhibitor for treating (e.g., reducing) aggression in BPD.

The methods of treatment and therapeutic uses described herein may in principle employ any KDM1A inhibitor, including the KDM1A inhibitors described in more detail herein below. However, it is preferred that the KDM1A inhibitor for use in the methods and uses of the invention 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]oxadiazole-5(1,4),8(1)-dibenzene-4(1,2)-cyclopropaneoctaphan-15-amine, vafidemstat (INN) or ORY-2001, or a pharmaceutically acceptable salt or solvate thereof, and it is particularly preferred that the KDM1A inhibitor is the compound 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine (in 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]oxadiazole-5(1,4),8(1)-dibenzene-4(1,2)-cyclopropaneoctaphan-15-amine", "wafidemstat" or "ORY-2001" are used interchangeably herein.

Accordingly, the present document provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of BPD.

The present invention also provides a method of treating 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.

The present invention further provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of BPD.

The present invention further provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of BPD.

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD.

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

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

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

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

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

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

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

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

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

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

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

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

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of 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.

In some embodiments, the present invention relates to a method of treating BPD in a patient (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of 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.

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more major features of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for treating a patient with BPD by treating (e.g., alleviating or improving) one or more core features of BPD.

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating or improving) one or more non-invasive symptoms of BPD, comprising administering to the patient a therapeutically effective amount of vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for treating a patient with BPD by treating (e.g., alleviating or improving) one or more non-aggressive symptoms of BPD.

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) aggression.

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

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) aggression.

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

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation.

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

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation.

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

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

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention 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., alleviating or improving) one or more core features of BPD and by treating (e.g., reducing) agitation and aggression.

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

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in treating a patient 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.

In some embodiments, the present invention relates to a method of treating a patient with BPD (preferably a human) by treating (e.g., alleviating 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.

In some embodiments, the present invention 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., alleviating or improving) one or more non-aggressive symptoms of BPD and by treating (e.g., reducing) agitation and aggression.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for treating a patient 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.

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of one or more major features of BPD.

In some embodiments, the present invention relates to a method of treating one or more major features 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.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of one or more major features of BPD.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of one or more major features of BPD.

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

In some embodiments, the present invention relates to a method of treating 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.

In some embodiments, the present invention provides the use of vafidemstat 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.

In some embodiments, the present invention 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.

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of one or more core features of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention relates to a method of treating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of one or more core features of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention provides the use of vafidemstat or a pharmaceutically acceptable salt or solvate thereof for the treatment of one or more core features of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention provides vafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of one or more non-aggressive symptoms of BPD, as well as agitation and/or aggression.

In some embodiments, the present invention relates to a method of treating 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 vafidemstat or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the present invention provides the use of vafidemstat 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.

In some embodiments, the present invention 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, as well as agitation and/or aggression.

Preferably, the KDM1A inhibitor for use in the treatment methods and uses described herein, such as vafidemstat (or a pharmaceutically acceptable salt or solvate thereof), is administered orally. Examples of formulations that can be administered orally are described in more detail below.

As explained above, in preferred embodiments, the present document provides the compound wafidemstat or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of PRL. Accordingly, the invention relates to the compound wafidemstat in free base form (in non-salt form) for use in the treatment of PRL and, further, the invention also relates to a pharmaceutically acceptable salt or solvate of wafidemstat for use in the treatment of PRL.

As illustrated in the examples, in the context of the present invention it has been surprisingly found that KDM1A inhibitors, such as, for example, vafidemstat, can be used to treat BPD. In a Phase IIa clinical trial evaluating the KDM1A inhibitor vafidemstat as a treatment for aggression in humans with a range of CNS disorders, vafidemstat was shown to produce a significant reduction in aggressive behavior in patients with BPD, as shown in Example 3 and Figure 1. As shown in Figure 1, treatment with the KDM1A inhibitor vafidemstat produced a statistically significant reduction in aggression scores in these patients with BPD, as demonstrated by comparing the score after 8 weeks of treatment with the KDM1A inhibitor vafidemstat (assessment at visit 7) with the score at baseline before starting treatment with vafidemstat (assessment at visit 1). The effectiveness of treatment for patients with BPD is preferably assessed using a validated scale specifically developed for BPD, such as the Borderline Personality Disorder Checklist (BPDCL). As explained in more detail in Example 3.3, the BPDCL includes assessment of aggression-related as well as non-aggression (i.e., aggression-independent) domains or symptoms of BPD. By assessing the effect of treatment on the BPD total score, which includes aggression-related as well as non-aggression scores, and/or on the BPD composite score corresponding to those BPD domains that are non-aggression-related, as detailed in Example 3.3, the effectiveness of a medication for treating BPD can be assessed over and above (i.e., separately from) its specific effect on aggression. As shown in Example 3 and Figures 2 and 3, it was unexpectedly found that in addition to the therapeutic effect on aggression, treatment with the KDM1A inhibitor vafidemstat resulted in significant improvements in overall BPD and non-aggressive features of BPD, as demonstrated by statistically significant reductions in the BPDCL total score (as shown in Figure 2) and the non-aggression composite score (as shown in Figure 3) after 8 weeks of treatment. These results demonstrate that KDM1A inhibitors, including vafidemstat, have a broad therapeutic effect in BPD, exerting therapeutic effects in patients with BPD beyond the treatment of aggression, and thus can be used to treat BPD, including the core features of BPD defined above.

KDM1A inhibitors

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

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

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

Non-limiting examples of KDM1A inhibitors that can be used according to the present invention are described, for example, in: 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

(vafidemstat);

(iadademstat);

(GSK-LSD1);

(T-3775440);

;

(seclidemstat);

;

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

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

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

including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. Any of the above-described compounds containing a 1,2-substituted cyclopropyl ring may 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 of the corresponding specific trans isomers (wherein the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the depicted structure; or wherein the two substituents on the cyclopropyl ring each have the opposite absolute configuration as shown in the depicted structure).

The following non-limiting examples of KDM1A inhibitors to be used according to the present invention are described, for example, in the works: K Taeko et al, Bioorg Med Chem Lett 2015, 25(9):1925-8. doi: 10.1016/j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID: 25827526; S Valente et al, Eur J Med Chem. 2015, 94:163-74. doi: 10.1016/j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID:25768700; MN Ahmed Khan et al Med. Chem. Commun., 2015,6, 407-412, DOI: 10.1039/C4MD00330F epub 29 Sep 2014; M Pieroni et al, Eur J Med Chem. 2015;92:377-386. doi: 10.1016/j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID:25585008; V Rodriguez et al, Med. Chem. Commun., 2015,6, 665-670 DOI: 10.1039/C4MD00507D, Epub 23 Dec 2014; P Vianello et al, Eur J Med Chem. 2014, 86:352-63. doi: 10.1016/j.ejmech.2014.08.068. Epub 2014 Aug 27; DP 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; C. J. Kutz et al Medchemcomm. 2014, 5(12):1863-1870 PMID: 25580204; C Zhou et al, Chemical Biology & Drug Design, 2015, 85(6):659-671. doi:10.1111/cbdd.12461, epub 22-dec-2014; P Prusevich et al, ACS Chem Biol. 2014, 9(6):1284-93. doi: 10.1021/cb500018s. Epub 2014 Apr 7; B Dulla et al, Org Biomol Chem 2013, 11, 3103-3107, doi: 10.1039/c3ob40217g; JR Hitchin et al, MedChemCommun,2013, 4, 1513-1522 DOI: 10.1039/c3md00226h; and Y Zhou et al, Biorg Med Chem Lett, 2015, online publication 20-Jun-2015, doi:10.1016/j.bmcl.2015.06.054. Reversible inhibitors of KDM1A that may be used in the methods/uses of the invention include, but are not limited to, any of the compounds described in: WO2010/043721, WO2010/084160, WO2011/035941, WO2011/042217, WO2011/131697, WO2012/013727, WO2012/013728, WO2012/045883, WO2013/057320, WO2013/057322, WO2010/143582, US2010-0324147, WO2011/131576, WO2012/135113, 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; V Rodriguez et al, Med. Chem. Commun., 2015,6, 665-670 DOI: 10.1039/C4MD00507D, Epub 23 Dec 2014; or P Vianello et al, Eur J Med Chem. 2014, 86:352-63. doi: 10.1016/j.ejmech.2014.08.068. Epub 2014 Aug 27, and

(vafidemstat);

(iadademstat);

(GSK-LSD1);

(T-3775440);

;

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

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

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

including any optically active stereoisomer thereof, or any pharmaceutically acceptable salt or solvate thereof. Any of the above-described compounds containing a 1,2-substituted cyclopropyl ring may 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 of the corresponding specific trans isomers (wherein the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the drawing of the structure; or wherein the two substituents on the cyclopropyl ring each have the opposite absolute configuration as shown in the depicted structure).

Reversible inhibitors of KDM1A that may be used in the methods/uses of the invention include, but are not limited to, any of the compounds described 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

;

including any optically active stereoisomer thereof or any pharmaceutically acceptable salt or solvate thereof.

In some embodiments of the invention in the methods and uses of the invention, the KDM1A inhibitor is an irreversible KDM1A inhibitor, preferably a 2-(hetero)arylcyclopropylamino KDM1A inhibitor. As used herein, "2-(hetero)arylcyclopropylamino KDM1A inhibitor" or "2-(hetero)arylcyclopropylamino compound" means a KDM1A inhibitor whose chemical structure comprises a cyclopropyl ring substituted at position 1 with an amino group that is optionally substituted and substituted at position 2 with an aryl or heteroaryl group (wherein the aryl or heteroaryl group is optionally substituted).

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

A particularly preferred KDM1A inhibitor for use in the methods and uses of the invention 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine;

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

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

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

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

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

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

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

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

N1-methyl-N4-((trans)-2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;

N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-N4-methylcyclohexane-1,4-diamine;

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

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

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

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

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

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

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

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

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

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

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

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

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

Tert-butyl(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate;

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

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

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

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

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

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

4-(2-((4-aminocyclohexyl)amino)cyclopropyl)phenol;

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

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

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

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

(R)-1-(4-(((trans)-2-(3ʼ-(trifluoromethyl)-[1,1ʼ-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-(4ʼ-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1ʼ-biphenyl]-3-yl)-2-cyanobenzenesulfonamide;

6-amino-N-(4ʼ-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1ʼ-biphenyl]-3-yl)pyridine-3-sulfonamide;

N-(4ʼ-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1ʼ-biphenyl]-3-yl)piperazine-1-sulfonamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;

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

(trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-((trans)-2-phenylcyclopropyl)piperidin-4-amine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-((trans)-2-phenylcyclopropyl)decahydroquinoline-4-amine;

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

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

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

N-((trans)-2-phenylcyclopropyl)-2,3-dihydrospiro[indene-1,4ʼ-piperidine]-3-amine;

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

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

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

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

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

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

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

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

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

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

N-(2-(2-fluorophenyl)cyclopropyl)piperidin-4-amine;

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

N-(2-(4-methoxyphenyl)cyclopropyl)piperidin-4-amine;

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

N-(2-methyl-2-phenylcyclopropyl)piperidin-4-amine;

N-(6-methoxy-4ʼ-((trans)-2-(piperidin-4-ylamino)cyclopropyl)-[1,1ʼ-biphenyl]-3-yl)methanesulfonamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(trans)-2-(4ʼ-chloro-[1,1ʼ-biphenyl]-4-yl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)cyclopropanamine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(T-3775440);

;

including any of its optically active stereoisomers,

or a pharmaceutically acceptable salt or solvate thereof.

Pharmaceutical formulations

Although it is possible that a KDM1A inhibitor, such as vafidemstat, can be administered for use in therapy directly as such, it is typically administered in the form of a pharmaceutical composition that includes the compound as an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients or carriers.

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

The KDM1A inhibitor may be administered by any route that achieves its intended target. Examples include oral, parenteral (including, for example, intravenous, subcutaneous, or intracerebral administration), or topical administration.

For oral delivery, the compound can be included in a formulation that contains pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The composition can be delivered orally, for example, in the form of closed gelatin capsules or compressed tablets. Capsules and tablets can be prepared by any conventional methods. Capsules and tablets can also be coated with various coatings known in the art to alter the aroma, taste, color, and shape of the capsules and tablets. In addition, liquid carriers such as a fatty oil can be included in the capsules.

Suitable oral formulations may also be in the form of a suspension, syrup, chewing gum, capsule, elixir, and the like. If desired, conventional flavor, taste, color, and carrier media for special formulations may also be included. In addition, for convenient administration via an enteral feeding tube to patients unable to swallow, the active compounds may be dissolved in a suitable lipophilic carrier of vegetable oil, such as olive oil, corn oil, and safflower oil.

The compound can also be administered parenterally as a solution or suspension, or in a lyophilized form that can be converted to a solution or suspension form before use. Diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used in such formulations. Other common solvents, pH buffers, stabilizers, antibacterial agents, surfactants and antioxidants can be included. For example, components used include sodium chloride, acetates, citrate or phosphate buffers, glycerol, dextrose, fixed oils, methylparabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid and the like. Parenteral formulations can be stored in any common containers such as vials and ampoules.

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

A suitable route of administration for sustained release of the compound may also be subcutaneous implantation. This entails surgical procedures for implanting the active compound in any suitable composition into the subcutaneous space, for example, beneath the anterior abdominal wall. See, for example, Wilson et al . (1984) J. Clin. Psych. 45:242-247. Hydrogels may be used as a carrier for sustained release of the active compounds. Hydrogels are widely known in the art. They are typically prepared by cross-linking high molecular weight biocompatible polymers into a network that swells in water to form a gel-like material. Preferably, the hydrogels are biodegradable or biosorbable. Hydrogels made from polyethylene glycols, collagen, or poly(glycolic co-L-lactic acid) may be used for the purposes of this invention. See, for example, Phillips et al . (1984) J. Pharmaceut. Sci. , 73: 1718-1720.

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

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

Pharmaceutical compositions like oral and parenteral compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for administration to subjects, 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.

In therapeutic use, pharmaceutical compositions should be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the art. The appropriate dose, appropriate duration and frequency of administration will be determined by, among other things, such factors as the patient's condition, the type and severity of the disease, the particular form of the active ingredient, the route of administration. Typically, an appropriate dose and route of administration will provide the pharmaceutical composition in an amount sufficient to provide a therapeutic effect, for example, an improved clinical outcome such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a reduction in the severity of symptoms, or any other objectively identifiable improvement noted by a physician. Effective doses can generally be estimated or extrapolated using experimental models, such as dose-response curves obtained from in vitro test systems or animal models, or from clinical trials.

The pharmaceutical compositions of the invention may be included in a container, package or dispenser together with instructions for use.

KDM1A inhibitors such as vafidemstat have been found to have orally active and are effective in the treatment of BPD when administered orally, as also shown in Example 3. Accordingly, it is preferred that a KDM1A inhibitor (e.g., vafidemstat) be administered orally when treating BPD.

The present invention also encompasses the use of KDM1A inhibitors in which one or more atoms are replaced with a specific isotope of the corresponding atom. For example, the invention encompasses the use of a KDM1A inhibitor in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced with deuterium atoms (i.e., ² H; also referred to as "D"). Accordingly, the invention also encompasses deuterium-rich KDM1A inhibitors. The naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol% hydrogen 1 ( ¹ H) and about 0.0156 mol% deuterium ( ² H or D). The deuterium content of one or more hydrogen positions in a KDM1A inhibitor can be increased using a deuteration method known in the art. For example, a KDM1A inhibitor, reagent or precursor to be used in the synthesis of a KDM1A inhibitor can be subjected to a H/D exchange reaction using, for example, heavy water ( _D2O ). Further suitable deuteration methods are described in: Atzrodt J et al., Bioorg Med Chem , 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals , 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem , 79, 5861-5868, 2014. The deuterium content can be determined, for example, by mass spectrometry or NMR spectroscopy. Unless otherwise specifically stated, it is preferred that the KDM1A inhibitor used according to the present invention is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or ¹ H hydrogen atoms in the KDM1A inhibitor is preferred. It is generally preferred that none of the atoms in the KDM1A inhibitor used in accordance with the invention be replaced by a specific isotope.

Definitions

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

Throughout this description and in the claims, unless otherwise specifically stated, the following definitions apply.

"Patient" or "subject" for the purposes of the present invention includes both humans and other animals, especially mammals. Thus, the methods and uses of the invention are applicable to both human and veterinary treatment. 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 human male or female; which may be an adult, e.g., a human aged 18 years or older, or a child, e.g., a human aged 17 years or younger).

The terms "treatment", "cure" and the like are used herein to mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease (in this case BPD) or a symptom thereof and/or may be therapeutic in terms of partially or completely curing or alleviating the disease (i.e. BPD) and/or a symptom or adverse effect attributed to the disease, or partially or completely stopping the progression of the disease and/or a symptom or adverse effect attributed to the disease. The term "treatment" as used herein encompasses treating the disease (i.e. BPD) in a patient and includes, without limitation, any one or more of the following: (a) preventing BPD in a patient who may be predisposed/at risk for developing BPD; (b) delaying the onset of BPD; (c) inhibiting BPD, i.e. stopping, delaying or slowing its development/progression; or (d) alleviating the BPD, i.e. causing (complete or partial) regression, correction or alleviation of the BPD. The present invention specifically and expressly relates to each of these forms of treatment.

As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect) in a subject. Accordingly, a therapeutically effective amount of a compound may be an amount sufficient to treat a disease (i.e., BPD) and/or delay the onset or progression of the disease and/or alleviate one or more symptoms of the disease, when administered to a subject suffering from or susceptible to the disease.

As used in this document, the abbreviation "BPD" refers to borderline personality disorder.

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

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

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

As used herein, the term "small molecule" refers to an organic compound with a molecular weight below 900 daltons, preferably below 500 daltons. The molecular weight is the mass of a molecule, which is calculated as the sum of the atomic masses of each constituent element multiplied by the number of atoms of that element in the molecular formula.

As used herein, the term "comprising" (or "include," "includes," "contains," "contains," or "comprising"), unless otherwise clearly indicated or contradicted by the context, has the meaning of "comprising, inter alia," that is, "comprising, among further optional elements...." In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C," has the meaning of "A comprising, inter alia, B and C," where A may contain further optional elements (e.g., "A comprising B, C, and D" would also be included), but the term also includes the meaning of "A consisting essentially of B and C," and the meaning of "A consisting of B and C" (that is, no components other than B and C are included in A).

As used herein, unless otherwise clearly indicated or contradicted by context, the terms "one" and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising a KDM1A "inhibitor" may be interpreted as referring to a composition comprising "one or more" KDM1A inhibitors.

EXAMPLES

The following examples illustrate various aspects of the invention. The examples are, of course, to be understood as merely illustrating only certain embodiments of the invention and not as limiting the scope of the invention. The results are also shown and described in the figures and in the figure captions.

Example 1: KDM1A inhibitor

Vafidemstat is a 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]oxadiazole-5(1,4),8(1)-dibenzene-4(1,2)-cyclopropaneoctaphane-15-amine or ORY-2001, and the chemical structure of which is shown below.

This compound can be prepared as described in WO2012/013728.

Example 2: In vitro KDM1A inhibition assay

The inhibitory activity of a compound against KDM1A can be determined using the method described below.

Human recombinant KDM1A protein was used (GenBank accession number NM_015013, amino acids at the 158-end with N-terminal GST tag, MW: 103 kDa).

Serial 3-fold dilutions of the test compound ranging from 30 μM to 1 nM were pre-incubated for 15 min with human recombinant KDM1A enzyme (BPS Bioscience, Ref. 50100) on ice in assay buffer (50 mM sodium phosphate, pH 7.4). Each inhibitor concentration was tested in duplicate. The enzymatic reaction was initiated by the addition of dimethyl peptide substrate H3K4 (Anaspec, Ref. 63677), at the _{appK M} level of KDM1A. After 30 min incubation at 37°C, Amplex Red horseradish peroxidase (HRP) reagent was added to detect _H2O2 generated in the enzymatic reaction according to the recommendations provided by the supplier (Invitrogen). The mixture was incubated for 5 min at room temperature in the dark and the conversion of Amplex Red reagent to highly fluorescent resorufin was analyzed using a Tecan Infinite F200 fluorescence microplate reader (excitation=540 nm, emission=590 nm). The maximum KDM1A demethylase activity was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of KDM1A. The _IC50 value for each inhibitor was calculated using GraphPad Prism5 software from at least two independent experiments.

Vafidemstat is an inhibitor of KDM1A as demonstrated by a mean IC50 value of ₁₀₁ ±40 nM 40 nM obtained in the KDM1A assay described herein.

Example 3: Evaluation of the effect of KDM1A inhibitors for the treatment of BPD in humans

As part of a phase IIa clinical trial (REIMAGINE study, EudraCT number 2018-002140-88) to evaluate the safety, tolerability and efficacy of the KDM1A inhibitor vafidemstat for the treatment of aggression in an adult population of patients with various CNS disorders, a cohort of patients with BPD was recruited and treated with vafidemstat for 8 weeks. A summary of the protocol of this clinical trial and the results obtained in the BPD cohort are presented below.

3.1 Clinical trial design

Reimagine is a single-center, open-label, single-arm, 8-week clinical study to evaluate the efficacy, safety, and tolerability of vafidemstat in aggression in adults 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 being recruited for each disorder.

The primary objective of the study was to evaluate the safety and tolerability of vafidemstat in adults with Alzheimer's disease (AD), dementia with Lewy bodies (LBD), attention deficit hyperactivity disorder in adults (ADHD), borderline personality disorder (BPD), and autism spectrum disorder (ASD).

Secondary objectives of the study: to investigate the efficacy of vafidemstat in aggression in adults with Alzheimer's disease (AD), dementia with Lewy bodies (LBD), adult attention deficit hyperactivity disorder (ADHD), borderline personality disorder (BPD), autism spectrum disorder (ASD).

Main inclusion criteria:

- age 18-85 years

- current diagnosis of AD, LBD, ADHD, BPD or ASD according to DSM-5 criteria

- significant or persistent agitation or aggression that interfered with the patient's daily life or caused harm to the patient for at least 3 days a week for at least 4 weeks prior to the screening visit

Treatment: All patients received vafidemstat (free base) at a dose of 1.2 mg/day administered orally as one capsule, 5 days on/2 days off for 8 weeks.

3.2 BPD Cohort

Six patients with BPD were recruited, but there was one dropout, and therefore the results reported here correspond to the 5 subjects with BPD eligible for analysis. A summary of the patients included in this BPD cohort (baseline demographics) can be found in Table 1.

Table 1:

Demographic data of patients with BPD number of patients 6 Floor Male 0 (0%) Female 6 (100%) Age Average (years) 37.33 (min, max) (25/46) Race Caucasoid 6 (100%) Weight Average (kg) 60.72 (min, max) (52.7/89.8) Height Average (cm) 164.37 (min, max) (162/172) BMI Average 22.51 (min, max) (19.39/33.39)

3.3 Evaluation of effectiveness in the BPD cohort

The evaluation of treatment efficacy in patients with BPD was conducted using a validated BPD-specific scale, the Borderline Personality Disorder Checklist (BPDCL). The BPDCL is an instrument specifically designed to assess the subjective burden of BPD in the past month, as well as to assess changes in BPD following therapeutic intervention. Originally developed in Dutch, the BPDCL was subsequently translated into English, Spanish, and other languages and administered to clinical and non-clinical samples. The BPDCL has been shown to exhibit adequate psychometric properties and is currently considered the most reliable scale for assessing the efficacy of treatments targeting BPD.

The BPDCL is a 47-item self-report questionnaire; items were based on the DSM-IV BPD criteria, literature describing BPD presentations, and clinical observations. Items are rated on a 5-point Likert scale ranging from “not at all” to “extremely,” indicating how bothered the respondent has been by 47 different BPD complaints during the past month. The 47 items in the BPDCL can be grouped together into the following 9 BPD domains:

1) Abandonment

2) Relationships

3) Violation of identity

4) Impulsivity

5) (Para)suicide

6) Affective instability

7) Emptiness

8) Anger control

9) Dissociation

The overall BPDCL total score (BPDCL total score) can be used as an overall index of subjective burden caused by BPD symptoms, or total scores for one or more individual BPD domains can be used.

The BPDCL was performed on day 1 (visit 1), corresponding to baseline (i.e., before initiation of vafidemstat treatment), and at week 8 of vafidemstat treatment (visit 7). Efficacy assessments were always performed before treatment assignment on the corresponding visit day.

Efficacy was assessed by assessing the change from baseline (Visit 1) to Week 8 (Visit 7) in the BPDCL aggression-related domain composite score (i.e., the score resulting from the combination of the scores of the BPDCL domains related to aggressive behavior, namely, anger control, impulsivity, and (para)suicide), the BPDCL total score, and the BPDCL non-aggression-related domain dominance score (i.e., the score resulting from the combination of all other BPDCL domain scores, namely, abandonment, relationships, identity disturbance, affective instability, emptiness, and dissociation).

Statistical analysis was performed using paired one-tailed t-tests to compare visit 1 values with visit 7 values.

3.4 Results

Treatment with vafidemstat in patients with BPD was safe and well tolerated, without significant adverse effects.

Treatment of BPD patients with vafidemstat for 8 weeks resulted in a significant reduction in aggression, as evidenced by a statistically significant reduction in the combined score of the aggression-related domains of the BPDCL (as detailed above in Example 3.3) from Visit 1 to Visit 7, as shown in Figure 1 (p=0.0029).

Surprisingly, not only the aggression-related composite score but also the BPDCL total score and the BPDCL non-aggression domain composite score showed statistically significant reductions after 2 months of vafidemstat treatment, as shown in Figure 2 (BPDCL total score, p=0.0048) and Figure 3 (BPDCL non-aggression domain composite score, p=0.0234).

The significant improvements observed in the BPDCL total score and in the non-aggressiveness composite score when treating patients with BPD with vafidemstat indicate that KDM1A inhibitors such as vafidemstat have additional therapeutic effects in patients with BPD beyond treating aggression.

Taken together, the data and results obtained in Example 3 support the conclusion that KDM1A inhibitors, especially vafidemstat, may be useful for the treatment of BPD, including the treatment of core features of BPD or non-aggressive BPD symptoms.

Using the protocol described in Example 3 herein, the therapeutic effects of other KDM1A inhibitors as treatments for BPD can be tested.

All publications, patents and patent applications cited in this document are hereby incorporated by reference in their entireties.

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

Although the invention has been described in connection with specific embodiments thereof, it is to be understood that it is susceptible of further modifications, and this application is intended to cover any variations, uses or adaptations of the invention, following generally the principles of the invention and including such departures from the present description as come within known or customary practice in the art to which the invention pertains and as may be applied to the essential features set forth above and as further set forth in the appended claims.

Claims (12)

1. A method of treating borderline personality disorder in a patient by treating one or more non-aggressive symptoms of borderline personality disorder, comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor, 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. 2. The method according to claim 1, wherein the patient to be treated is a human. 3. The method according to claim 1 or 2, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine. 4. The method according to any one of claims 1-3, wherein the method comprises orally administering a KDM1A inhibitor. 5. Use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of borderline personality disorder by treating one or more non-aggressive symptoms of borderline personality disorder, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)-cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or a pharmaceutically acceptable salt or solvate thereof. 6. The use according to paragraph 5, where the patient to be treated is a human. 7. The use according to claim 5 or 6, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine. 8. Use according to any of paragraphs 5-7, where the medicinal product is intended for oral administration. 9. Use of a KDM1A inhibitor for the treatment of borderline personality disorder by treating one or more non-aggressive symptoms of borderline personality disorder, 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 use according to paragraph 9, where the patient to be treated is a human. 11. The use according to claim 9 or 10, wherein the KDM1A inhibitor is 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine. 12. The use according to any one of claims 9-11, wherein the KDM1A inhibitor is administered orally.

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