Compound for use in the treatment of depression, obsessive-compulsive disorder, post-traumatic stress disorder and / or borderline personality disorder

Abstract

The present invention relates to Compound 1 for the use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder, and / or Borderline Personality Disorder, chemical synthesis of Compound 1, polymorphs of Compound 1, and pharmaceutical compositions comprising Compound 1 and / or its polymorphs.

Description

[0001] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 1 - 05.05.2025New medical use of Compound 1The present inven^on relates to Compound 1 for the use in the treatment of Major DepressiveDisorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodesassociated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c StressDisorder, and / or Borderline Personality Disorder, chemical synthesis of Compound 1,polymorphs of Compound 1, and pharmaceu^cal composi^ons comprising Compound 1 and / orits polymorphs. Major depressive disorder (MDD) has been ranked as the third cause of the burden of diseaseworldwide in 2008 by WHO, which has projected that this disease will rankfirst by 2030 (MalhiGS, Mann JJ. Depression. Lancet.2018 Nov 24;392(10161):2299-2312). It is diagnosed when anindividual has a persistently low or depressed mood, anhedonia or decreased interest in pleasurable ac^vi^es, feelings of guilt or worthlessness, lack of energy, poor concentra^on, appe^te changes, psychomotor retarda^on or agita^on, sleep disturbances, or suicidal thoughts. Per the Diagnos^c and Sta^s^cal Manual of Mental Disorders, 5th Edi^on (DSM-5), an individual must havefive of the above-men^oned symptoms, of which one must be a depressed mood or anhedonia causing social or occupa^onal impairment, to be diagnosedwith MDD. The 12-month prevalence of major depressive disorder varies considerably acrosscountries but is approximately 6%, overall. The life^me risk of depression is three ^mes higher (15–18%), meaning major depressive disorder is common, with almost one infive peopleexperiencing one episode at some point in their life^me. The onset of depression is usuallygradual, but it can be abrupt some^mes, and depression’s course throughout life variesconsiderably. This disorder is a recurrent lifelong illness, and with treatment e.gan^depressants, episodes last about 3–6 months, and most pa^ents recover within 12 months. Longer-term (2–6 years), the propor^on of people who recover is much less, dropping to approximately 60% at 2 years, 40% at 4 years, and 30% at 6 years with comorbid anxiety having a key role in limi^ng recovery. The pharmacotherapy for major depressive disorder has been founded on enhancement of monoaminergic neurotransmission, e.g. by selec^ve serotoninreuptake inhibitors (SSRIs), but treatment response is only around 40-50% (Steinert T, WorldPsychiatry.2018 Feb;17(1):114-115), so that ul^mately there are about 30% of pa^ent, wheretreatment failed and meet the criteria treatment-resistant (McIntyre et al. World Psychiatry.2023 Oct; 22(3): 394–412). Newer genera^ons of poten^al an^depressants try to target otherBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 2 - 05.05.2025brain systems such as the glutamatergic and / or GABAergic system by e.g. inhibi^on of N-methyl-D-aspartate (NMDA) receptors. Bipolar disorder (BD) is a serious and debilita^ng psychiatric disorder affec^ng mul^pledomains of mood, emo^ons, and cogni^on (Jawad et al. Brain Sci.2023 Jun 4;13(6):909).Overall, BD has a global prevalence of >1% and cons^tutes a major healthcare burden. Pa^entswith BD o^en have two dis^nct mood episodes, i.e., mania / hypomania and depression. Usingthe criteria for mood episodes and their dura^on, severity, and occurrence, BD is broadlyclassified into BD-I, BD-II, and cyclothymia in the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5th edi^on. Bipolar depression accounts for the majority of ^me spent unwell for pa^ents with bipolar disorder; high rates of morbidity and mortality arise from fullsymptoma^c episodes and interepisode subsyndromal symptoms (McIntyre et al., Curr MedRes Opin.2019 Nov;35(11):1993-2005). Life^me and 12 month prevalence of bipolar II disorder, a common bipolar phenotype that is related to chronic depression, have been es^mated at 1.1% and 0.8%, respec^vely, with briefer and less severe hypomanic episodes thought to be experienced by up to 4–6% of the popula^on. More than 90% of individuals who have a manic episode proceed to develop recurrent mood episodes and about 60% of manicepisodes occur immediately before a major depressive episode. Though mania / hypomania arethe defining features of BD, pa^ents typically spend rela^vely more ^me experiencing depressive symptoms, and despite the significant burden of bipolar depression, there are only a handful of Food and Drug Administra^on (FDA)-approved treatments for this specific condi^on (i.e., olanzapine andfluoxe^ne combina^on, que^apine, lurasidone, cariprazine, andlumateperone), which have significant long-term adverse effects (Cordner ZA., GeneralPsychiatry, 2022;35:e100760. doi:10.1136 / gpsych-2022-100760).Obsessive compulsive disorder (OCD) is a long-las^ng disorder in which a person experiencesuncontrollable and recurring thoughts (obsessions), engages in repe^^ve behaviors(compulsions), or both (Na^onal Ins^tute of Mental Health homepage:www.nimh.nih.gov / health / topics / obsessive-compulsive-disorder-ocd). People with OCD,classified by the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5th edi^on, have^me-consuming symptoms that can cause significant distress or interfere with daily life andthey may have obsessions, compulsions, or both. Obsessions^are repeated thoughts, urges, ormental images that are intrusive, unwanted, and make most people anxious. Commonobsessions include: Fear of germs or contamina^on; Fear of forge^ng, losing, or misplacingsomething; Fear of losing control over one’s behavior; Aggressive thoughts toward others orBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 3 - 05.05.2025oneself; Unwanted, forbidden, or taboo thoughts involving sex, religion, or harm; Desire to have things symmetrical or in perfect order. Compulsions are repe^^ve behaviors a person feels the urge to do, o^en in response to an obsession. Common compulsions include: Excessive cleaning or handwashing; Ordering or arranging items in a par^cular, precise way; Repeatedly checking things, such as that the door is locked or the oven is off; Compulsivecoun^ng; Praying or repea^ng words silently. OCD has a life^me prevalence of 2–3% and ismore common in females than in males (Stein et al., Nat Rev Dis Primers, 2019 Aug 1;5(1):52.doi: 10.1038 / s41572-019-0102-3). OCD typically starts early in life and has a long dura^on, and in females, onset o^en occurs during adolescence. Treatment of OCD comprises several components, star^ng with building a therapeu^c alliance with the pa^ent and psychoeduca^on, followed by psychological and / or pharmacological approaches. Regarding pharmacotherapy, SSRIs are thefirst-line pharmacological treatment for OCD based on their evidence of efficacy, tolerability, safety and absence of abuse poten^al, but responder rates are poor and side effects might limit their use in OCD, so that ul^mately, be^er (and preferably faster) treatments are needed to help more individuals with OCD.Post-Trauma^c Stress Disorder (PTSD) is a disorder that develops in some people who haveexperienced a shocking, scary, or dangerous event, and it is characterized by symptoms of re- experiencing, avoidance, nega^ve altera^ons in cogni^on and mood, and marked altera^ons in arousal and reac^vity following exposure to a trauma^c event (Merians et al., Med Clin North Am.2023 Jan;107(1):85-99. doi: 10.1016 / j.mcna.2022.04.003). Symptoms of PTSD usually begin within 3 months of the trauma^c event, but they some^mes emerge later. Based on the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5thedi^on, to meet the criteria for PTSD, a person must have symptoms for longer than 1 month, and the symptoms must be severe enough to interfere with aspects of daily life, such as rela^onships or work. Thesymptoms also must be unrelated to medica^on, substance use, or other illness. In America,around 3.6% of the grown-up popula^on, which is es^mated to be 5.2 million, have PTSD over a year (Thakur et al., Curr Mol Pharmacol.2022;15(3):502-516). PTSD is a long-life effect of the con^nuous occurrence of trauma^c condi-^ons, leading to the produc^on of feelings of helplessness, intense fear, and horror in the person. Treatment of PTSD includes the removal or reduc^on of th-ese emo^onal feelings or symptoms with the aim to improve the daily life func^oning of a person, and it might include also pharmacotherapy with SSRIs. However, based on reviews and meta-analyses showing that pharmacotherapies are less effec^ve than trauma- focused psychotherapeu^c interven^ons in reducing PTSD severity, pharmacotherapies are recommended as only as second-line treatment.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 4 - 05.05.2025Boderline Personality Disorder (BPD) is a serious mental health disorder characterized by pervasive instability in moods, interpersonal rela^onships, self-image, and behavior. The disorder's pervasive instability in moods, interpersonal rela^onships, self-image, and behavior o^en disrupts family dynamics, work life, and the individual's sense of self-iden^ty. BPD is a mental health condi^on that places a significant burden not only on the individuals diagnosed with it but also on their families and the broader health-care systems. BPD affects approximately 1.6% of the general popula^on, but thisfigure may be as high as 5.9%. It is more commonly diagnosed in females, with 75% of diagnoses made in women. BPD can occur in anyone, but the onset of a coherent syndrome of BPD typically occurs during adolescence, generally a^er the age of 12 years (Bohus M, Stoffers-Winterling J, Sharp C, Krause-Utz A, Schmahl C, Lieb K, Lancet October 23, 2021; Volume 398 (Issue 10310), 1528- 1540. doi: 10.1016 / S0140-6736(21)00476-1.). This cri^cal period of development is o^en marked by significant emo^onal and psychological changes, which can exacerbate the symptoms of BPD. The disorder appears to be more common in those with a family history of the disorder or a history of child abuse, neglect, or separa^on from caregivers in early childhood. BPD o^en co-develops with or is preceded by symptoms of internalizing disorders such as depression and anxiety, and externalizing disorders like conduct problems, hyperac^vity, and substance use. This comorbidity further complicates the diagnosis and management of BPD. The disorder is associated with various adverse outcomes, including low occupa^onal and educa^onal a^ainment, lack of long-term rela^onships, increased partner conflict, sexual risk-taking, low levels of social support, and low life sa^sfac^on. These outcomes highlight the pervasive impact of BPD on mul^ple aspects of an individual's life. Increased service use is another significant concern associated with BPD. Individuals with the disorder o^en require extensive mental health services, including psychotherapy and, in some cases, medica^on for comorbid condi^ons or during crises when psychosocial interven^ons are insufficient.WO2020 / 079039 discloses a number of 4-pyrazin-2-ylmethyl-morpholines showing NR2Bnega^ve allosteric modula^ng proper^es. Among others, WO2020 / 079039 discloses Compound 1Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 5 - 05.05.2025 Further, WO2020 / 079039 generically discloses that the compounds exemplified therein may be used in the treatment of psychiatric disorders, diseases and condi^ons wherein nega^ve allosteric modula^on of NR2B is of therapeu^c benefit, e.g. (1) mood disorders and mood affec^ve disorders; (2) schizophrenia spectrum disorders; (3) neuro^c, stress-related and somatoform disorders including anxiety disorders; (4) disorders of psychological development;(5) behavioral syndromes associated with physiological disturbances and physical factors; (6)substance-related and addic^ve disorders; (7) disease associated with symptoms of nega^ve and posi^ve valence; (8) pain; (9) cerebrovascular diseases; (10) episodic and paroxysmal disorders; (11) neurodegenera^ve diseases. Specifically, WO2020 / 079039 discloses that the compounds exemplified therein may be used inthe treatment of a disorder, disease or condi^on selected from the list consis^ng of(1) treatment of mood disorders and mood affec^ve disorders including bipolar disorder I depressed, hypomanic, manic and mixed form; bipolar disorder II; depressive disorders, such assingle depressive episode or recurrent major depressive disorder, minor depressive disorder,depressive disorder with postpartum onset, depressive disorders with psycho^c symptoms; major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psycho^c features, mood-incongruent psycho^c features, catatonia. (3) treatment of disorders belonging to the neuro^c, stress-related and somatoform disorders including anxiety disorders, general anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive compulsiveBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 6 - 05.05.2025disorder; reac^on to sever stress and adjustment disorders, such as post-trauma^c stress disorder; other neuro^c disorders such as depersonaliza^on-derealisa^on syndrome. The objec^ve technical problem underlying the present inven^on is thus to provide a drugsubstance which may be used in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and / or Borderline Personality Disorder.In a clinical study designed to inves^gate Compound 1 for the treatment of Major DepressiveDisorder it was surprisingly found that administra^on of Compound 1 – in comparison withplacebo – resulted in promising preliminary efficacy signals of a rapid, sustained effect withgood tolerability.According to the present inven^on, Compound 1 has surprisingly been found to fulfil theabove-men^oned criteria required for use in the treatment of Major Depressive Disorder,Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and / or Borderline Personality Disorder.According to afirst aspect, the present inven^on provides Compound 1: Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 7 - 05.05.2025for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, BipolarDepressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and / or Borderline Personality Disorder. According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that 0.5 - 40 mg of Compound 1 are to beadministered. According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that 2.5 - 25 mg, preferably 5 – 20 mg, of Compound1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or 40 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 5, 10, or 20 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that Compound 1 is to be administered once daily,twice weekly, every other day or once weekly. According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that Compound 1 is to be administered once daily.According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that Compound 1 is to be administered orally.According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that Compound 1 is to be administered in addi^on totreatment with another an^depressant drug.According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered as an adjunc^ve therapy to another an^depressant drug.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 8 - 05.05.2025According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 to be administered as an adjunc^ve therapy to another an^depressant drug for the treatment of Major Depressive Disorder. According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that the an^depressant drug is selected from thegroup consis^ng of selec^ve serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI).According to another aspect, the present inven^on provides Compound 1 according to any oneof the preceding aspects, characterized in that the an^depressant drug is selected from thegroup consis^ng of Sertraline, Sertraline Hydrochloride, Escitalopram, Escitalopram Oxalate,Fluoxe^ne, Duloxe^ne, Citalopram, Citalopram Hydrobromide, Desvenlafaxine Succinate Monohydrate, Doxepin, Fluoxe^ne Hydrochloride, Mirtazapine, Trazodone, and Venlafaxine Hydrochloride.WO2020 / 079039 discloses the synthesis of Compound 1 Form II. Now, it has surprisingly beenfound that another polymorphic form, Compound 1 Form I, exists. Both Compound 1 Form IIand Compound 1 Form I, respec^vely, can be synthesized in pure form. Compound 1 Form IIwas obtained in a purity >99% (ra^o between Compound 1 Form II and Compound 1 Form I>99:1 based on XRPD).Further, both Compound 1 Form II and Compound 1 Form I are characterized by itscorresponding XRPD, Raman, and DSC data.The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising a peak at thefollowing 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å,40kV, 40mA: 6.8° ±0.2°. The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising peaks at any one orall of the following 2-theta values measured using monochroma^c CuKα1 radia^on of λ =1.54056 Å, 40kV, 40mA: 6.8° ±0.2°, 10.8° ±0.2°, 11.6° ±0.2°, 17.6° ±0.2°, 22.1° ±0.2°. The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising a peak at theBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 9 - 05.05.2025following 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å,40kV, 40mA: 6.8° ±0.2°, and the Raman spectrum comprises a peak at the following Raman shi^ expressed in wavenumbers in cm-1: 89.8 ±1.5. The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, has a purity >75% (ra^o between Compound 1 Form II and Compound 1Form I >75:25 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, has a purity >90% (ra^o between Compound 1 Form II and Compound 1Form I >90:10 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, has a purity >95% (ra^o between Compound 1 Form II and Compound 1Form I >95:5 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020 / 079039, namelyCompound 1 Form II, has a purity >99% (ra^o between Compound 1 Form II and Compound 1Form I >99:1 based on XRPD).According to another aspect, the present inven^on provides Compound 1 Form I showing a X-ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured usingmonochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°.According to another aspect, the present inven^on provides Compound 1 Form I showing a X-ray powder diffrac^on pa^ern comprising peaks at any one or all of the following 2-thetavalues measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3°±0.2°, 10.7° ±0.2°, 16.0° ±0.2°, 20.3° ±0.2°, 21.2° ±0.2°.According to another aspect, the present inven^on provides Compound 1 Form I showing a X-ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured usingmonochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°, and the Ramanspectrum comprises peaks at any one or all of the following Raman shi^s expressed inwavenumbers in cm-1: 64.9 ±1.5, 99.6 ±1.5.According to another aspect, the present inven^on provides Compound 1 Form I having apurity >10% (ra^o between Compound 1 Form I and Compound 1 Form II >10:90 based onXRPD).Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 10 - 05.05.2025According to another aspect, the present inven^on provides Compound 1 Form I having apurity >20% (ra^o between Compound 1 Form I and Compound 1 Form II >20:80 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >30% (ra^o between Compound 1 Form I and Compound 1 Form II >30:70 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >40% (ra^o between Compound 1 Form I and Compound 1 Form II >40:60 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >50% (ra^o between Compound 1 Form I and Compound 1 Form II >50:50 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >60% (ra^o between Compound 1 Form I and Compound 1 Form II >60:40 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >70% (ra^o between Compound 1 Form I and Compound 1 Form II >70:30 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >75% (ra^o between Compound 1 Form I and Compound 1 Form II >75:25 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >80% (ra^o between Compound 1 Form I and Compound 1 Form II >80:20 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >90% (ra^o between Compound 1 Form I and Compound 1 Form II >90:10 based onXRPD).According to another aspect, the present inven^on provides Compound 1 Form I having apurity >95% (ra^o between Compound 1 Form I and Compound 1 Form II >95:5 based onXRPD).Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 11 - 05.05.2025According to another aspect, the present inven^on provides Compound 1 Form I having apurity >99% (ra^o between Compound 1 Form I and Compound 1 Form II >99:1 based onXRPD).In another aspect, the present inven^on relates to Compound 1, Compound 1 Form I,Compound 1 Form II or mixtures thereof for use in the treatment of above men^oneddiseases, condi^ons and symptoms. Further, it has surprisingly been found that by combining lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and / or Magnesium stearate withCompound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in apharmaceu^cal composi^on the drug load can be adjusted to the same level for all dose strengths and a fast dissolu^on of the tablet can be reached. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprisingCompound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and lactosemonohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and / or Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of Compound 1, Compound 1 Form I, Compound 1 Form II,or a mixture thereof, and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.1-10 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 50-90 % (wt / wt) lactose monohydrate, 10-50 %(wt / wt) microcrystalline cellulose, 0.5-15 % (wt / wt) hydroxypropyl cellulose, 0.5-15 % (wt / wt) croscarmellose sodium and 0.1-3 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.3-7 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 55-80 % (wt / wt) lactose monohydrate, 15-45 %(wt / wt) microcrystalline cellulose, 1-7 % (wt / wt) hydroxypropyl cellulose, 1-7 % (wt / wt) croscarmellose sodium and 0.2-1 % (wt / wt) Magnesium stearate.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 12 - 05.05.2025According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.6-1 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 60-70 % (wt / wt) lactose monohydrate, 20-40 %(wt / wt) microcrystalline cellulose, 2-4 % (wt / wt) hydroxypropyl cellulose, 2-4 % (wt / wt) croscarmellose sodium and 0.3-0.8 % (wt / wt) Magnesium stearate. Further, it has surprisingly been found that by combining mannitol and / or maize starch withCompound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in apharmaceu^cal composi^on the stability can be increased. Further, it has surprisingly been found that by adding afilm coa^ng comprising propylene glycol to the pharmaceu^cal composi^on (tablet core) the stability can be increased. The aforemen^onedfilm coa^ng is enveloping the pharmaceu^cal composi^on (tablet core) whichis comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof andmannitol and / or maize starch. Further, it has surprisingly been found that by combining mannitol, maize starch,croscarmellose sodium and / or Magnesium stearate with Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof in a pharmaceu^cal composi^on the drug load canbe adjusted to the same level for all dose strengths and a fast dissolu^on of the tablet can be reached. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprisingCompound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitoland / or maize starch. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprisingCompound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol,maize starch, croscarmellose sodium and / or Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of Compound 1, Compound 1 Form I, Compound 1 Form II,or a mixture thereof, and mannitol, maize starch, croscarmellose sodium and Magnesiumstearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.1-10 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 40-95 % (wt / wt) mannitol, 2-20 % (wt / wt)Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 13 - 05.05.2025maize starch, 0.5-10 % (wt / wt) croscarmellose sodium and 0.1-3 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.3-7 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 50-90 % (wt / wt) mannitol, 3-15% (wt / wt) maizestarch, 1-7 % (wt / wt) croscarmellose sodium and 0.3-2 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 0.6-5 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 60-88 % (wt / wt) mannitol, 5-10 % (wt / wt)maize starch, 2-5 % (wt / wt) croscarmellose sodium and 0.5-1.5 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 3-20 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 40-95 % (wt / wt) mannitol, 2-20 % (wt / wt)maize starch, 0.5-10 % (wt / wt) croscarmellose sodium and 0.1-3 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 4-15 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 50-90 % (wt / wt) mannitol, 3-15 % (wt / wt)maize starch, 1-7 % (wt / wt) croscarmellose sodium and 0.3-2 % (wt / wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^oncomprising a tablet core consis^ng of 6-10 % (wt / wt) Compound 1, Compound 1 Form I,Compound 1 Form II, or a mixture thereof, and 60-88 % (wt / wt) mannitol, 5-10 % (wt / wt)maize starch, 2-5 % (wt / wt) croscarmellose sodium and 0.5-1.5 % (wt / wt) Magnesium stearate. Another aspect of the present inven^on relates to a pharmaceu^cal composi^on as defined above for use in the above-men^oned diseases, condi^ons and symptoms. Another aspect of the present inven^on relates to a method of treatment of above-men^oned diseases, condi^ons and symptoms.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 14 - 05.05.2025Brief Descrip^on of the FiguresFigure 1 shows the X-ray powder diffractogram of Compound 1 Form IFigure 2 shows the X-ray powder diffractogram of Compound 1 Form IIFigure 3 shows the RAMAN spectrum of Compound 1 Form IFigure 4 shows the RAMAN spectrum of Compound 1 Form IIFigure 5 shows the Differen^al Scanning Calorimetry profile for Compound 1 Form IFigure 6 shows the Differen^al Scanning Calorimetry profile for Compound 1 Form IIFigure 7 shows Adjusted mean (SE) of absolute change from baseline in MADRS total score over ^me

[0002] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 15 - 05.05.2025General defini^ons Terms not specifically defined herein should be given the meanings that would be given tothem by one skilled in the art in light of the disclosure and the context.Compound 1If not otherwise specified, the term Compound 1 relates to the compound of the followingstructure in any polymorphic form or mixtures or pharmaceu^cally acceptable salts or hydrates thereof.Subject Human pa^ent.

[0003] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 16 - 05.05.2025EXPERIMENTAL PART List of abbrevia^onsAc acetateAE Adverse Eventa.m.u. atomic mass unitarb arbitraryATP Adenosine triphosphateBoc tert-butyloxycarbonylcAMP Cyclic adenosine monophosphateCbz BenzyloxycarbonylCDI 1,1’-carbonyldiimidazoleconc concentratedCpd CompoundDIEA diisopropylethylamineDMSO Dimethyl sulfoxideDSM-5 Diagnos^c and Sta^s^cal Manual of Mental Disorders, 5th edi^onECG electrocardiogramEGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraace^c acid),also known as egtazic acidESI electrospray ioniza^onh hourHCl hydrochloric acidHEK293 cell line derived from human embryonic kidney cellsHEPES hydroxyethyl-piperazineethane-sulfonic acid bufferHR high-resolu^onHRMS high resolu^on mass spectrometryIC50 half maximal inhibitory concentra^onIPA isopropanolIPAc isopropyl acetateKetoABNO 9-azabicyclo[3,3,1]nonan-3-one-9-oxylkg kilogramL literM mole, mol / LMDD Major depressive disorderMe methylBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 17 - 05.05.2025MedDRA Medical Dic^onary for Drug Regulatory Ac^vi^esMHz megahertzmL milliliterMMRM mixed model for repeated measureMS mass spectrometrym / z mass-to-charge ra^oN number of pa^entsNMDA N-methyl-D-aspartate receptorNMP 1-methyl-2-pyrrolidoneNMR nuclear magne^c resonanceNR1 N-methyl D-aspartate receptor subtype 1NR2B N-methyl D-aspartate receptor subtype 2BpH poten^al of hydrogenpsi pounds per square inchqd quaque die (once a day)q.s. quantum sa^srpm revolu^ons per minuteRT room temperatureSAE Serious Adverse EventSE Standard ErrorSNRI Serotonin-Norepinephrine Reuptake InhibitorSSRI Selec^ve Serotonin Reuptake InhibitorTHF tetrahydrofuranTMEDA tetramethylethylenediamineTS Treated setwt weightXRPD X-ray powder diffrac^onBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 18 - 05.05.2025Prepara^on and physicochemical characteriza^on of Compound 1 Descrip^on of analy^cal methods used ESI mass spectrometry (ESI+)Instrument Thermo Orbitrap Fusion LumosInstrument control so^ware XCalibur Version 4.4.16.14Ion source HESI (Heated Electrospray)Detector OrbitrapResolving power 120,000Automa^c Gain Control (AGC) 50 ms (Maximum Injec^on Time)Microscans 1Polarity Posi^veData Type ProfileSpray Voltage (Sta^c) 3.5 kVSheath Gas Flow Rate 40 arbAux Gas Flow Rate 10 arbSweep Gas Flow Rate 0 arbVaporizer Temperature 350 °CIon Transfer Tube Temperature 300 °CRF Lens 60%Desolva^on gas NitrogenSample inlet Thermo Vanquish UPLCSpray solventflow rate 0.3 mL / minSample concentra^on < 0.05 mg / mLBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 19 - 05.05.2025Reagents Fisher Op^ma LC / MS Water, Acetonitrile, Formic AcidScan range (m / z) 100 – 700 a.m.u.1H NMR spectroscopyInstrument Bruker 400 MHzFrequency 400.13 MHzSo^ware Topspin 4.1.3Pulse program zg10Solvent CDCl3Concentra^on 10 mg / 500 µLTemperature 300 KCalibra^on CDCl3; 7.24 ppmSweep width 14.7 ppm; 5882.4 HzSize 64 KPulse width 10 degreesRelaxa^on delay 2.0 sNumber of scans 16Dummy scans 4Apodiza^on 327681H NMR spectroscopyInstrument Bruker 600 MHzFrequency 600.20 MHzSo^ware Topspin 4.1.4Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 20 - 05.05.2025Pulse program zg10Solvent DMSOConcentra^on 2.8 mg / 250 µLTemperature 300 KCalibra^on DMSO; 2.50 ppmSweep width 20.83 ppm; 12500 HzSize 32768 ptsPulse width 10 degreesRelaxa^on delay 2.0 sNumber of scans 64Dummy scans 2Apodiza^on Exponen^al, 0.05 Hz13C NMR spectroscopyInstrument Bruker 400 MHzFrequency 100.62 MHzSo^ware Topspin 4.1.3Pulse program ZgpgSolvent CDCl3Concentra^on 10 mg / 500 µLTemperature 300 KCalibra^on CDCl3; 77.0 ppmSweep width 236.6 ppm; 23809.5 HzSize 64 KBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 21 - 05.05.2025Pulse width 90 degreesRelaxa^on delay 2.0 sNumber of scans 2000Dummy scans 4Apodiza^on 3276813C NMR spectroscopyInstrument Bruker 600 MHzFrequency 150.92 MHzSo^ware Topspin 4.1.4Pulse program zgpg30Solvent DMSOConcentra^on 2.8 mg / 250 µLTemperature 300 KCalibra^on DMSO; 39.50 ppmSweep width 236.62 ppm; 35714.285 HzSize 65536 ptsPulse width 30 degreesRelaxa^on delay 0.5 sNumber of scans 16384Dummy scans 8Apodiza^on Exponen^al, 1.0 HzBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 22 - 05.05.202519F NMR spectroscopyInstrument Bruker 400 MHzFrequency 376.46 MHzSo^ware Topspin 4.1.3Pulse program zgigSolvent CDCl3Concentra^on 10 mg / 500 uLTemperature 300 KCalibra^on C6F6 in C6D6 at -164.9 ppmSweep width 198.2 ppm; 74626.8 HzPulse width 90 degreesRelaxa^on delay 1.0 sNumber of scans 16Dummy scans 4Apodiza^on 89552X-ray powder (XRPD) diagramX-ray powder diagrams were generated using a Bruker D8 Advance Davinci-diffractometer inreflectance modefi^ed with a LynxEye Posi^on Sensi^ve detector and a Cu-anode as X-raysource with monochroma^c CuK^1 radia^on (λ = 1.54056 Å, 40kV, 40mA). The standard errorrange for the 2-theta values is ±0.2°. RAMAN spectroscopy Raman spectra were collected using an Agilent TRS 1000. Data was acquired over spectralrange 38 – 2400 cm-1 using a 830 nm enhanced photo diode excita^on laser, a spot size of 4mm and spectral resolu^on of < 8 cm-1. The spectral resolu^on is 1.5 cm-1.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 23 - 05.05.2025Differen^al Scanning Calorimetry diagramThe compounds are characterised by a mel^ng point determined by Differen^al ScanningCalorimetry (DSC), evaluated by the peak maximum or onset temperature. The hea^ng rate ofthe experiment is 10°C / min. The values given were determined using a TA InstrumentsDiscovery DSC 2500TM.

[0004] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 24 - 05.05.2025Prepara^on of Compound 1 General descrip^on of the synthe^c route Two synthesis routes have been developed. Synthesis route I requires a total of seven isola^onsteps to obtain Compound 1 from commercially available star^ng materials. Synthesis route IIoffers a shorter sequence withfive isola^on steps. Synthesis route I impactCH3NH2•HCl CDI, pyridine MeCN(impact-milled) Prepara^on of Compound I-3 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 25 - 05.05.2025I-1 ([33332-25-1], 17.1 kg, 99.1 mol) and potassium carbonate (16.3 kg, 117.9 mol) are chargedto a reactor followed by addi^on of 1-methyl-2-pyrrolidone (70.0 kg). To the resul^ng slurry isadded I-2 ([452-81-3], 13.95 kg, 110.6 mol) at a rate to maintain the internal batch temperatureat 20-35 °C. The reac^on mixture is then heated to 60-65 °C and s^rred for about 2 hours. A^er the reac^on is complete, the batch is cooled to 5-10 °C. Water (204 kg) is added over not less than 30 min at a rate to maintain the internal batch temperature below 25 °C. The slurry is s^rred for not less than 8 hours. The product is collected byfiltra^on and rinsed with water (85.0 kg). The product is then dried in an oven at ~40 °C under reduced pressure for not less than 12 hours.I-3 is obtained as solid (25.2 kg, 97%).1H NMR (400 MHz, CDCl3) δ: 8.80 (d, J = 1.3 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 7.14-7.09 (m, 1H),7.04-6.99 (m, 2H), 4.00 (s, 3H), 2.38 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 164.2, 161.0, 153.9 (d, J = 247.7 Hz), 144.2, 138.1 (d, J = 6.8Hz), 137.7, 137.1 (d, J = 12.7 Hz), 135.0, 125.5 (d, J = 3.3 Hz), 123.2 (d, J = 1.1 Hz), 117.7 (d, J =17.8 Hz), 53.0, 21.2 (d, J = 1.3 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.1.HRMS (ESI): m / z calcd for C13H12N2O3F [M+H]+: 263.0827, found: 263.0826.Prepara^on of Compound I-4 To a solu^on of I-3 (24.1 kg, 91.9 mol) in acetonitrile (113.3 kg) is added methanol (9.65 kg) followed by a slow addi^on of a solu^on of 4.1 M lithium borohydride in tetrahydrofuran (24.6 kg, 110.3 mol) at a rate to maintain the internal batch temperature at 20-25 °C. The reac^on mixture is s^rred at 20-25 °C for about 2 hours un^l comple^on. To the batch is added water (144 kg) over not less than 2 hrs. Vola^les are removed under reduced pressure at 30-35 °C. The batch is cooled to 5-10 °C and added seed crystals I-4 (48.0 g). The resul^ng slurry is aged for notBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 26 - 05.05.2025less than 1 hour prior to addi^on of water (96.0 kg) over not less than 30 minutes at a rate to maintain the internal batch temperature at 5-10 °C. The batch temperature is adjusted to 20-25°C and the slurry is aged for not less than 2 hours. The product is collected byfiltra^on and rinsedwith water (96.0 kg). The product is dried in an oven at 40-50 °C under reduced pressure for notless than 8 hours. I-4 is obtained as solid (15.2 kg).Seed crystals I-4 can be obtained by crystalliza^on of I-4 in acetonitrile and water.1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 1.4 Hz, 1H), 8.10-8.09 (m, 1H), 7.13-7.08 (m, 1H), 7.03-6.97 (m, 2H), 4.75 (s, 2H), 3.20 (br s, 1H), 2.37 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.2 (d, J = 247.3 Hz), 148.7, 139.0, 137.7 (d, J = 12.5Hz), 137.4 (d, J = 6.8 Hz), 133.9, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.3 Hz), 117.6 (d, J = 17.9 Hz),62.7, 21.1 (d, J = 1.3 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m / z calcd for C12H12N2O2F [M+H]+: 235.0877, found: 235.0877. Prepara^on of Compound I-5 A solu^on of I-4 (28.1 kg, 120.0 mol) in acetonitrile (118 kg) isfiltered through a pad of Celite (5.25 kg) and rinsed with acetonitrile (79 kg) to remove insoluble solids. Thefiltrate is concentrated under reduced pressure at 50-55 °C to ~80 L. Thionyl chloride (15.25 kg, 128.2 mol) is added at ~10 °C, while the internal batch temperature is controlled to be below 25 °C. The reac^on mixture is s^rred for about 1 hour and addi^onal thionyl chloride (9.1 kg, 76.1 mol) is added. A^er the reac^on is complete, the batch is cooled to 0-5 °C and added 2 M aqueous sodium hydroxide solu^on (121 kg), at a rate to maintain the internal temperature below 20 °C. The batch is then seeded with I-5 (100 g). Addi^onal 2 M aqueous sodium hydroxide solu^on (121 kg) is added to adjust the pH value to be >10. To the batch is then added water (56 kg) andBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 27 - 05.05.2025aged at ~10 °C for about 1 hour. The slurry of the product isfiltered and washed with water (112 kg). The product is dried in a vacuum oven at about 40 °C for not less than 8 hours. I-5 is obtained as brown solid (26 kg). Recrystalliza^onI-5 (25.4 kg, mol) is suspended in a mixture of isopropanol (48.0 kg) and water (16.0 kg) at ~20°C. The slurry is heated to 55-60 °C for dissolu^on,filtered at ~60 °C, and rinsed with a mixture of isopropanol (7.88 kg) and water (2.62 kg). The batch is then cooled to 35-40 °C, seeded withI-5 (102 g), and aged for ~1 hour. The batch is cooled to 5-10 °C over 2 hours and aged for notless than 8 h. The slurry of the product isfiltered and washed with water (50.9 kg). The productis dried in an oven at about 40 °C under reduced pressure for not less than 8 hours. I-5 is obtainedas solid (22.9 kg, 55% over two steps star^ng from I-3).Seed crystals I-5 can be obtained by crystalliza^on of I-5 in isopropanol and water.1H NMR (400 MHz, CDCl3) δ: 8.45 (d, J = 1.4 Hz, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.13-7.08 (m, 1H),7.04-6.98 (m, 2H), 4.66 (s, 2H), 2.37 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.2 (d, J = 247.4 Hz), 145.9, 140.6, 137.6 (d, J = 6.7Hz), 137.5 (d, J = 12.6 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.3 (d, J = 1.3 Hz), 117.6 (d, J = 17.9 Hz),43.6, 21.1 (d, J = 1.3 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.4.HRMS (ESI): m / z calcd for C12H11N2OClF [M+H]+: 253.0539, found: 253.0538.Prepara^on of Compound I-7 A solu^on of I-6 ([868689-63-8], 17.2 kg, 74.4 mol) in acetonitrile (54 kg) is cooled to about -10°C. To the mixture is added 1,1’-carbonyldiimidazole (19.2 kg, 118.4 mol) as solid por^ons wise at a rate to maintain the internal batch temperature at not more than 0 °C. The reac^on mixtureBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 28 - 05.05.2025is s^rred at -10 °C for about 4 hours. A^er full conversion, methylamine hydrochloride (7.55 kg, 111.8 mol) is added followed by the addi^on of pyridine (8.75 kg, 110.6 mol). The batch is s^rredat -10 °C for about 1 hour un^l comple^on. The reac^on mixture is quenched by the addi^on ofwater (24 kg) and 3 M aqueous hydrochloric acid solu^on (60.6 kg). Organic vola^les are removed under reduced pressure at 40-50 °C to reduce the reactor volume to about 130 L. The remaining aqueous solu^on is extracted twice with isopropyl acetate (89 kg and 60 kg, respec^vely). The combined organic phase is washed sequen^ally with 3 M aqueoushydrochloric acid solu^on (82 kg) and 5 wt% aqueous sodium hydroxide solu^on (54 kg). Thesolvent is removed under reduced pressure at 45-50 °C to a remaining volume of about 60 L. Heptane (47 kg) is added and the the reactor volume is further reduced to about 60 L. Themixture is cooled to 35-40 °C and heptane (58 kg) is added over 30 min. Seed crystals I-7 (85 g)is added and the slurry is aged at 30-40 °C for 1 hour. The slurry is then cooled to 20-25 °C over 1 hour and aged overnight. The slurry of the product isfiltered and washed with heptane (23 kg). The product is dried in an oven at 40-45 °C under reduced pressure for not less than 8 hours.I-7 is obtained as solid (12.1 kg, 67%).Seed crystals I-7 can be obtained by crystalliza^on of I-7 in isopropyl acetate and heptane.1H NMR (400 MHz, CDCl3) δ:6.55 (br s, 1H), 4.32 (d, J = 10.8 Hz, 1H), 3.93-3.83 (m, 3H), 3.54 (td,J = 11.7, 2.9 Hz, 1H), 2.87-2.67 (m, 2H), 2.81 (d, J = 5.0 Hz, 3H), 1.44 (s, 9H).13C{1H} NMR (100 MHz, CDCl3) δ: 169.5, 154.7, 80.5, 75.3, 66.5, 46.3, 42.9, 28.4, 25.6.HRMS (ESI): m / z calcd for C11H21N2O4 [M+H]+: 245.1496, found: 245.1497.

[0005] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 29 - 05.05.2025Prepara^on of Compound 1 crude To a solu^on of I-7 (20.3 kg, 83.1 mol) in acetonitrile (45 kg) is added concentrated hydrochloricacid (24.4 kg, 248.2mol) at 20 °C. The reac^on mixture is s^rred at 20 °C for about 1 hour. A^erfull conversion, to the reac^on mixture is added diisopropylethylamine (42.8 kg, 330.8 mol) at arate to maintain the internal batch temperature not more than 35 °C. A solu^on of I-5 (19.1 kg,75.2 mol) in acetonitrile (45 kg) is then added. The resul^ng reac^on mixture is heated to about 60 °C and s^rred for about 4 hours un^l comple^on. The mixture is concentrated under reduced pressure at 40-45 °C to remove about 70 L of solvent. The resul^ng mixture is cooled to 30-35 °C and isopropyl acetate (66 kg) is added prior to cooling the batch to 20-25 °C. Water (76 kg) is added followed by addi^on of concentrated hydrochloric acid (11.4 kg) to adjust the pH to not more than 5. A^er phase separa^on, the organic layer is discarded and the pH of the aqueous layer is adjusted to pH not less than 8 by addi^on of 2M NaOH (80 kg). Dichloromethane (151 kg) is added for extrac^on. A^er phase separa^on, the organic layer is par^ally removed under reduced pressure at 35-40 °C to reduce the reactor volume to about 47 L. At 30-35 °C, Heptane (104 kg) is added over about 1 hour and the slurry is cooled to 20-25 °C and aged for not less than 8 hours. The slurry of the product isfiltered and washed with heptane (65 kg). The productis dried in an oven at 40-45 °C under reduced pressure for not less than 6 hours. 1 crude isobtained as solid (23.7 kg, 85%). 8.42 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.55-6.54 (m, 1H), 4.04 (dd, J = 10.5, 2.7 Hz, 1H), 3.90 (ddd, J = 11.3, 3.3,1.5 Hz, 1H), 3.71 (td, J = 11.4, 2.5 Hz, 1H), 3.65 (s, 2H), 3.21 (dt, J = 14.2, 2.8 Hz, 1H), 2.80 (d, J =5.0 Hz, 3H), 2.70 (dd, J = 11.5, 1.8 Hz, 1H), 2.36 (s, 3H), 2.25 (td, J = 11.5, 3.3 Hz, 1H), 2.06 (dd, J= 11.2, 10.8 Hz, 1H).Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 30 - 05.05.202513C{1H} NMR (100 MHz, CDCl3) δ: 170.3, 158.9, 154.3 (d, J = 247.3 Hz), 146.5, 141.0, 137.7 (d, J =12.5 Hz), 137.3 (d, J = 6.7 Hz), 134.4, 125.3 (d, J = 3.3 Hz), 123.5 (d, J = 1.2 Hz), 117.6 (d, J = 17.9Hz), 75.7, 66.6, 61.2, 55.5, 53.8, 25.6, 21.1 (d, J = 1.2 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.6. HRMS (ESI): m / z calcd for C18H22N4O3F [M+H]+: 361.1671, found: 361.1669.Prepara^on of Compound 1 Form II 1 crude (22.55 kg, 62.6 mol) is suspended in a mixture of isopropanol (26.1 kg) and H2O (33.1kg). The batch is heated to 60-65 °C to ensure complete dissolu^on of solids. The solu^on is polishfiltered at 60-65 °C and rinsed with a mixture of isopropanol (17.4 kg) and water (22 kg).The solu^on is then cooled to 40-45 °C and added seed crystals Compound 1 Form II (44 g). Theslurry is aged at 40-45 °C for not less than 1 hour. Water (242 kg) is added over not less than 2 hours. The slurry is cooled to 20-25 °C over about 30 min and aged for not less than 6 hours. Theslurry isfiltered and the solid product is washed with water (44 kg). The product is dried in anoven at about 65 °C under reduced pressure for not less than 12 hours. Compound 1 Form II isobtained as solid (21.0 kg, 96%).Seed crystals Compound 1 Form II can be obtained by crystalliza^on of 1 in isopropanol andwater. Prepara^on of Compound 1 Form I 1 crude (7.5g) is suspended in a mixture of isopropanol (37.5 ml) and water (37.5ml). The batch is heated to 60oC to ensure complete dissolu^on and the solu^on is polishfiltered. Thefiltered solu^on is then transferred to a 1Lflask and water (375ml) is immediately added to quicklyprecipitate the solid, as Form I is a metastable form that must be collected quickly beforeconversion to Form II. The solid is then isolated byfiltra^on and dried under vacuum at 60oC.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 31 - 05.05.2025Synthesis route II Prepara^on of Compound II-2 a) Condi^on I (Cs2CO3):II-1 ([23229-26-7], 1.0 kg, 4.2 mol) and cesium carbonate (1.65 kg, 5.1 mol) are charged to areactor followed by addi^on of isopropyl acetate (3.5 kg). To the resul^ng suspension is added 2-fluoro-4-methylphenol ([452-81-3], 0.58 kg, 4.6 mol) at a rate to maintain the internal batch temperature at no more than 30 °C. The mixture is heated to about 80 °C over 30 min and s^rred for about 2 hours. A^er the reac^on is complete, water (4 kg) is added and the solu^on is cooled to about 40 °C. The agita^on is stopped and the aqueous layer is discarded. The organic layer is concentrated under reduced pressure at about 80 °C to remove isopropyl acetate (~4 L). The batch is cooled to about 60 °C and added isopropanol (3 L). The batch is cooled to about 50 °C and added isopropanol (0.5 L). The batch is cooled to about 40 °C and added isopropanol (0.5 L).The batch is cooled to about 30 °C and added a suspension of seed crystals II-2 (2 g) inisopropanol (20 mL). The slurry is aged at about 30 °C for not less than 30 min and cooled to 5- 10 °C over 2 hours. Water (4 kg) is added over 1 hour. The slurry of the product is aged for not less than 1 hour at about 5 °C. The slurry isfiltered and washed with water (4 kg). The product isBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 32 - 05.05.2025dried in an oven at about 40 °C under reduced pressure for not less than 24 hours. II-2 is obtainedas solid (1.09 kg, 90%).Seed crystals II-2 can be obtained by crystalliza^on of 1 in isopropanol and water.b) Condi^on II (K2CO3):II-1 (1.0 kg, 4.20 mol) and potassium carbonate (0.70 kg, 5.06 mol) are charged to a reactorfollowed by addi^on of acetonitrile (3.19 kg). To the resul^ng slurry is added I-2 (0.55 kg, 4.36mol) over not less than 10 min and the addi^on line is rinsed with acetonitrile (0.4 kg). The mixture is heated to about 70 °C over not less than 45 minutes and s^rred for about 24 hours.A^er the reac^on is complete, the batch is added water (1.5 kg) and cooled to 40-50 °C. Theagita^on is stopped and the lower aqueous layer is discarded. Water (2 kg) is added. Acetonitrile (~3.25 L) is removed under reduced pressure at 60-70 °C. The batch temperature is adjusted to about 60 °C and isopropanol (2.33 kg) is added. The batch is cooled to about 50 °C and added isopropanol (0.4 kg). The batch is cooled to about 40 °C and added isopropanol (0.4 kg). The batch is cooled to 5-10 °C and added water (2.98 kg). The resul^ng slurry is aged at 5-10 °C for about 1 hour. The slurry isfiltered and washed with water (3 kg). The product is dried in an ovenat about 40 °C under reduced pressure for not less than 12 hours. II-2 is obtained as solid (1.0kg, 83%).1H NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.12-7.07 (m, 1H),7.04-6.98 (m, 2H), 2.38 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.1 (d, J = 247.5 Hz), 143.5, 137.8 (d, J = 6.7 Hz), 137.5(d, J = 12.5 Hz), 134.9, 132.4, 125.5 (d, J = 3.3 Hz), 123.2 (d, J = 1.2 Hz), 117.7 (d, J = 17.8 Hz), 21.2(d, J = 1.3 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.4.HRMS (ESI): m / z calcd for C11H9N2OBrF [M+H]+: 282.9877, found: 282.9877.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 33 - 05.05.2025Prepara^on of Compound II-3 To a clean and dry pressure reactor is added II-2 (504.5 g, 1.78 mol), palladium (II) acetate (3.0g, 0.013 mol) and cataCXium A ([321921-71-5], 15 g, 0.042 mol). A solu^on of tetramethylethylenediamine (200 mL, 1.33 mol) in toluene (de-gassed, 3.5 kg) is added to thereactor. The reactor is sealed and purged with syngas (1:1 molar ra^o of CO:H2). The reactor ispressurized to 500 psi with syngas and heated to about 90 °C. A^er 24 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. The mixture isfiltered through Celite (0.1 kg) and rinsed with toluene (0.9 kg). Thefiltrate is washed with 10 wt% aqueous citric acid solu^on (1.66 kg). The organic phase is concentrated under reduced pressure at about 45 °C toobtain a solu^on of II-3 in toluene (668 g, 48.4 wt% by 1H NMR, 79%).1H NMR (400 MHz, CDCl3) δ: 10.1 (s, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.58 (d, J = 1.3 Hz, 1H), 7.15-7.10 (m, 1H), 7.06-7.00 (m, 2H), 2.39 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 190.9, 161.5, 153.9 (d, J = 247.7 Hz), 142.8, 142.0, 138.2 (d, J =6.8 Hz), 137.1 (d, J = 12.8 Hz), 135.4, 125.5 (d, J = 3.3 Hz), 123.1 (d, J = 0.7 Hz), 117.7 (d, J = 17.8Hz), 21.2 (d, J = 1.3 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.1.HRMS (ESI): m / z calcd for C12H10N2O2F [M+H]+: 233.0721, found: 233.0720.Prepara^on of Compound II-4 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 34 - 05.05.2025To a solu^on of I-7 (1.95 kg, 7.98 mol) in acetonitrile (4.7 kg) is added concentrated hydrochloricacid (2.36 kg, 23.9 mol) at a rate to maintain the internal batch temperature at not more than25 °C. The reac^on mixture is s^rred at 15-20 °C for about 2 hours. A^er full conversion, thereac^on mixture is cooled to 0-5 °C and added 50 wt% aqueous sodium hydroxide solu^on (1.92 kg, 23.9 mol) at a rate to maintain the internal batch temperature at not more than 20 °C. Isopropyl acetate (7 kg) and water (8 kg) are added and the batch temperature is adjusted to 5- 10 °C. To the reac^on mixture is added a solu^on of benzyloxy chloroformate (1.58 kg, 8.78 mol) in isopropyl acetate (1 kg) followed by addi^on of 50 wt% aqueous sodium hydroxide solu^on (0.51 kg, 6.38 mol) at a rate to maintain the internal batch temperature at 5-10 °C. The expected pH value is 11-12. The reac^on mixture is then s^rred at 20-25 °C for about 1.5 hours. A^er comple^on, the lower aqueous layer is discarded and the organic layer is washed with water (6 kg). The organic layer is concentrated under reduced pressure at 50-60 °C to reduce the reactor volume to about 4-6 L. Methyl tert-butyl ether (8 L) is added over 15 min at 50-60 °C and thebatch temperature is adjusted to 40-45 °C. A slurry of seed crystals II-4 in methyl tert-butyl ether(200 mL) is added and the batch is cooled to about 25 °C over 1 hour. A mixture of methyl tert-butyl ether (8 L) and heptane (8 L) is added and the slurry is aged for about 1 hour. The slurry ofthe product isfiltered and washed with heptane (16 L). The product is dried in an oven at about50 °C under reduced pressure for not less than 12 hours. II-4 is obtained as solid (1.6 kg, 71%).1H NMR (400 MHz, CDCl3) δ: 7.36-7.29 (m, 5H), 6.54 (br s, 1H), 5.15 (ABq, J = 12.3 Hz, 2H), 4.47(d, J = 11.2 Hz, 1H), 4.00-3.89 (m, 3H), 3.61-3.55 (m, 1H), 3.01-2.78 (m, 2H), 2.83 (d, J = 5.0 Hz,3H).13C{1H} NMR (100 MHz, CDCl3) δ: 169.2, 155.3, 136.4, 128.7, 128.3, 128.2, 75.2, 67.6, 66.5, 46.2, 43.4, 25.7. HRMS (ESI): m / z calcd for C14H19N2O4 [M+H]+: 279.1339, found: 279.1340.Seed crystals II-4 can be obtained by crystalliza^on of II-4 in isopropyl acetate, methyl tert-butylether, and heptane.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 35 - 05.05.2025Prepara^on of Compound 1 crude To a clean and dry pressure reactor is added 10% palladium on carbon (13.5 g, 0.013 mol) andII-4 (776 g, 2.79 mol). Ethanol (1.91 kg) is added to the reactor. The reactor is sealed and purgedwith nitrogen. The reactor is pressurized to 30 psi with hydrogen and heated to about 35 °C. A^er 4 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. A solu^onof II-3 in toluene (1.38 kg, 42.3 wt%, 2.51 mol) is added. The reactor is sealed and purged withnitrogen. The reactor is pressurized to 30 psi with hydrogen and heated to about 50 °C. A^er 12 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. The mixture is filtered through Celite (0.1 kg) and rinsed with ethanol (0.3 kg). To thefiltrate is added water (1.77 kg) and 3 M aqueous hydrochloric acid solu^on (1.23 kg). Ethanol and toluene (4-5 L) are removed under reduced pressure at about 45 °C. The batch is added isopropyl acetate (3.85 kg) and cooled to about 25 °C. A^er phase separa^on, the organic layer is discarded and the aqueous layer is washed with isopropyl acetate (1.72 kg). To the aqueous is added isopropyl acetate (4.18 kg) followed by addi^on of 6 M aqueous sodium hydroxide solu^on (1.5 kg) to adjust the pH to about 10-11. A^er phase separa^on, the organic layer is collected and the aqueous layer is extracted with isopropyl acetate (2.52 kg). The combined organic phase is concentrated under reduced pressure at about 50 °C to reduce the reactor volume to about 1-1.2 L. The batch is cooled to about 40 °C and added heptane (4.1 kg). The batch is cooled to about 20 °C over 30 min and aged for not less than 2 hours. The slurry isfiltered and washed with heptane (1.7 kg). The product is dried in an oven at 50-60 °C under reduced pressure for not less than 8 hours.1crude is obtained as solid (0.8 kg, 87%).Recrystalliza^on of 1 crude to prepare Compound 1 Form II can be performed according to theprocedure described in Synthesis route I.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 36 - 05.05.2025Milling process Compound 1 The milling was performed using the pilot plant impact classifier mill (Hosokowa Alpine MPA 50ZPS) applying the following process parameters for Compound 1 (unmilled Form II):Beater disc speed Classifier SpeedDosage [kg / h] Process gasflow[rpm] [rpm] [m3 / h] 10000 5000 2 80****measured a^er product separa^onfilter unitA par^cle size distribu^on of x50 < 25mm was achieved. Par^cle size was analyzed using aSympatec H4055 with ASPIROS dosing unit at 2 bar pressure and an R2 lense. Prepara^on of metabolite M-1Synthesis route III has been developed to provide synthe^c access to metabolite M-1.Synthesis route III Prepara^on of Compound III-1 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 37 - 05.05.2025I-7 (40 g, 164 mmol) and KetoABNO (10.6 g, 65.5 mmol) are charged to a reactor followed byaddi^on of acetonitrile (200 mL). The batch is cooled to 0-10 °C. To the resul^ng slurry is added perace^c acid (103 mL, 491 mmol) at a rate to maintain the internal batch temperature at 0-15°C. The reac^on mixture is s^rred at 10 °C for about 20 hours. An aqueous 21 wt% sodium sulfitesolu^on (49 g) is added to quench peroxides. Ethyl acetate (200 mL) is added followed by the addi^on of saturated aqueous sodium bicarbonate solu^on (472 mL) to adjust pH to 6-8. A^er phase separa^on, the organic layer is concentrated under reduced pressure at about 50 °C to give a crude reac^on mixture which is purified by silica gel chromatography (gradient 50-100%methyl tert-butyl ether in hexanes). III-1 is obtained as solid (13.9 g, 33%).1H NMR (600 MHz, CDCl3) δ: 8.02-8.01 (NH, m, 1H), 4.41 (dd, J = 9.3, 3.9 Hz, 1H), 4.26 (ABq, J =11.0 Hz, 2H), 3.95 (dd, J = 13.1, 3.9 Hz, 1H), 3.62 (dd, J = 15.5, 6.9 Hz, 1H), 2.61 (d, J = 3.1 Hz, 3H),1.46 (s, 9H).13C{1H} NMR (150 MHz, CDCl3) δ: 168.0, 166.8, 150.5, 82.7, 72.2, 67.3, 45.9, 27.5, 25.4. Prepara^on of Compound M-1 III-1 (4.0 g, 15.5 mmol) is charged to a pressure reactor followed by addi^on of 2,2,2-trifluoroethanol (20 mL). The reactor is sealed and heated to about 120 °C. The reac^on mixture is s^rred for about 2 hours. A^er full conversion, the batch is concentrated under reduced pressure at 50-55 °C to dryness. Methyl tert-butyl ether (40 mL) is added and the solvent is removed under reduced pressure at 50-55 °C. Methyl tert-butyl ether (40 mL) is added and the slurry is s^rred for about 0.5 hour. The product is collected byfiltra^on and dried in an oven atabout 40 °C under reduced pressure for not less than 12 hours. III-2 is obtained as solid (2.3 g,Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 38 - 05.05.202592%). III-2 (2.2 g, 14.2 mmol) is added to a round bo^omflask followed by addi^on of THF (14mL). NaH (60 wt%, 1.4 g, 15.6 mmol) is added in one por^on at 20-25 °C. The reac^on mixtureis s^rred for about 1 hour. A solu^on of I-5 (3.9 g, 15.6 mmol) in THF (5 mL) is then added andthe resul^ng mixture is s^rred at 50-55 °C for about 12 hours. A^er comple^on, the batch iscooled to about 10 °C. Water (27 mL) and ethyl acetate (14 mL) are added sequen^ally. A^erphase separa^on, the organic layer is collected and the aqueous layer is extracted with isopropylacetate (14 mL). The combined organic phase is washed with brine (14 mL), dried over MgSO4, filtered, and concentrated under reduced pressure at about 55 °C to give a crude reac^onmixture (6.4 g, 44.2 wt%). The crude reac^on mixture is then purified by supercri^calfluidchromatography following the condi^on below: Column: 30 x 150 mm, 5µ Methane Sulfonamide (MS) Mobile Phase A (MPA): Compressed liquid CO2Mobile Phase B (MPB): Methanol Opera^ng Parameters1) Mobile Phase: 15% Isocra^c MPB in MPA, Flowrate: 80 mL / min2) Back Pressure Regulator (BPR) set at 120 bar, T = 35 °C3) Column Temperature: Room Temperature4) Detec^on set @ 2 wavelengths: 220 and 254 nm5) Loading; 210 mg (per injec^on) every 7 minutesFrac^ons containing product are combined and concentrated to dryness under reduced pressureat 30 °C and then at 20 °C for not less than 12 hours. M-1 is obtained as solid (2.2 g, 41%).1H NMR (400 MHz, CDCl3) δ: 8.40 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.09 (t, J = 8.0 Hz,1H), 7.02-6.97 (m, 2H), 6.56-6.54 (m, 1H), 4.69 (ABq, J = 15.0 Hz, 2H), 4.32 (ABq, J = 16.5 Hz, 2H),4.29 (dd, J = 10.9, 3.5 Hz, 1H), 3.79 (dd, J = 12.4, 3.6 Hz, 1H), 3.54 (dd, J = 12.2, 11.1 Hz, 1H), 2.84(d, J = 5.0 Hz, 3H), 2.36 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 168.2, 165.9, 159.1, 154.2 (d, J = 247.3 Hz), 145.1, 140.4, 137.6(d, J = 12.7 Hz), 137.5 (d, J = 6.8 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.1 Hz), 117.6 (d, J= 17.9 Hz), 73.1, 67.6, 49.0, 48.6, 25.8, 21.1 (d, J = 1.2 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m / z calcd for C18H20N4O4F [M+H]+: 375.1463, found: 375.1463.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 39 - 05.05.2025Solid state proper^es of Compound 1 unmilled (Form I or Form II)AppearanceIn the solid state, Compound 1 Form I and Compound 1 Form II are white / off-white powders.Crystallinity and polymorphismCompound 1 Form I is highly crystalline as can be seen in the X-ray powder diffrac^on diagramin Figure 1 and RAMAN spectrum in Figure 3.The X-ray powder reflec^on and intensi^es (standardised) are shown in Table 1. Table 1 2q [°] d-value [Å ] Intensity I / I0 [%]5.34 16.54 10010.67 8.28 2215.99 5.54 820.27 4.38 1021.22 4.18 6In Table 1 above the value "2-theta [°]" denotes the angle of diffrac^on in degrees and the d-value [Å] denotes the specified distances in Å between the la^ce planes.The crystalline Compound 1 Form I is characterised in that in the x-ray powder diagram has,inter alia, the characteris^c values 2-theta = 5.3° ±0.2° (100% rela^ve intensity), 10.7° ±0.2°(22% rela^ve intensity), 16.0° ±0.2° (8% rela^ve intensity), 20.3° ±0.2° (10% rela^ve intensity),21.2° ±0.2° (6% rela^ve intensity), (most prominent peaks in the diagram of Figure 1, Table 1).Compound 1 Form I is characterised in that in the x-ray powder diagram has a strong uniquereflec^on at the value 2-theta = 5.3 ±0.2° and a further unique reflec^on at the value 2-theta =16.0 ±0.2°.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 40 - 05.05.2025Compound 1 Form I is characterised in that in the x-ray powder diagram has a strong uniquereflec^on at the value 2-theta = 5.3 ±0.2°.The crystalline Compound 1 Form I is characterised in that in the Raman spectrum hascharacteris^c bands at 64.9 cm-1 ±1.5, 99.6 cm-1 ±1.5.The thermoanalysis of the crystalline Compound 1 Form I shows an onset of mel^ng at 124.0 ±1.1 °C (with a mel^ng peak at 124.8 ± 0.5 °C, DSC: 10 K.min-1 hea^ng rate; DSC / TG diagram isshown in Figure 5).Compound 1 Form II is highly crystalline as can be seen in the X-ray powder diffrac^on diagramin Figure 2 and RAMAN spectrum in Figure 4.The X-ray powder reflec^on and intensi^es (standardised) are shown in Table 2. Table 2 2q [°] d-value [Å ] Intensity I / I0 [%]6.80 12.98 4310.78 8.20 10011.57 7.64 2217.64 5.02 5422.11 4.02 4123.98 3.71 725.10 3.55 6In Table 2 above the value "2-theta [°]" denotes the angle of diffrac^on in degrees and the d-value [Å] denotes the specified distances in Å between the la^ce planes.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 41 - 05.05.2025The crystalline Compound 1 Form II is characterised in that in the x-ray powder diagram has,inter alia, the characteris^c values 2-theta = 6.8° ±0.2° (43% rela^ve intensity), 10.8° ±0.2°(100% rela^ve intensity), 11.6° ±0.2° (22% rela^ve intensity), 17.6° ±0.2° (54% rela^veintensity), 22.1° ±0.2° (41% rela^ve intensity), (most prominent peaks in the diagram of Figure2, Table 2).Compound 1 Form II is characterised in that in the x-ray powder diagram has a strong uniquereflec^on at the value 2-theta = 6.8° ±0.2° (43% rela^ve intensity), and a further uniquereflec^on at the value 2-theta = 22.1° ±0.2° (41% rela^ve intensity).Compound 1 Form II is characterised in that in the x-ray powder diagram has a strong uniquereflec^on at the value 2-theta = 6.8° ±0.2°.The crystalline Compound 1 Form II is characterised in that in the Raman spectrum hascharacteris^c band at 89.8 cm-1 ±1.5.The thermoanalysis of the crystalline Compound 1 Form II shows an onset of mel^ng at 128.3 ±1.5 °C (with a mel^ng peak at 129.4 ± 1.5 °C, DSC: 10 K.min-1 hea^ng rate; DSC / TG diagram isshown in Figure 6).

[0006] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 42 - 05.05.2025Examples for pharmaceu^cal composi^onThe pharmaceu^cal composi^on according to the inven^on is a tablet core or a tablet for oraladministra^on. The tablet core is comprising Compound 1, Compound 1 Form I, Compound 1Form II, or a mixture thereof and lactose monohydrate, microcrystalline cellulose,hydroxypropyl cellulose, croscarmellose sodium and / or Magnesium stearate. According to another aspect, the pharmaceu^cal composi^on according to the inven^on is atablet core or a tablet for oral administra^on. The tablet core is comprising Compound 1,Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol, maize starch,croscarmellose sodium and / or Magnesium stearate. The tablet is op^onally comprising afilm coa^ng, enveloping said tablet core. Examples for Formula^on 1 (shown in Table 3)Table 3 Composi^on of tablet core Formula^on 1Dose strength 0.5 mg 2.5 mg 5 mg % per tabletDrug load (%, wt / wt) 0.735 0.735 0.735 0.735Ingredient [mg / tab] [mg / tab] [mg / tab] [%, wt / wt]Compound 1 (milled) 0.500 2.500 5.000 0.735Lactose monohydrate 42.680 213.400 426.800 62.765Cellulose, microcrystalline 20.400 102.000 204.000 30.000Hydroxypropyl cellulose 2.040 10.200 20.400 3.000Croscarmellose sodium 2.040 10.200 20.400 3.000Magnesium stearate 0.340 1.700 3.400 0.500Water, purified 1 q.s. q.s. q.s. q.s.Total Mass 68.000 340.000 680.000 100.0001Removed during processing, not present in thefinal productBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 43 - 05.05.2025Examples for Formula^on 2 (shown in Table 4)Table 4 Composi^on of tablet core Formula^on 2% per % per tablet Dose strength 0.5 mg 2.5 mg10 mg tablet Drug load (%, wt / wt) 0.7353 0.7353 0.753 2.9412 2.9412Ingredient [mg / tab] [mg / tab] [%, wt / wt] [mg / tab] [%, wt / wt]Compound 1 (milled) 0.5000 2.5000 0.7353 10.0000 2.9412Mannitol 59.3400 296.7000 87.2647 289.2000 85.0588Maize starch 5.4400 27.2000 8.0000 27.2000 8.0000Croscarmellose sodium 2.0400 10.2000 3.0000 10.2000 3.0000Magnesium stearate 0.6800 3.4000 1.0000 3.4000 1.0000Total Mass 68.000 340.000 100.000 340.0000 100.000Examples for Formula^on 3 (shown in Table 5 and Table 6)Table 5 Composi^on of tablet core of Formula^on 3% per Dose strength 5 mg 10 mg 20 mgtablet Drug load (%, wt / wt) 8 8 8 8Ingredient [mg / tab] [mg / tab] [mg / tab] [%, wt / wt]Compound 1 (milled) 5 10 20 8Mannitol 50 100 200 80Maize starch 5 10 20 8Croscarmellose sodium 1.875 3.75 7.5 3Magnesium stearate 0.625 1.25 2.5 1Sub-total Core 62.500 125.000 250.000 100.000Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 44 - 05.05.2025Table 6 Composi^on offilm coated tablets Formula^on 3Dose strength 5 mg 10 mg 20 mg[mg / tab] [mg / tab] [mg / tab]tablet core of Formula^on 3 62.5 125 250Film-coat* 4 6 10Water, purified 1 q.s. q.s. q.s.Total Film coated tablet 66.5 131 260*Based on the intended color, thefilm coat consists of different, and commonly used amounts of hypromellose, propylene glycol, talc, calcium carbonate, and iron oxides.1Removed during processing, not present in thefinal product Formula^on 1, Formula^on 2, and Formula^on 3 exhibit very fast and complete dissolu^on characteris^cs. The results of the drug substance-excipient compatibility study indicate that Formulations 2 and 3 containing mannitol and maize starch exhibit an increased stability. Further, the stress stability results indicate that the film-coating containing propylene glycol as a plasticizer shows superior stability compared to the film-coating containing macrogol. A pharmaceu^cal composi^on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in Formula^on 3 leads to adjustment of the drug load to the same level for all dose strengths, and a fast dissolu^on of the tablet can be reached. For Formula^on 3, this results in a moreflexible usage of the granules, as they can be compressed to all dose strengths at adequate tablet size and tablet weight. A colouredfilm coat may be added that allows differen^a^on of the different dosage strengths.Formula^on 1, Formula^on 2, and Formula^on 3 may be obtained by using Compound 1,Compound 1 Form I, Compound 1 Form II, or mixtures thereof, respec^vely.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 45 - 05.05.2025The use of Compound 1 Form II for the manufacture of Formula^on 1, Formula^on 2 and Formula^on 3 is preferred. Formula^on 1, Formula^on 2, and Formula^on 3 are useful pharmaceu^cal composi^ons. Manufacturing offilm-coated tablets A) Material usedTable 7 Descrip^on of needed excipient gradesPar^cular preferred grade / type [in addi^on to pharmacopoeial USP / NF (United States Ingredient Pharmacopeia and the Na^onal Formulary), Ph.Eur., JP, CN specifica^on] Mannitol No addi^onal specifica^onMaize starch No addi^onal specifica^onCroscarmellose sodium No addi^onal specifica^onMagnesium stearate No addi^onal specifica^onReady to usefilm-coa^ng mixture No addi^onal specifica^onPurified water No addi^onal specifica^onB) Equipment used The following equipment was used in the process of preparing the pharmaceu^cal composi^on according to the inven^on. The Formulation 1 is preferably produced using the following equipment: -High-shear granulator- Screening mill- Tray dryer or fluid-bed dryer- Screening mill- Diffusion mixerBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 46 - 05.05.2025- Tablet pressThe Formula^on 2 is preferably produced using the following equipment: -Diffusion mixer- Screening mill- Roller compactor- Tablet pressThe Formula^on 3 is preferably produced using the following equipment: -Diffusion mixer- Screening mill- Roller compactor- Tablet press- Mixing vessel with propeller mixer and / or homogenizer for film-coating suspension- Film coaterC) Process descrip^on: Wet granula^on process (preferably for produc^on of Formula^on 1) Granula^onFor high shear granula^on the required quan^ty of Compound 1 (depending on the dosestrength), lactose monohydrate, microcrystalline cellulose and hydroxypropyl cellulose arefilled in the product bowl of a high-shear mixer / granulator, then mixed homogeneously for about 1-5 min using impeller and chopper blades. Next, the granula^on liquid is added eithermanually or by spray nozzles and the wet mass is granulated for about 1-10 min, again usingimpeller and chopper blades. A^er discharging of the high shear mixer / granulator, the wet granules are wet-screened through a 1-5 mm mesh size sieve to destroy large agglomerates. The wet-screened material is transferred to a conven^onal tray drier (orfluid bed drier) anddried at an inlet air temperature of approximately 50 - 100 °C. Granules are dried when thewater ac^vity of the resul^ng dry granules is below 0.6. The dried granules are then dry screened with the help of a screening mill, e.g. Comil screen machine.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 47 - 05.05.2025The screened granules arefilled into a suitable diffusion mixer, e.g. a container mixer, croscarmellose sodium (crosslinked carboxymethylcellulose sodium) and magnesium stearateare added subsequently, and blended for in sum 5 - 20 min, preferably 13 minutes at a mixingspeed of 10 rpm un^l homogeneous. Tabletting Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press or single tablet press) to the respec^ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g. in case of 0.5 mg tablets: 5.5 mm round biconvex, in case of 2.5 mg tablets: 10 mm round biconvex and in case of 5 mg tablets: 17.8×8.6 mm oval biconvex). Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP / NF. Dry granula^on process (preferably for produc^on of Formula^on 2 and 3) GranulationFor dry granula^on the required quan^ty of Compound 1 (depending on the dose strength),mannitol, maize starch and croscarmellose sodium are mixed using a diffusion mixerhomogeneously for about 5-30 min. Then, the mixture is screened with the help of a screening mill. Next, the screened mixture isfilled into a suitable diffusion mixer, e.g. a container mixer,and magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably5 minutes at a mixing speed of 18 rpm un^l homogeneous. The resul^ng blend is compressed with a roller compactor into ribbons, which are subsequently milled by an integrated screening mill into granules. Next, the granules are filled into a suitable diffusion mixer, e.g. a container mixer, andmagnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5minutes at a mixing speed of 18 rpm until homogeneous.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 48 - 05.05.2025Tabletting Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press) to the respec^ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g. in case of 0.5 mg tablets: 5.5 mm round; biconvex and in case of 2.5 mg and 10 mg tablets: 10 mm round; biconvex) or (e.g. in case of 5 mg tablets: 5.5 mm roundbiconvex, in case of 10 mg tablets: 7 mm round biconvex and in case of 20 mg tablets: 7 mmround biconvex). Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP / NF. Film-coating A coloredfilm coa^ng may be applied to the tablet cores for product differen^a^on to prevent from medica^on errors. For this purpose, a coa^ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and thenhydroxypropylmethylcellulose with the help of a propeller or high shear s^rrer. In a next stepan aqueous slurry of calcium carbonate, talc, iron oxide yellow and / or iron oxide red if needed (in case of coloredfilm tablets) is poured and s^rred into thefilm-forming polymer solu^on. The dry ma^er of this coa^ng suspension is in the range of 10 -20%, preferably about 10-15 %. The suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components. The above prepared tablet cores arefilled into a suitablefilm coater (i.e. with perforated panand top spray system, alterna^vely Accela Cota pan with perforated pan and top spray systemis also applicable, less preferred is a pan coater), and preheated up to a temperature ofapproximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C,preferably at 65 °C. A^er this product temperature is reached the coa^ng suspension is sprayedonto the cores with the help of one or more spray nozzles. A spray rate of about 10 - 600 g / min(depending on the batch size as well as drum speed and other opera^ng condi^ons) at an inletair temperature of about 40 - 80 °C, preferably 65 °C. A^er the spraying isfinished thefilm-coated tablets may be dried if needed, then cooled down to 45 °C or below before theBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 49 - 05.05.2025equipment is discharged. The total process ^me for thefilm-coa^ng is in the range of 1 - 6 hours(depending on the spray rate as well as the batch size), other process dura^ons are also feasible. Direct compression process (preferably for produc^on of Formula^on 3) BlendingCompound 1, mannitol, maize starch and croscarmellose sodium are blended using a diffusionmixer. The powder mixture is sieved with the help of a screening mill. The sieved mixture isblended using a diffusion mixer. Then, the mixture is sieved together with magnesium stearate.Thenfinal blending is performed for in sum 5 - 20 min, preferably 13 minutes at a mixing speedof 10 rpm un^l homogeneous. Table^ng Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press) to therespec^ve target weight of the required dose strength of Compound 1 tablets using theappropriate tools (e.g. in case of 5 mg tablets: 5.5 mm round biconvex, in case of 10 mg tablets:7 mm round biconvex and in case of 20 mg tablets: 9 mm round biconvex).Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP / NF. Film-coating A coloredfilm coa^ng may be applied to the tablet cores for product differen^a^on to prevent from medica^on errors. For this purpose, a coa^ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and thenhydroxypropylmethylcellulose with the help of a propeller or high shear s^rrer. In a next stepan aqueous slurry of calcium carbonate, talc, iron oxide yellow and / or iron oxide red if needed (in case of coloredfilm tablets) is poured and s^rred into thefilm-forming polymer solu^on. The dry ma^er of this coa^ng suspension is in the range of 10 -20%, preferably about 10-15 %.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 50 - 05.05.2025The suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components. The above prepared tablet cores arefilled into a suitablefilm coater (i.e. with perforated panand top spray system, alterna^vely Accela Cota pan with perforated pan and top spray systemis also applicable, less preferred is a pan coater), and preheated up to a temperature ofapproximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C,preferably at 65 °C. A^er this product temperature is reached the coa^ng suspension is sprayedonto the cores with the help of one or more spray nozzles. A spray rate of about 10 - 600 g / min(depending on the batch size as well as drum speed and other opera^ng condi^ons) at an inletair temperature of about 40 - 80 °C, preferably 65 °C. A^er the spraying isfinished thefilm-coated tablets may be dried if needed, then cooled down to 45 °C or below before theequipment is discharged. The total process ^me for thefilm-coa^ng is in the range of 1 - 6 hours(depending on the spray rate as well as the batch size), other process dura^ons are also feasible. Based on the quality of the tablets produced by the industrial process, the use of Compound 1 Form II for the manufacture of Formula^on 3 is preferred. Formula^on 1, Formula^on 2, and Formula^on 3 are useful pharmaceu^cal composi^ons.

[0007] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 51 - 05.05.2025CLINICAL TRIALS Clinical trial 1: single oral administra^on of Compound 1A randomized, double-blind, placebo-controlled, parallel-group single administra^on trialassessing the safety, tolerability, PK, and preliminary efficacy of Compound 1 in two differentdoses (5 mg and 20 mg) versus placebo (1:1:1 randomiza^on) as an adjunc^ve therapy toselec^ve serotonin reuptake inhibitors (SSRI) / serotonin and norepinephrine reuptake inhibitors(SNRI) in pa^ents with Major Depressive Disorder.STUDY medicineCompound 1 (5 mg and 20 mg) and matching placebo were supplied as un-coated tablets(Formula^on 1, oral administra^on).STUDY POPULATION In total, 59 pa^ents with depression (Major Depressive Disorder, MDD) on stable an^depressant treatment (Table 8) as described below were randomized into this trial.Table 8 selec^ve serotonin reuptake inhibitors / serotonin and norepinephrine reuptakeinhibitors for concomitant an^depressant therapy Placebo Cpd 1Cpd 1 Cpd 1 Total 5 mg 20 mg total Preferred name N % N % N % N % N %Number of pa^ents 19 100.0 20 100.0 20 100.0 40 100.0 59 100.0Number of pa^ents with at19 100.0 20 100.0 20 100.0 40 100.0 59 100.0least one concomitant medica^on ANTIDEPRESSANTS 19 100.0 20 100.0 20 100.0 40 100.0 59 100.0SERTRALINE 8 42.1 7 35.0 8 40.0 15 37.5 23 39.0SERTRALINE2 10.5 4 20.0 3 15.0 7 17.5 9 15.3HYDROCHLORIDE ESCITALOPRAM 1 5.3 2 10.0 3 15.0 5 12.5 6 10.2ESCITALOPRAM OXALATE 1 5.3 4 20.0 1 5.0 5 12.5 6 10.2FLUOXETINE 1 5.3 2 10.0 2 10.0 4 10.0 5 8.5Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 52 - 05.05.2025Placebo Cpd 1Cpd 1 Cpd 1 Total 5 mg 20 mg total Preferred name N % N % N % N % N %DULOXETINE 3 15.8 0 0.0 1 5.0 1 2.5 4 6.8CITALOPRAM 1 5.3 1 5.0 0 0.0 1 2.5 2 3.4CITALOPRAM0 0.0 0 0.0 1 5.0 1 2.5 1 1.7HYDROBROMIDE DESVENLAFAXINE1 5.3 0 0.0 0 0.0 0 0.0 1 1.7SUCCINATE MONOHYDRATE DOXEPIN 0 0.0 1 5.0 0 0.0 1 2.5 1 1.7FLUOXETINE0 0.0 0 0.0 1 5.0 1 2.5 1 1.7HYDROCHLORIDE MIRTAZAPINE 1 5.3 0 0.0 0 0.0 0 0.0 1 1.7TRAZODONE 0 0.0 0 0.0 1 5.0 1 2.5 1 1.7VENLAFAXINE1 5.3 0 0.0 0 0.0 0 0.0 1 1.7HYDROCHLORIDE INCLUSION CRITERIA1) Established diagnosis of Major Depressive Disorder (MDD) as confirmed at the ^me ofscreening by the Mini Interna^onal Neuropsychiatric Interview (MINI), with a dura^on of current depressive episode ≥ 8 weeks and ≤ 24 months at the ^me of screening visit.2) At least moderate severity of MDD confirmed by a trained site-based rater.3) In the current episode, pa^ents have shown insufficient treatment response (defined byless than 50 % response to one or more an^depressant drugs of adequate dose and treatment dura^on (according to Summary of Product Characteris^cs) as evaluated by An^depressant Treatment Response Ques^onnaire (ATRQ). Pa^ents, who, in addi^on to their monotherapy with an SSRI / SNRI, are taking addi^onal low dose an^depressant medica^ons for purposes other than trea^ng depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD. Use of bupropion is not allowed.4) Documented ongoing monotherapy treatment of ≥ 6 weeks at randomisa^on with aprotocol specified Selec^ve Serotonin Reuptake Inhibitors (SSRI) or Serotonin- Norepinephrine Reuptake Inhibitors (SNRI) at adequate dose (according to ATRQ assessment).Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 53 - 05.05.2025EXCLUSION CRITERIA1) Pa^ent had met diagnos^c criteria per Diagnos^c and Sta^s^cal Manual of MentalDisorders, 5th edi^on (DSM-5) for schizophrenia, schizoaffec^ve disorder, schizophreniform disorder, bipolar disorder, delusional disorder or MDD with psycho^c features at any ^me point in the pa^ent's life.2) Diagnosis of any other mental disorder that was the primary focus of treatment within 6months prior to screening, as per clinical discre^on of the inves^gator.3) Pa^ents with a Body Mass Index (weight [kg] / height [m]²) lower than 18 kg / m² atscreening.4) Diagnosis of a moderate to severe substance-related disorder within the last 6 monthsbefore screening visit (with excep^on of caffeine and tobacco). RANDOMIZATION Pa^ents eligible for the trial based on the before men^oned criteria were assigned at randomin a 1:1:1 ra^o to one of 3 study arms (placebo, 5 mg Compound 1, 20 mg Compound 1; in asingle administra^on, oral) and followed up for 2weeks. VARIABLES ASSESSED The results of the primary and key secondary efficacy endpoints and the primary and secondary endpoints are summarized below. Efficacy Endpoints Maximum decrease from baseline (peak decrease) in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) at any day within a 7 days-interval. MADRS is a ten-item ques^onnaire used to measure the severity of Major Depressive Disorder (MDD). Nine of the items are based upon pa^ent reports and one is on the rater's observa^on (apparent sadness) during the ra^ng interview. MADRS items are rated on a 0 to 6 con^nuum (0=no abnormality, 6=severe). The possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). Up to Day 15Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 54 - 05.05.2025Secondary Endpoints Montgomery-Åsberg Depression Ra^ng Scale Area under the response curve from pre-dose to the last measurement during inpa^ent stay at 166:30 hours (MADRS AUC0-166:30) MADRS is a ten-item ques^onnaire used to measure the severity of Major Depressive Disorder (MDD). Nine of the items are based upon pa^ent reports and one is on the rater's observa^on (apparent sadness) during the ra^ng interview. MADRS items are rated on a 0 to 6 con^nuum (0=no abnormality, 6=severe). The possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). Up to Day 15 Other Endpoints- Number and percentage of pa^ents with drug-related AEs from start of treatment to Day15.- Change from baseline in MADRS total score at individual ^me points throughout the trial- MADRS response (defined as a reduc^on of at least 50% from baseline, at individual ^mepoints)- Remission (defined as a value ≤10, at individual ^me points), and change from baseline inLeuven affect and pleasure scale (LAPS) subscales at individual ^me points.- PK parameters of Compound 1, including maximum plasma concentra^on (Cmax), ^mefrom dosing to Cmax (tmax), area under for concentra^on-^me curve from 0 to lastquan^fiable data point (AUZ0–tz) and t1 to 2 (AUCt1–t2), were evaluated.- The following criteria to consider this trial successful regarding efficacy were:^ Observed MADRS change from baseline compared to Placebo ≥ 3 points at one ^mepoint, AND ^≥ 2 points at a neighboring ^me point within a week, AND^ Adequate safety.STATISTICAL METHODSAnalysis of covariance (ANCOVA) has been used for the analysis of the primary and secondaryendpoints. These models includefixed effects for baseline MADRS total score and treatment.Further con^nuous endpoints have been analysed using a mixed model for repeated measures.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 55 - 05.05.2025This model includesfixed effects for baseline value, treatment, ^me, treatment-by-^meinterac^on, and baseline-by-^me interac^on; random subject effects have been incorporatedinto an unstructured within-subject covariance matrix. Descrip^ve sta^s^cs have beencalculated for all endpoints. RESULTS Overall, 59 pa^ents were eligible and were randomized and treated (placebo, n=19; Compound1, 5 mg, n=20; Compound 1, 20 mg, n=20). Of the 40 pa^ents receiving single dose Compound1, four (5 mg, n=3; 20 mg n=1) prematurely discon^nued the study. Fi^y-five (93%) pa^ents completed the study. Demographic and baseline characteris^cs were generally balanced between groups. The median age (range) was 54.0 (18–65) years, the majority were female (54.2%), 53.5% were Black or African American, and 71.2% were non-Hispanic or La^no. At baseline, the median (range) BMI was 29.4 kg / m2 (21.6–50.1 kg / m2) and the mean (SD) MADRS total score was 34.6 (5.8). Overall, 36% had a history of cannabis use (22% current; 14% former), with mostcannabis users (43%) randomized to the Compound 1, 5 mg group.Surprisingly, promising preliminary efficacy signals of a rapid, sustained effect with good tolerability have been observed. Surprisingly, it was found that in comparison with placebo, the difference in adjusted meanchange from baseline in MADRS total score (standard error) was as follows (Figure 7):- Compound 1, 5 mg: at Day 1, -1.9 (3.1); Day 2, -1.6 (3.1); Day 4, -0.9 (3.0); Day 6, -0.8 (3.7);Day 8, 3.5 (3.6);- Compound 1, 20 mg: at Day 1, -1.6 (3.1); Day 2, -3.4 (3.0); Day 4, -3.6 (2.9); Day 6, -4.9(3.7); Day 8, -0.7 (3.5). Surprisingly, the 20 mg dose demonstrated rapid ac^ng an^depressant effects, sustained forfive days post-administra^on – a difference of 3.4, 3.6 and 4.9 MADRS points improvementover placebo at Day 2, 4, and 6 a^er a single oral administra^on.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 56 - 05.05.2025A clinically meaningful change from baseline was found a^er 8 days for both 5 mg and 20 mg(see Table 9 and Figure 7). This is a signal not only of a rapid effect but also of an effect that issustained over ^me. Table 9: Change from baseline in MADRS total score Time Point / N Adjusted SE Adjusted SE Standardized EffectTreatment Mean difference Size Day 1 Placebo 18 -9.5 2.25 mg Compound 1 18 -11.4 2.2 -1.9 3.1 -0.1920 mg Compound 1 20 -11.1 2.1 -1.6 3.1 -0.17Day 2 Placebo 19 -10.3 2.25 mg Compound 1 20 -11.9 2.1 -1.6 3.1 -0.1620 mg Compound 1 20 -13.7 2.1 -3.4 3.0 -0.36Day 4 Placebo 19 -10.4 2.15 mg Compound 1 20 -11.3 2.1 -0.9 3.0 -0.1020 mg Compound 1 20 -14.0 2.0 -3.6 2.9 -0.39Day 6 Placebo 19 -11.6 2.65 mg Compound 1 20 -12.4 2.6 -0.8 3.7 -0.0720 mg Compound 1 20 -16.5 2.6 -4.9 3.7 -0.42Day 8 Placebo 19 -15.4 2.55 mg Compound 1 20 -11.8 2.5 3.5 3.6 0.3220 mg Compound 1 20 -16.0 2.5 -0.7 3.5 -0.06N: number of pa^ents, SE: Standard ErrorBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 57 - 05.05.2025In Clinical trial 1, Compound 1 exhibited an unexpectedly favorable safety and tolerability profile. No severe adverse events, no dissocia^on, no clinically relevant changes on group level forblood pressure and no notablefindings in the electrocardiogram (ECG) were observed.Furthermore, the compound's safety profile is further corroborated by the results obtainedfrom the Clinician-Administered Dissocia^ve States Scale (CADSS, Table 10). This scale revealedvery benign outcomes regarding dissocia^ve side effects, since few pa^ents had a CADSS scoreof clinically relevant severity of >4 at any ^me point measured a^er administra^on ofCompound 1 and no pa^ent had dissocia^on as an adverse event.In addi^on to the CADSS, the compound was also evaluated regarding suicidality using the Columbia Suicide Severity Ra^ng Scale (CSSRS, Table 11). The results from these assessmentsdemonstrated no dissocia^on (CADSS), and no signs of increased suicidality (CSSRS).Table 10: Frequency [%] of pa^ents (N: number of pa^ents) categorized by CADSS total scorebased on clinician's ra^ngs - Treated setN 0 >=1 to 4 >4 MissingTreatment / Visit - Time point N % N % N % N %Placebo Baseline 19 17 89.5 1 5.3 0 0.0 1 5.3Day 1, 1:00 19 16 84.2 2 10.5 0 0.0 1 5.3Day 1, 7:00 19 14 73.7 2 10.5 0 0.0 3 15.8Day 15 19 16 84.2 1 5.3 0 0.0 2 10.55 mg Compound 1 Baseline 20 17 85.0 0 0.0 1 5.0 2 10.0Day 1, 1:00 20 18 90.0 1 5.0 0 0.0 1 5.0Day 1, 7:00 20 17 85.0 0 0.0 0 0.0 3 15.0Day 15 20 13 65.0 0 0.0 0 0.0 7 35.0Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 58 - 05.05.2025N 0 >=1 to 4 >4 MissingTreatment / Visit - Time point N % N % N % N %20 mg Compound 1 Baseline 20 20 100.0 0 0.0 0 0.0 0 0.0Day 1, 1:00 20 19 95.0 0 0.0 0 0.0 1 5.0Day 1, 7:00 20 18 90.0 2 10.0 0 0.0 0 0.0Day 15 20 18 90.0 0 0.0 0 0.0 2 10.0Compound 1 totalBaseline 40 37 92.5 0 0.0 1 2.5 2 5.0Day 1, 1:00 40 37 92.5 1 2.5 0 0.0 2 5.0Day 1, 7:00 40 35 87.5 2 5.0 0 0.0 3 7.5Day 15 40 31 77.5 0 0.0 0 0.0 9 22.5Total Baseline 59 54 91.5 1 1.7 1 1.7 3 5.1Day 1, 1:00 59 53 89.8 3 5.1 0 0.0 3 5.1Day 1, 7:00 59 49 83.1 4 6.8 0 0.0 6 10.2Day 15 59 47 79.7 1 1.7 0 0.0 11 18.6Time points 1:00 or 7:00 refer to a ^me point 1 h or 7 h a^er administra^on of Placebo / Compound 1, respec^vely. Thesefindings, when considered in conjunc^on with the promising results on depressivesymptoms determined by the MADRS total score (Table 9), suggest a new therapeu^capplica^on for Compound 1. Specifically, the absence of dissocia^ve effects (Table 10), alongwith the compound's favorable safety profile, align with the therapeu^c needs of pa^ents with borderline personality disorder.

[0008] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 59 - 05.05.2025Table 11: Changes to worst C−SSRS categories from baseline during treatment – Treated SetTreatment Category_ Treatment Baseline Category No suicidalSuicidal Suicidal idea^on or idea^on behavior behavior n (%) n (%) n (%) Placebo No suicidal idea^on17 (100.0) 0 (0.0) 0 (0.0)(N = 17) or behavior Suicidal idea^on 0 (0.0) 0 (0.0) 0 (0.0)Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)5 mg Compound 1 No suicidal idea^on18 (100.0) 0 (0.0) 0 (0.0)(N = 18) or behavior Suicidal idea^on 0 (0.0) 0 (0.0) 0 (0.0)Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)20 mg Compound No suicidal idea^on19 (95.0) 0 (0.0) 0 (0.0)1 (N = 20) or behavior Suicidal idea^on 0 (0.0) 1 (5.0) 0 (0.0)Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)Compound 1 total No suicidal idea^on37 (97.4) 0 (0.0) 0 (0.0)(N = 38) or behavior Suicidal idea^on 0 (0.0) 1 (2.6) 0 (0.0)Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)Total (N = 55) No suicidal idea^on 54 (98.2) 0 (0.0) 0 (0.0)or behavior Suicidal idea^on 0 (0.0) 1 (1.8) 0 (0.0)Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)

[0009] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 60 - 05.05.2025In Clinical trial 1, the pharmacokine^c (PK) profiles and pharmacokine^c parameters weredetermined (Table 12).Table 12: Non-compartmental PK parameters of Compound 1 a^er single oral administra^on of Compound 1 as tablet in fasted condi^ons.Dose Group 5 mg Compound 1 20 mg Compound 1N gMean gCV% N gMean gCV%Cmax (nmol / L) 20 185 44.8 18 681 48.6tmax (h)1 20 0.500 0.250-3.10 18 0.500 0.250-4.00AUC0-24 (nmol·h / L) 20 601 24.7 18 2270 21.4AUC0-∞(nmol·h / L) 20 623 26.4 18 2340 20.7t1 / 2 (h) 20 4.98 30.1 18 5.21 21.0Compound 1 was rapidly absorbed a^er oral administra^on as tablet. Therea^er, plasma concentra^ons decreased rapidly in a monophasic manner. Plasma exposure increases propor^onally with the dose between 5 mg and 20 mg. Addi^onally, its pharmacokine^c (PK) profile is characterized by rapid ac^on and clearance, afeature o^en referred to as a 'hit and run' profile. These characteris^cs support the poten^alfor daily administra^on of the Compound 1.The long-las^ng efficacy as seen in Figure 7 may support twice weekly, every other day or onceweekly administra^on.The human metabolite M-1 has been observedHz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.02-6.97 (m, 2H), 6.56-6.54 (m, 1H), 4.69 (ABq, J = 15.0 Hz, 2H), 4.32 (ABq, J = 16.5 Hz, 2H),Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 61 - 05.05.20254.29 (dd, J = 10.9, 3.5 Hz, 1H), 3.79 (dd, J = 12.4, 3.6 Hz, 1H), 3.54 (dd, J = 12.2, 11.1 Hz, 1H), 2.84(d, J = 5.0 Hz, 3H), 2.36 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 168.2, 165.9, 159.1, 154.2 (d, J = 247.3 Hz), 145.1, 140.4, 137.6(d, J = 12.7 Hz), 137.5 (d, J = 6.8 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.1 Hz), 117.6 (d, J= 17.9 Hz), 73.1, 67.6, 49.0, 48.6, 25.8, 21.1 (d, J = 1.2 Hz).19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m / z calcd for C18H20N4O4F [M+H]+: 375.1463, found: 375.1463.Determina^on of in vitro Pharmacological Ac^vityThe ac^vity of the human metabolite M-1 was demonstrated using the following in-vitroNMDA receptor NR1 / 2B cell assay via whole-cell patch-clamp electrophysiology:Cell culture:A HEK293 cell line expressing human NR1 / 2B was used. Expression of receptor was induced bytreatment with tetracycline (1μg / ml). Cell viability was improved by applica^on of Ketamine(2.0 mM) to the culture media 14h - 24h before recordings cells. Cells were plated onto glasscoverslips for patch clamp experiments.Test solu^ons: Intracellular (pipe^e) solu^on: (all concentra^ons in mM) CsCl 20, CsF 110, HEPES 10, EGTA 5, MgCl21, cAMP 0.4, Mg-ATP 4; Perfusion solu^on (vehicle): Perfusion solu^on (baseline) + 100μM NMDA and 1μM Glycine; Perfusion solu^on (metabolite M-1): Perfusion solu^on(vehicle) + M-1 at a concentra^on of 0.03 - 10μM dissolved in DMSO at afinal concentra^on of0.1 %.Inhibi^on of NR1 / 2B during constant channel opening:Patch clamp recordings were performed in whole-cell configura^on by use of PatchMasterso^ware. Following seal forma^on and establishing the whole cell configura^on by disrup^ngthe cell membrane in the ^p of the patch pipe^e, cells were typically clamped in whole cellmode at a poten^al of -60 mV. A^er reaching a stable baseline recording, the cell wassuperfused with control solu^on and subsequently with a concentra^on of 0.03 - 10μM of themetabolite M-1. Solu^ons were applied by a gravity driven system for 120 sec in presence ofthe agonists NMDA (100μM) and Glycin (1μM). M-1 was tested in a cumula^ve manner atBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 62 - 05.05.2025concentra^ons of 0 µM (control), 0.03, 0.1, 0.3, 1, 3 and 10µM with an applica^on dura^on of60s for each compound concentra^on. Cells were recorded as long as the seal resistance, seriesresistance and leakage current remained stable. Only cells with stable parameters wereincluded to the analysis. At the end of the recordings Ketamine (10μM) was applied to inhibitNR1 / 2B dependent currents. Current responses for analysis were taken as a mean amplitude ofthe last 10 seconds of control or compound applica^on.Data evalua^on and IC50 calcula^on:For the M-1 test concentra^on a [%] block is calculated by dividing the current induced duringcompound applica^on by the mean measured NMDA / Glycine induced current (control). TheIC50 was calculated by applying a Bolzman equa^on:Y = Bo^om + (Top-Bo^om) / 1+10^((LogEC50-X)*Hillslope)).Using this assay the metabolite M-1 exhibits an IC50 of 599 nM.Compound 1 may be used as a medicament, characterized in that Compound 1 is to beadministered orally. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered orally. Compound 1 may be used in the treatment of Major Depressive Disorder, Treatment-resistantDepression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolardisorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and / or BorderlinePersonality Disorder characterized in that Compound 1 is to be administered orally.Compound 1 may be used as a medicament, characterized in that Compound 1 is to beadministered once daily, twice weekly, every other day or once weekly. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 63 - 05.05.2025Compound 1 may be used as a medicament, characterized in that 5 to 20 mg of Compound 1are to be administered. Compound 1 may be used as a medicament, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5 to 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered. The above data suggest Compound 1 has the poten^al to address core symptoms of depression, emo^onal dysregula^on, anxiety and suicidality, all of which are domainssugges^ve of its effect in Borderline Personality Disorder (BPD).These results show that by administra^on of Compound 1 borderline personality disorder may successfully be treated.

[0010] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 64 - 05.05.2025Clinical trial 2: once daily oral administra^on of Compound 1A 6-week, mul^-centre, randomised, double-blind (pa^ent and inves^gator),placebo-controlled, dose-finding trial to evaluate the efficacy, tolerability, and safety ofdifferent doses of oral Compound 1 (5 mg, 10 mg, and 20 mg) as adjunc^ve therapy toSSRI / SNRI in pa^ents with Major Depressive Disorder (MDD).STUDY medicineCompound 1 (2.5 mg, and 10 mg) and matching placebo will be supplied as un-coated tablets(Formula^on 2, oral administra^on, once daily).STUDY POPULATIONIn total, approximately 204 pa^ents with depression (Major Depressive Disorder, MDD) onstable an^depressant treatment as described below will be randomized into this trial in orderto have approximately 180 pa^ents evaluable for the primary analysis.INCLUSION CRITERIA1) Established diagnosis of major depressive disorder (MDD), single episode or recurrent, asconfirmed at the ^me of screening by the mini-interna^onal neuropsychiatric interview (MINI) with a dura^on of current depressive episode ≥8 weeks at the ^me of screening visit.2) Hamilton Depression Ra^ng Scale-17 (HDRS-17) - Severity scale score >17.3) A documented ongoing monotherapy treatment of ≥6 weeks at the randomisa^on visit,with an selec^ve serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) specified in the inves^gator sitefile (ISF) at adequate dose (at least minimum effec^ve dose as per prescribing informa^on). -The pa^ent must adhere to the screening visit dose of the background SSRI / SNRI un^lthe end of the trial. Pa^ents should be on a stable dose for at least 4 weeks prior to randomisa^on. -Pa^ents, who, in addi^on to their monotherapy with an SSRI / SNRI, are takingaddi^onal low dose an^depressant medica^ons for purposes other than trea^ngBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 65 - 05.05.2025depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD.4) In the current episode, pa^ents have shown insufficient treatment response defined byless than 50% response to a maximum of 4 an^depressant treatments of adequate dose and treatment dura^on (according to Summary of Product Characteris^cs) as evaluated by the an^depressant treatment response ques^onnaire (ATRQ). EXCLUSION CRITERIA1) Per MINI, have ever met diagnos^c criteria for schizophrenia, schizoaffec^ve disorder,schizophreniform disorder, bipolar disorder, or delusional disorder.2) Diagnosis with an^social, paranoid, schizoid or schizotypal personality disorder, or MDDwith psycho^c features as per Diagnos^c and Sta^s^cal Manual of Mental Disorders, Fi^h Edi^on (DSM-5) criteria, at the ^me of screening visit. Any other personality disorder at screening visit that significantly affects current psychiatric status and likely to impact trial par^cipa^on, as per the judgement of inves^gator.3) Diagnosis of any other mental disorder that was the primary focus of treatment within 6months prior to screening (as per clinical discre^on of the inves^gator).4) History or presence (upon clinical examina^on) of seizure disorders or an increased risk ofseizures (first degree rela^ve with epilepsy), stroke, brain tumour or any other major neurological illness that could impact par^cipa^on in the trial.5) A current or recent history of clinically significant suicidal idea^on with intent within thepast 3 months, corresponding to a score of 4 or 5 for idea^on on the Columbia-suicide severity ra^ng scale (C-SSRS) or a suicidal a^empt within the past year, as indicated by theC-SSRS at screening visit.6) Pa^ents with a body mass index (weight [kg] / height [m]²) lower than 18 kg / m² or greaterthan 40 kg / m² at screening. RANDOMIZATIONPa^ents eligible for the trial based on the aforemen^oned criteria will be assigned at random ina 2:1:1:2 ra^o to one of 4 study arms (placebo qd, 5 mg Compound 1 qd, 10 mg Compound 1qd, 20 mg Compound 1 qd) and treated for 6 weeks.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 66 - 05.05.2025VARIABLES ASSESSED The primary and key secondary efficacy endpoints are summarized below. Efficacy Endpoints Change from baseline in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) total score at Day 8. The MADRS evaluates core symptoms of depression. It is a clinician-rated measure of depression severity and consists of 10 items. MADRS items are rated on a 0-6 con^nuum (0 =no abnormality, 6 = severe). The possible total score could range from 0 to 60 - from normalwith absence of symptoms to severe depression. Secondary Endpoints Change from baseline in MADRS total score at Week 6. Response defined as ≥50% MADRS reduc^on from baseline at Day 8. Response defined as ≥50% MADRS reduc^on from baseline at Week 6. Remission defined as MADRS total score ≤10 at Week 6. Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Day 8. The SMDDS is a 16-item, pa^ent-reported outcome (PRO) measure developed to capture the core symptoms of major depressive disorder (MDD). Pa^ents respond to each ques^on using a ra^ng scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"). The total score ranges from 0 to 60 with a higher score indica^ng more severe depressive symptomatology. It is calculated by crea^ngfirst a single score for items 11 and 12 by selec^ng the highest severity on either item, and then crea^ng the sum of the 15 responses. Change from baseline in SMDDS total score at Week 4.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 67 - 05.05.2025STATISTICAL METHODS To demonstrate clinical efficacy and to evaluate the dose response rela^onship for Compound 1, a mul^ple comparison procedure with modelling techniques (MCPMod) approach is planned to be used for the primary analysis. As a basis for the MCPMod analysis and to assess quan^ta^ve treatment benefit, a mixed model for repeated measure (MMRM) analysis will be used to generate covariate adjusted es^mates of mean change from baseline in MADRS total score at Day 8 and associated covariance matrices.

[0011] Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 68 - 05.05.2025Clinical trial 3: once daily oral administra^on of Compound 1A 6-week, mul^-centre, randomised, double-blind (pa^ent and inves^gator), placebo-controlled, dose-finding trial to evaluate the efficacy, tolerability, and safety of different doses(5 mg, 10 mg, and 20 mg) of oral Compound 1 in pa^ents with major depressive disorder.STUDY medicineCompound 1 (2.5 mg, and 10 mg) and matching placebo will be supplied as un-coated tablets(Formula^on 2, oral administra^on, once daily).STUDY POPULATIONIn total, approximately 222 pa^ents with depression (Major Depressive Disorder, MDD) will berandomized into this trial in order to have approximately 180 pa^ents evaluable for theprimary analysis. INCLUSION CRITERIA- Established diagnosis of MDD, single episode or recurrent with a dura^on of currentdepressive episode ≥8 weeks and ≤24 months at the ^me of randomisa^on- Hamilton Depression Ra^ng Scale-17 (HDRS-17) – Severity score ≥20- Clinical Global Impression Severity Scale (CGI-S) score ≥4EXCLUSION CRITERIA- Have ever met diagnos^c criteria for schizophrenia, schizoaffec^ve disorder, schizophreniformdisorder, bipolar disorder, or delusional disorder- Diagnosis of any other mental disorder that was the primary focus of treatment within 6months prior to screening, as per clinical discre^on of the inves^gator- Treatment failure to 2 or more an^depressants in the current episodeBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 69 - 05.05.2025- A current or recent history of clinically significant suicidal idea^on with intent within the past3 months or a suicidal a^empt within the past year- Pa^ents with a body mass index (weight [kg] / height [m]2) lower than 18 kg / m² or greaterthan 40 kg / m2at screening- Diagnosis of a moderate to severe substance related disorder within 6 months prior toscreening visit (with excep^on of caffeine and tobacco)- Frequent use of benzodiazepinesRANDOMIZATION Pa^ents will be randomized to the 6-week double-blind treatment period and will be assigned to placebo or one of 3 doses of Compound 1 (low to high dose) in a 2:1:1:2 ra^o.Placebo: approximately 74 pa^entsCompound 1 (5 mg): approximately 37 pa^entsCompound 1 (10 mg): approximately 37 pa^entsCompound 1 (20 mg): approximately 74 pa^entsVARIABLES ASSESSED The primary and key secondary efficacy endpoints are summarized below.Primary EndpointsChange from baseline in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) total score at Week 6. Secondary Endpoints None.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 70 - 05.05.2025Other Endpoints MADRS- Change from baseline in MADRS total score at Day 8- Rela^ve (percent) change from baseline in total MADRS score at individual ^me points- Response defined as ≥50% MADRS reduc^on from baseline at individual ^me points- Remission defined as MADRS total score ≤10 at individual ^me points- Change from baseline in MADRS anhedonia subscale score at individual ^me pointsSMDDS- Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) at individual^me points Pharmacokine^cs The following PK assessments will be performed for Compound 1:- pre-dose plasma concentra^ons of Compound 1 and relevant metabolites at different ^mepoints (if applicable)- three post-dose plasma concentra^ons of Compound 1 and relevant metabolites at one ^mepoint (if applicable)- At End of Trial Visit: plasma concentra^ons of Compound 1 and relevant metabolites (ifapplicable) 24 h a^erfinal dose Other- Change from baseline in Clinical Global Impression-Severity (CGI-S) score at individual ^mepoints- Change from baseline in Pa^ent Global Impression-Severity (PGI-S) score at individual ^mepoints- Pa^ent Global Impression- Change in Clinical Status (PGI-C) score at End of TrialBoehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 71 - 05.05.2025- Change from baseline in EQ-5D-5 L VAS score at individual ^me points- Change from baseline in Generalised Anxiety Disorder-7 assessment (GAD-7) at individual^me points STATISTICAL METHODSTo demonstrate clinical efficacy and to evaluate the dose response rela^onship for Compound1, a mul^ple comparison procedure with modelling techniques (MCPMod) approach is planned to be used for the primary analysis. As a basis for the MCPMod analysis and to assess quan^ta^ve treatment benefit, a mixed model for repeated measure (MMRM) analysis will be used to generate covariate adjusted es^mates of mean change from baseline in MADRS total score at Week 6 and associated covariance matrices. Use in treatment / method of use:Compound 1 may be used as a medicament, characterized in that 0.5 - 40 mg of Compound 1are to be administered.Preferably, Compound 1 may be used as a medicament, characterized in that 2.5 - 25 mg ofCompound 1 are to be administered. Compound 1 may be used as a medicament, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or40 mg of Compound 1 are to be administered.Preferably, Compound 1 may be used as a medicament, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered.Compound 1 may be used as a medicament, characterized in that Compound 1 it to beadministered once daily, twice weekly, every other day or once weekly.

Claims

Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 72 - 05.05.2025CLAIMS1. Compound 11, for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression,Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders,Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and / or Borderline Personality Disorder characterized in that 0.5 - 40 mg of Compound 1 are to beadministered once daily, twice weekly, every other day or once weekly.

2. The compound for use according to claim 1 characterized in that Compound 1 is to beadministered orally.

3. The compound for use according to any one of the claims 1 to 2 characterized in thatCompound 1 is to be administered in addi^on to treatment with another an^depressantdrug.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 73 - 05.05.20254. A process for preparing Compound 1characterized in that a) compound II-1 is reacted with compound I-2 under condi^ons facilita^ng nucleophilic subs^tu^on and elimina^on of HBr to yield compound II-2, b) compound II-2 is carbonylated to yield compound II-3Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 74 - 05.05.2025c) compound II-4 is deprotected by hydrogena^on followed by reduc^ve amina^on of compound I-8 and compound II-3 to yield Compound 1.

5. An intermediate compound selected from the group consis^ng of.showing a X-ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured using monochroma^c CuK^1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°.Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1- 75 - 05.05.20257. A pharmaceu^cal composi^on comprising Compound 1and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and / or Magnesium stearate.

8. A pharmaceu^cal composi^on comprising Compound 1and mannitol and / or maize starch.

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