Ghrelin o-acyl transferase (GOAT) inhibitors for use in the treatment of substance use disorder in patients with high impulsivity

Abstract

The present invention relates to compounds of general formula (I), wherein the groups R1, R2 and n are defined as in claim 1, which are ghrelin O-acyl transferase (GOAT) inhibitors for use in the treatment of substance use disorder (SUD,) in particular for use in the treatment of opioid use disorder (OUD) or stimulant use disorder (StimUD), in patients with high impulsivity.

Description

[0001] Boehringer Ingelheim 01-3614 ff -1 -Ghrelin O-acyl transferase (GOAT) inhibitorsfor use in the treatment of substance use disorder in patients with high impulsivity Field of the inventionThe present invention relates to oxadiazolopyridine derivatives that are inhibitors of theghrelin O-acyl transferase (GOAT), and to pharmaceutical compositions containingthese compounds, for use in the treatment of substance use disorder (SUD) includingboth opioid use disorder (OUD) and stimulant use disorder (StimUD), in patients withhigh impulsivity. Background of the Invention Up to 40 million Americans are impacted by substance use disorders (SUDs), with ahigh associated personal, familial, and societal burden. Opioid use disorder (OUD) isestimated to impact from 3 million to 5.5 million Americans and up to 16 million peopleworldwide. Stimulant use disorder (StimUD) is estimated to impact 6.5 millionAmericans, with global estimates of 7.4 million people with amphetamine dependence and 5 million with cocaine dependence.Impulsivity is a neuroendophenotype that can be defined as a “pre-disposition towardrapid, unplanned reactions to internal or external stimuli without regard to the negativeconsequences of these reactions to the impulsive individual or to others” (Moeller FG,Barratt ES, Dougherty DM, et al. Psychiatric aspects of impulsivity, Am J Psychiatry; 2001; 158(11); 1783-1793). Impulsivity plays an important role in all phases of the addiction lifecycle: high trait impulsivity is associated with a higher risk of conversionfrom casual drug use to compulsive drug taking (Jupp B, Dalley JW, Behavioralendophenotypes of drug addiction: etiological insights from neuroimaging studies. Neuropharmacology 2014; 76; 487-497). High impulsivity is also seen during active addiction including risky and unpredictable behavior while intoxicated or while seekingdrugs (Schaub AC, Vogel M, Lang UE, et al. Transdiagnostic brain correlates of self-reported trait impulsivity: a dimensional structure-symptom investigation. Neuroimage Clin 2023; 38; 103423; Lahbbairi N, Laniepce A, Segobin S, et al. Determinants of Boehringer Ingelheim 01-3614 ff -2 -health-related quality of life in recently detoxified patients with severe alcohol use disorder. Health Qual Life Outcomes; 2022; 20; 149). Finally, impulsivity also plays acritical role in the risk of relapse during abstinence (Jupp B, Dalley JW, Behavioralendophenotypes of drug addiction: etiological insights from neuroimaging studies. Neuropharmacology 2014; 76; 487-497). In particular, cue reactivity, defined as the subjective, neural, physiologic, and behavioral associations to drug-associated cues (Drummond DC: What does cue-reactivity have to offer clinical research? Addiction 2000; 95 (Suppl 2); S129-S144), and the impulsive responses to them play a criticalrole in relapse (Vafaie N, Kober H. Association of drug cues and craving with drug useand relapse: a systematic review and meta-analysis: JAMA Psychiatry 2022; 797:641-650). It is hypothesized that SUD patients with high impulsivity may both be morevulnerable to drug-associated cues, as well as less able to resist the impulses thatthose cues generate by engagement of top-down neural circuitry (Cunningham KA,Anastasio NC. Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 2014; 76:460-478). Thus, patients with high impulsivity are a particularly vulnerable and high-risk subgroup within SUDs more broadly. Despite increased efforts at treatment and prevention, OUD and StimUD, particularly in the United States, have only grown in incidence and show few signs of improvement. Since the 1990s, OUD incidence and overdose deaths via opioids have reached epidemic proportions. The number of people who died from a drug overdose in 2021 was over 6x that seen in 1999. From 2020 to 2021 alone, drug overdose deaths increased more than 16%. While opioid overdoses are the most common drug- associated cause of mortality, stimulant-associated deaths are not far behind. From 2013 through 2018, the age-adjusted rate of cocaine-associated overdose fatalitiesnearly tripled- an increase by about 27% per year. The costs of SUDs are not onlyreflected in individual figures relating to health care resources utilization (HCRU), morbidity, and mortality, but also pay a heavy toll on families and society at large. These broader impacts can be captured in escalating rates of children in the foster- care system, drug-associated arrests and crimes, escalating rates of unhoused peoplewith SUDs, and the costs to local and federal governments to manage these crises. Boehringer Ingelheim 01-3614 ff -3 -Ghrelin O-Acyltransferase (GOAT) is a member of the membrane-bound O-acyl transferase (MBOAT) protein family, and the only enzyme in humans capable of promoting an acylation reaction on the peptide hormone ghrelin. By linking a medium- chain fatty acid to the Serine-3 position of the 28-amino acid peptide, GOAT converts unacylated ghrelin (UAG) to acylated ghrelin (AG) which is the natural ligand of the ghrelin receptor GHSR1a (growth hormone secretagogue receptor 1a).The enzyme ghrelin o-acyl transferase (GOAT) leads to reduced levels of the activatedform of ghrelin (acylated ghrelin). Acyl-ghrelin (AG) can cross the blood brain barrier and bind to its receptor in the brain, where it increases the excitability of dopaminergic neurons that modulate the basal ganglia, in key areas that regulate impulsive behavior and cue-related reward responding. While classically studied as a feeding peptide, ghrelin levels and ghrelin signaling have since been implicated in the pathophysiologyof addiction (Zallar LJ, Farokhnia M, Tunstall BJ, et al. The role of the ghrelin systemin drug addiction. Int Rev Neurobiol; 2017; 136; 89-119; Engel JA, Nylander I, Jerlhag E. A ghrelin receptor (GHS-R1a) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice. EurNeuropsychopharmacol; 2015; 25; 2364-2371) and the expression of impulsivebehaviors (Ralevski E, Shanabrough M, Newcomb J, et al. Ghrelin is related topersonality differences in reward sensitivity and impulsivity. Alcohol Alcohol 2018;531:52-56; Anderberg RH, Hansson C, Fenander M, et al. The stomach-derivedhormone ghrelin increases impulsive behavior. Neuropsychopharmacology; 2016; 41; 1199-1209)).WO 2018 / 024653 discloses ghrelin O-acyl transferase (GOAT) inhibitors of formula (I),their preparation and certain details regarding their biological properties. Object of the present invention The object of the present invention is to provide compounds, hereinafter described as compounds of formula I, in particular oxadiazolopyridine derivatives, which are ghrelinO-acyl transferase (GOAT) inhibitors for use in the treatment of substance use disorder(SUD) in patients with high impulsivity, particularly for use in the treatment of opioid Boehringer Ingelheim 01-3614 ff -4 -use disorder (OUD) in patients with high impulsivity and for use in the treatment ofstimulant use disorder (StimUD) in patients with high impulsivity.A further object of the present invention is to provide a pharmaceutical compositioncomprising at least one compound of formula (I) for use in the treatment of substanceuse disorder (SUD) in patients with high impulsivity, particularly for use in the treatmentof opioid use disorder (OUD) in patients with high impulsivity or for use in the treatmentof stimulant use disorder (StimUD) in patients with high impulsivity.A further object of the present invention is to provide a combination of at least onecompound of formula (I) with one or more additional therapeutic agents for use in thetreatment of substance use disorder (SUD) in patients with high impulsivity, particularlyfor use in the treatment of opioid use disorder (OUD) in patients with high impulsivityor for use in the treatment of stimulant use disorder (StimUD) in patients with highimpulsivity. A further object of the present invention is to provide the use of a compound of formulaI or a pharmaceutical composition comprising a compound of formula I for thetreatment of substance use disorder (SUD) in patients with high impulsivity, particularlyfor use in the treatment of opioid use disorder (OUD) in patients with high impulsivityor for use in the treatment of stimulant use disorder (StimUD) in patients with highimpulsivity, wherein preferably, the patients are humans.A further object of the present invention is to provide a method for treating substanceuse disorder (SUD) in patients with high impulsivity, particularly for use in the treatmentof opioid use disorder (OUD) in patients with high impulsivity or for use in the treatmentof stimulant use disorder (StimUD) in patients with high impulsivity, wherein thepatients are preferably mammals, and the method includes the step of administeringto a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition comprising a compound fo formula I. Boehringer Ingelheim 01-3614 ff -5 -A further object of the present invention is to provide the use of a compound of formulaI in the manufacture of a medicament for treating substance use disorder (SUD) inpatients with high impulsivity, particularly for use in the treatment of opioid use disorder(OUD) in patients with high impulsivity or for use in the treatment of stimulant usedisorder (StimUD) in patients with high impulsivity.Further objects of the present invention will become apparent to the one skilled in theart from the entirety of the disclosure and the examples.Summary of the Invention In a first aspect, the invention relates to a compound of formula whereinX is CH or N;R1 is selected from the group R1-G1 consisting of CH3, -CH2OH and Cl;R2 is independently of each other selected from the group R2-G1 consisting of H,F, Cl, Br, I, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, -O-(C1-6-alkyl), -O-(C3-7-cycloalkyl), -O-(C1-3-alkyl)-(C3-7-cycloalkyl), -O-heterocyclyl, -O-(C1-3-alkyl)-heterocyclyl, -O-aryl, -O-heteroaryl, -S-(C1-3-alkyl), -SO-(C1-3-alkyl), -SO2-(C1-3-alkyl), -NH2, -NH-(C1-6-alkyl), -NH-(C3-6-cycloalkyl), -NH-(C1-3-alkyl)- heterocyclyl, -NH-(C1-6-alkyl)-C(=O)-NH2, -C(=O)-NH2, -C(=O)-NH-(C1-3-alkyl), -C(=O)-N(C1-3-alkyl)2, -C(=O)OH, -C(=O)-O-(C1-4-alkyl), -C(=O)-(C1-4-alkyl), - C1-3-alkyl-C(=O)-O-(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl, Boehringer Ingelheim 01-3614 ff -6 -wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and wherein each heterocyclyl group is selected from a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C=O, and wherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and C1-3- alkyl, wherein each aryl group is selected from a group consisting of phenyl and naphthyl, and wherein each heteroaryl group is selected from a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F, CN andC1-3-alkyl, which is optionally substituted with one or more F; or, if two groups R2are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a –O-CH2-O-, -O-CH2-CH2-O- or –O-CH2-CH2-CH2-O- bridge, in which 1 or 2 H atoms may be replaced withF or C1-3-alkyl; and n is 1, 2 or 3;wherein each of the above-mentioned alkyl groups may be substituted with one ormore F; Boehringer Ingelheim 01-3614 ff -7 -the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof,for use in the treatment of substance use disorder (SUD) in patients with highimpulsivity, particularly for use in the treatment of opioid use disorder (OUD) orstimulant use disorder (StimUD), both in patients with high impulsivity. The treatment with a compound of formula (I) may be adjunctive to the standard ofcare, such as the treatment of an OUD patient with buprenorphine, methadone, L-methadone or naltrexone, particularly with buprenorphine.The extension -Gn used within the definitions is meant to identify genus n of therespective substituent. For example, R-G1 defines genus 1 of the substituent R. The expression "optionally substituted with 1 or more F atoms" means that none or one up to successively all H atoms bound to carbon atoms of the respective group or submoiety may be replaced by F atoms, preferably 1 to 5 H atoms or, more preferred,1 to 3 H atoms may be replaced by F atoms.In a further aspect this invention relates to a pharmaceutical composition, comprisingone or more compounds of general formula I or one or more pharmaceuticallyacceptable salts thereof according to the invention, optionally together with one ormore inert carriers and / or diluents, for use in the treatment of substance use disorder(SUD) in patients with high impulsivity, particularly for use in the treatment of opioiduse disorder (OUD) or stimulant use disorder (StimUD), both in patients with highimpulsivity. In a further aspect this invention relates to a method for treating substance use disorder(SUD), particularly treating opioid use disorder (OUD) or stimulant use disorder(StimUD), in a patient with high impulsivity in need thereof characterized in that acompound of general formula I or a pharmaceutically acceptable salt thereof isadministered to the patient. Boehringer Ingelheim 01-3614 ff -8 -According to another aspect of the invention, there is provided a method for treatingsubstance use disorder (SUD), particularly for treating opioid use disorder (OUD) orstimulant use disorder (StimUD), in a patient with high impulsivity in need thereofcharacterized in that a therapeutically effective amount of a compound of generalformula I or a pharmaceutically acceptable salt thereof is administered to the patient.According to another aspect of the invention, there is provided the use of a compoundof the general formula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for a therapeutic method as described hereinbefore and hereinafter. According to another aspect of the invention, there is provided a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof for use in a therapeuticmethod as described hereinbefore and hereinafter. In a further aspect this invention relates to a method for treating substance use disorder(SUD), particularly for treating opioid use disorder (OUD) or stimulant use disorder(StimUD), in a patient with high impulsivity that includes the step of administering tothe patient in need of such treatment a therapeutically effective amount of a compoundof the general formula I or a pharmaceutically acceptable salt thereof in combinationwith a therapeutically effective amount of one or more additional therapeutic agents. In a further aspect this invention relates to the use of a compound of the generalformula I or a pharmaceutically acceptable salt thereof in combination with one or moreadditional therapeutic agents for the treatment of substance use disorder (SUD),particularly for treating opioid use disorder (OUD) or stimulant use disorder (StimUD),in patients with high impulsivity. In a further aspect this invention relates to a pharmaceutical composition whichcomprises a compound according to general formula I or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agents, optionallytogether with one or more inert carriers and / or diluents, for use in the treatment of Boehringer Ingelheim 01-3614 ff -9 -substance use disorder (SUD), particularly for use in the treatment of opioid usedisorder (OUD) or stimulant use disorder (StimUD), in patients with high impulsivity.In addition, the present invention relates to a compound of formula I or apharmaceutical composition comprising a compound of formula I for use in^ Improving impulse control,^ Normalizing impulsivity, particularly in substance use disorder patients with highimpulsivity, ^Improving the results of impulsivity tasks or scales such as the DelayDiscounting Task (DDT), the 4-Choice Serial Reaction Time Test (4-CSRTT), the Barratt Impulsiveness Scale, version 11 (BIS-11), the Short Urgency,Premeditation, Perseverance, Sensation Seeking, Positive Urgency Impulsive Behavior Scale (S-UPPS-P) and / or the Opioid Craving Visual Analog Scale(OC-VAS), ^Reducing or normalizing cue reactivity, particularly in substance use disorderpatients with high impulsivity, ^Reducing or normalizing addictive behaviors, particularly in substance usedisorder patients with high impulsivity, ^Reducing relapse after abstinence,^ Reducing drug intake,^ Improving quality of life,^ Improving adherence and compliance with medications,^ Improving adherence and compliance to psychotherapy,^ Decreasing overall mortality and overdose mortality,^ Reducing criminal behavior to satisfy drug consumption, and / or^ Reducing craving, reducing drug use or abstaining from drug use or changingdrug use pattern, wherein drug includes opioids and stimulants,in SUD, OUD or StimUD patients, particularly in SUD, OUD or StimUD patients withhigh impulsivity. The above use of a compound of formula (I) may be adjunctive to the standard of care of the treated patients. For example, OUD patients to be treated with a compound of Boehringer Ingelheim 01-3614 ff -10 -formula (I) to achieve one of the above goals may be may also be takingbuprenorphine, methadone, L-methadone or naltrexone, particularly buprenorphine.In a preferred embodiment, the present invention relates to a compound of formula Ior a pharmaceutical composition comprising a compound of formula I for use in^ Normalizing impulsivity, particularly in substance use disorder patients with highimpulsivity, ^Reducing or normalizing cue reactivity, particularly in substance use disorderpatients with high impulsivity, ^Reducing or normalizing addictive behaviors, particularly in substance usedisorder patients with high impulsivity, ^Reducing relapse after abstinence,^ Reducing drug intake,^ Improving quality of life,^ Improving adherence and compliance with medications^ Improving adherence and compliance to psychotherapy,^ Decreasing overall mortality and overdose mortality,^ Reducing criminal behavior to satisfy drug consumption, and / or^ Reducing craving, reducing drug use or abstaining from drug use or changingdrug use pattern, wherein drug includes opioids and stimulants,in SUD, OUD or StimUD patients, particularly in SUD, OUD or StimUD patients withhigh impulsivity. In a more preferred embodiment, the present invention relates to a compound offormula I or a pharmaceutical composition comprising a compound of formula I for usein ^Reducing or normalizing addictive behaviors, particularly in substance usedisorder patients with high impulsivity, ^Reducing relapse after abstinence, and / or^ Reducing drug intake,in SUD, OUD or StimUD patients, particularly in SUD, OUD or StimUD patients withhigh impulsivity. Boehringer Ingelheim 01-3614 ff -11 -Another aspect of the present invention relates to a compound of formula I or apharmaceutical composition comprising a compound of formula I for use in thetreatment of alcohol use disorder in patients with high impulsivity.Furthermore, the present invention relates to a compound of formula I or apharmaceutical composition comprising a compound of formula I for use in thetreatment of behavioral addiction such as gambling disorder in patients with highimpulsivity. Other aspects of the invention become apparent to the one skilled in the art from the specification and the experimental part as described hereinbefore and hereinafter. Detailed DescriptionUnless otherwise stated, the groups, residues, and substituents, particularly X, R1, R2and n are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other. X:X is preferably CH or N.According to one embodiment, X is CH. According to another embodiment, X is N. R1: R1-G1: The group R1 is preferably selected from the group R1-G1 as defined hereinbefore. R1-G2:In one embodiment the group R1 is selected from the group R1-G2 consisting of CH3and Cl. Boehringer Ingelheim 01-3614 ff -12 -R1-G3:In another embodiment the group R1 is selected from the group R1-G3 consisting ofCH3 and -CH2OH.R1-G4:In another embodiment the group R1 is selected from the group R1-G4 consisting of-CH2OH and Cl. R1-G5:In another embodiment the group R1 is selected from the group R1-G5 consisting ofCH3. R1-G6:In another embodiment the group R1 is selected from the group R1-G6 consisting of-CH2OH. R1-G7:In another embodiment the group R1 is selected from the group R1-G7 consisting of Cl. The group R2is preferably selected from the group R2-G1 as defined hereinbefore. R2-G2:In another embodiment the group R2 is independently of each other selected from thegroup R2-G2 consisting of H, F, Cl, Br, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, -O-(C1-6-alkyl), -O-(C1-3-alkyl)-(C3-7-cycloalkyl), -O-heterocyclyl, -O-(C1-3-alkyl)-heterocyclyl, -O- aryl, -O-heteroaryl, -S-(C1-3-alkyl), -SO2-(C1-3-alkyl), -NH2, -NH-(C1-6-alkyl), -NH-(C3-6- cycloalkyl), -NH-(C1-3-alkyl)-heterocyclyl, -NH-(C1-6-alkyl)-C(=O)-NH2, -C(=O)-NH2, - Boehringer Ingelheim 01-3614 ff -13 -C(=O)-NH-(C1-3-alkyl), -C(=O)-(C1-4-alkyl), -C1-3-alkyl-C(=O)-O-(C1-4-alkyl),heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and wherein each heterocyclyl group is selected from a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C=O, and wherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and C1-3- alkyl, wherein each aryl group is selected from a group consisting of phenyl and naphthyl, and wherein each heteroaryl group is selected from a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F and C1-3-alkyl, which is optionally substituted with one or more F; or, if two groups R2are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a –O-CH2-O-, -O-CH2-CH2-O- or –O-CH2-CH2-CH2-O- bridge.R2-G3:In another embodiment the group R2 is independently of each other selected from thegroup R2-G3 consisting of F, Cl, Br, CN, C1-3-alkyl, C3-6-cycloalkyl, -O-(C1-4-alkyl), -O- Boehringer Ingelheim 01-3614 ff -14 -CH2-cyclopropyl, -O-CH2-heterocyclyl, -O-phenyl, -O-heteroaryl, -S-CH3, -NH2, -NH-(C1-4-alkyl), -NH-(C3-5-cycloalkyl), -NH-(CH2-heterocyclyl), -NH-(C1-4-alkyl)-C(=O)-NH2,-C(=O)-NH-(C1-3-alkyl), -C(=O)-(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, andwherein each heterocyclyl group is selected from a group consisting ofoxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, andwherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and CH3,wherein each heteroaryl group is selected from a group consisting of furanyl, isoxazolyl, thiazolyl and pyrazolyl, andwherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F, CH3and CF3. R2-G4: In another embodiment the group R2is independently of each other selected from thegroup R2-G4 consisting of F, Cl, Br, CN, CH3, C3-5-cycloalkyl, -O-(C1-4-alkyl), -O-CH2-heterocyclyl, -O-phenyl, -S-CH3, -NH2, -NH-(C1-4-alkyl), -NH-(C3-5-cycloalkyl), -NH- (CH2-heterocyclyl), -NH-(C1-4-alkyl)-C(=O)-NH2, heterocyclyl, heteroaryl and 5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, and Boehringer Ingelheim 01-3614 ff -15 -wherein each heterocyclyl group is selected from a group consisting ofoxetanyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently selected from F, OH and CH3, andwherein each heteroaryl group is selected from a group consisting of furanyl and thiazolyl.R2-G5: In another embodiment the group R2is independently selected from the group R2-G5 consisting of: Boehringer Ingelheim 01-3614 ff -16 -R2-G6: In another embodiment the group R2is independently selected from the group R2-G6consisting of H, F, Cl, Br, CN, -CF3, -CHF2, -CH2F, -O-CF3, -O-CHF2, -O-CH2F, -O-CH3, -NH2, -CO-NH2, -CO2H. n The index n is an integer selected from 1, 2 and 3. Preferably, n is 2 or 3. In another embodiment, n is 1 or 2. More preferably, n is 2.The following preferred embodiments of compounds of the formula I are describedusing generic formulae I.1 to I.11, wherein any tautomers, solvates, hydrates and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed. R2aand R2bare as defined for R2. Boehringer Ingelheim 01-3614 ff -17 - Boehringer Ingelheim 01-3614 ff -18 - Another embodiment concerns those compounds of formula wherein R1is CH3;R2a and R2b are each independently selected from the group consisting of: 3, - -,, Boehringer Ingelheim 01-3614 ff -19 -,, or a salt thereof, particularly a pharmaceutically acceptable salt thereof.Compounds of formula I include:Ex.Structure Ex.Structure No. No. 123 4 Boehringer Ingelheim 01-3614 ff -20 -5 67 89 1011 1213 1415 1617 18 Boehringer Ingelheim 01-3614 ff -21 -19 2021 2223 2425 26NH N N O N N F F F27 2829 30

[0002] Boehringer Ingelheim 01-3614 ff -22 -31 3233 3435 3637 3839 4041 42 Boehringer Ingelheim 01-3614 ff -23 -43 4445 4647 4849 NH2 50 N N O O N F N F F51 5253 5455 NH2O56 NH2 O N N N N N NH O O 2 N N N N 57 NHO58 NH2 N N N N O N O N N N Boehringer Ingelheim 01-3614 ff -24 -59 NH2N60 NH N N N2O N N N O O N N N N 61 NH N62H NHNN2N N N N N O N F O N FFN NFFF 63 NH2 64 N N NH2 O N N N N N O N N N 65 NH N 66 NH2NNHNN NH2O O N N N N N O N N 67 NH NNH68 NH N NN NHO O N N N N N SN N69 NH2 NH N NNH70 N 2 N N O O N N N N N O F F N 71 NH2 N 72 NH2 N N NN FO O N N Br N N N 73 F F NH NH 7422 NON N N O O N N N N N F NF F75 NH2 N 76 NH2 N N N N O N F O N N N N F N F N Boehringer Ingelheim 01-3614 ff -25 -77 NH278 NH2F N N N N F O N N O F N N N N N N 79 NH2F80 NH2 N N N N O F O O N N N N N N N N 81 NH2 82 NH2F FN N N N O N N O N N N N N N 83 NH2F 84 NH2F N N N N F F O F O N N N Br N N N Br 85 NHO86 NH2O ONN SNN SO O N N N N 87 NH288 NH N N N N O O O N O N N S N S O 89 NHONH O 2 90 N N N N NH NH O 2 O N N N F O N F F F F 91 NHFF92 NH F 2 N NON O O N F F N N Br O N N Br 93 NH2F94 NH2 N N O N O O F N OH O N N Br N N Br 95 NHO96 NH2F F N O N N O N F O O N N Br N N Br Boehringer Ingelheim 01-3614 ff -26 -97 NH2 98 NH2 N O N N O N O O O N N Br N N Br 99 NH2FFO 100 NH2 N N O N N F O O N N Br N N Br 101 NH2 NH2 NO F102 N N N S O O N N Br N N Br 103 NH2FF104 NH2N O N NN OO O O N N N N N N 105 NH2NH2 NO106 N OH N N O F O O N N N N N N 107 NH F F NO108 NH N NN OF F O O N N N N N N 109 NH F 11 NH2 F NN O0 F NN O FO O F N N N N N N 111 O NH2 112 NH2 NONN OF N O F O N N N N N N 113 NH H 114 NH2N N N O N N O O F N N N F N N O F 115 NH N NH N 1162N N N N O F O N N O N F N O F Boehringer Ingelheim 01-3614 ff -27 -117 NH2 N N 118 H2 N N N N N O O N N O N N O N N 119 NH N NH 120 NH H N N N O O N O N O N N O F FFF121 O122 NH2OH NH N N NH N N N O O N N N N Br Br 123 NHO124 2 NH2N N N NH2O N N NH O N N Br O N N Br 125126 ONH N N NH NH O N N NH N N Br O N N Br 127N128 F F NH NH N N NH N N NH O O N N N N Br Br 129FNH130 O2 F NH N N N 2 N N N O O N N Br N N Br 131 H 132 F N F NH O NH2 N N N N N N O O N N Br N N Br 133 NH N H 134 NH2 N F H N NN NF O F F O N N Br F N N Br Boehringer Ingelheim 01-3614 ff -28 -135 O136 NH O NN NNH2O NN NHN N O N N N N137 O138 NH N N NN NOH N N O O N N N N N N 139 NH 140 NH N H NNNN NHO F O N N N F N N N 141 H F N 142 NH O NH N N N NN NF O O N N N N N N 143 NH F NH H NN144 N F N N N F O O N F N N N N N 145 NH NN16 N H N F 4 F O F N NH N N NN NHO N N N147 O148 NH2 NH2 NH2N NHO NN NHN O O N N N N N N 149 NH2NNH NF150 N N N N O O N F N N N N N F Boehringer Ingelheim 01-3614 ff -29 -151 NH2 N N N 152 H2N N N N O O N N N F N N N F O 153 NH2 N N 154 NH N N N N O O N F N F N N N N H H F 155 NH2 N 156 NH N N N N N O O N N N N N F N N N FFF 157 NH2 N N N 158 H2N N N N O O N N N N N N N 159 NH 160 NH2 O O NN OHNN SO N O N S OON N S OO161 NHO ON 162 NH O O N S NN SO O N N Br N N N 163 NH2H 164 N N O O N N Br 165 NH2N 166 NH2 F N N N N O F N N O N N N N Cl FF167 NH2F N N F O N N N Cl FF Boehringer Ingelheim 01-3614 ff -30 -5 Boehringer Ingelheim 01-3614 ff -31 - ,or a salt thereof, particularly a pharmaceutically acceptable salt thereof.Particularly preferred compounds of formula I, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter. The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis for example, as described in WO 2018 / 024653. Boehringer Ingelheim 01-3614 ff -32 -Further modifications of compounds of formula I by methods known in the art and illustrated in the Examples below, may be used to prepare additional compounds of the invention.The compounds of general formula I may be resolved into their enantiomers and / ordiastereomers as mentioned below. Thus, for example, cis / trans mixtures may beresolved into their cis and trans isomers and racemic compounds may be separatedinto their enantiomers.The cis / trans mixtures may be resolved, for example, by chromatography into the cisand trans isomers thereof. The compounds of general formula I which occur asracemates may be separated by methods known per se into their optical antipodes anddiastereomeric mixtures of compounds of general formula I may be resolved into theirdiastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and / or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned below. The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids commonly used for such a purpose as well as optically active alcohols applicable as auxiliary residues are known to those skilled in the art. Boehringer Ingelheim 01-3614 ff -33 -As mentioned above, the compounds of formula I may be converted into salts,particularly for pharmaceutical use into the pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4- methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations from ammonia,L-arginine, calcium, 2,2’-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.Terms and definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. The term “substance use disorder”, “SUD” and the like refers to a mental disorder that affects a person's brain and behavior, leading to their inability to control their use ofsubstances such as legal or illegal drugs, alcohol, or medications. Substance usedisorder (SUD) is also called substance addiction or substance dependence.The term “opioid use disorder”, “OUD” and the like refers to a disease in which peoplecontinue to use opioids in spite of harms caused by their use. The term “opioid”includes drugs acting on opioid receptors, such as morphine, codeine, hydrocodone, Boehringer Ingelheim 01-3614 ff -34 -oxycodone, fentanyl and others. Opioid use disorder (OUD) is also called opioid addiction or opioid dependence.The term “stimulant use disorder”, “StimUD” and the like refers to a disease in whichpeople continue to use stimulants in spite of harms caused by their use. The term“stimulant” includes cocaine, amphetamine, methamphetamine and similar drugs.Stimulant use disorder (StimUD) is also called stimulant addiction or stimulantdependence. The term “alcohol use disorder” and the like refers to a disease in which peoplecontinue to use alcohol in spite of harms caused by their use. Alcohol use disorder isalso called alcohol dependence or alcohol addiction.The term “patients with high impulsivity” includes patients with moderate to severeimpulsivity and means patients who show above average impulsivity in tasks andscales such as DDT, 4-CSRTT, BIS-11, and S-UPPS-P, or are included in this patientgroup based on clinical judgement. Preferably, the term “patients with moderate tosevere impulsivity” means patients who show an impulsivity in tasks and scales suchas DDT, 4-CSRTT, BIS-11, and S-UPPS-P that is significantly above average.Significantly above average means impulsivity test result in the top 40% of the testedpatients. A more preferred patient group consists of the patients that have impulsivitytests results within the top 30 % of the tested patients.Even more preferably, SUD patients including OUD and StimUD patients withmoderate to severe impulsivity scores are those patients that prior to the treatmentaccording to the invention, have a baseline k parameter ≥0.025 on the behavioralversion of the DDT and / or at least 3 premature responses (≥3) on the short version ofthe 4CSRTT. A preferred patient group for the medical treatment according to theinvention have a baseline k parameter ≥0.025 on the behavioral version of the DDT.In another embodiment, SUD patients including OUD and StimUD patients with moderate to severe impulsivity scores are those patients that prior to the treatment Boehringer Ingelheim 01-3614 ff -35 -according to the invention, have a BIS-11 total score ≥70. This is another preferred patient group for the medical treatment according to the invention. The term “inhibitors of the ghrelin O-acyl transferase (GOAT)” as used herein refers to compounds which have an inhibiting effect on ghrelin O-acyl transferase (GOAT) invitro and / or in vivo. Preferably, the compounds used in the treatment according to theinvention possess suitable pharmacological and pharmacokinetic properties to use them as medicaments. The terms "compound(s) according to this invention", "compound(s) of formula (I)", "compound(s) of the invention" and the like denote the compounds of the formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvatesand hydrates of such tautomers, stereoisomers and salts thereof. Preferredcompounds of formula I include each of the specific compounds of examples 1 to 167,particularly the compound of example 70. The terms "treatment" and "treating" embrace both preventative, i.e. prophylactic, or therapeutic, i.e. curative and / or palliative, treatment. Thus the terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy. In addition the terms "treatment" and "treating" comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk. When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans. Boehringer Ingelheim 01-3614 ff -36 -The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein. The terms "modulated" or "modulating", or "modulate(s)", as used herein, unlessotherwise indicated, refer to the inhibition of the ghrelin O-acyl transferase (GOAT) withone or more compounds of the present invention. The terms "mediated" or "mediating" or "mediate", as used herein, unless otherwise indicated, refer to the (i) treatment, including prevention of the particular disease orcondition, (ii) attenuation, amelioration, or elimination of one or more symptoms of theparticular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein. The term "substituted" as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkyl-" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Boehringer Ingelheim 01-3614 ff -37 -The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached. For example, the term “3-carboxypropyl-group” represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-“, “2,2-dimethylpropyl-“ or “cyclopropylmethyl-“ group represent the following groups: , , . The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. In a definition of a group the term "wherein each X, Y and Z group is optionally substituted with" and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition "Rexdenotes H, C1-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl or C1-3-alkyl-O-, wherein each alkyl group is optionally substituted with one or more Lex." or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl and C1-3-alkyl-O-, the alkyl moiety may be substituted with Lexas defined. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E / Z isomers etc…) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically Boehringer Ingelheim 01-3614 ff -38 -acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention. The term halogen generally denotes fluorine, chlorine, bromine and iodine. The term “C1-n-alkyl”, wherein n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2- CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2- CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.The term "C1-n-alkylene" wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-4-alkylene includes -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, - (CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2- CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C Boehringer Ingelheim 01-3614 ff -39 -(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))- , -(CHCH(CH3) 2)- and –C(CH3)(CH2CH3)-.The term “C2-n-alkenyl”, is used for a group as defined in the definition for "C1-n-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. For example the term C2-3-alkenyl includes - CH=CH2, -CH=CH-CH3, -CH2-CH=CH2. The term “C2-n-alkynyl”, is used for a group as defined in the definition for "C1-n-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. For example the term C2-3-alkynyl includes - C^CH, -C^C-CH3, -CH2-C^CH. The term “C3-n-cycloalkyl”, wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]oc- tyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.Biological / Pharmacological PropertiesThrough normalization of ghrelin receptor-dependent signaling within the striatalcircuitry relevant for impulse control, GOAT inhibitors (such as compounds of general Formula I, including examples 1 to 167) may be effective in treating substance use disorders (SUD) in patients with high impulsivity. Individuals with opioid dependenceoften exhibit significant impairments in inhibitory control reflected in highly impulsiveaction, either because of chronic substance use or as a pre-existing trait that increases vulnerability to addiction (Verdejo-García, A., Lawrence, A. J., & Clark, L. Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk Boehringer Ingelheim 01-3614 ff -40 -research, problem gamblers and genetic association studies. Neurosci. Biobehav. Rev.;2008; 32(4), 777–810). Chronic opiate use leads to a preference for immediate rewards and impairs the ability to delay gratification (Tolomeo, S., Gray, S., Matthews, K., Steele, J. D., & Baldacchino, A. (2016). Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence. Psychol. Med; 2016; 46(13), 2841–2853). Even during sustained remission, patients struggle with impulsive actions (Psederska, E., & Vassileva, J. Neurocognitive Impulsivity in Opiate Users at Different Lengths of Abstinence. Int J Environ Res Public Health; 2023; 20(2), 1236.), significantly contributing to relapse (Jupp B, Dalley JW, Behavioral endophenotypes of drug addiction: etiological insights from neuroimaging studies. Neuropharmacology 2014; 76; 487-497). This underscores the need for targeted interventions, especially during early remission. Surprisingly, the novel potential of GOAT inhibitors to improve inhibitory control in SUDs is demonstrated by example 70, which enhances inhibitory control in high-impulsive rodents in the 5-choice serial reaction time task (5-CSRTT).Assessment of efficacy on impulsive behavior tested in the rat Five Choice SerialReaction Time Task (5-CSRTT) Assessment of efficacy on motor impulsive behavior may be investigated as follows:5-CSRTT task training took place according to standard protocols (Isherwood et al.Neuropharmacology 2017, 123: 249-260). Briefly, rats were trained to nose poke at the location of a light cue presented at 1 of 5 locations on a curved wall of an operant box (Med Associates Inc, St. Albans, Vermont). If a nose poke occurred at the illuminated location during or up to 1 s after stimulus presentation a sugar pellet was delivered in a reward receptacle located across the chamber. Infrared beams in each choice aperture and the reward receptacle allowed for precise detection of the rat at this task associated operanda. Motor impulsive behavior was defined as a response at any nose poke aperture which occurred before onset of the light cue (premature response). After reaching stable performance, a new analytical approach was applied which revealed trait-like (long-term) stability in the number of premature responses individual Boehringer Ingelheim 01-3614 ff -41 -animals made across several months. In general, this analysis made it possible torobustly stratify animals into high- and low-impulsive groups based on longitudinalassessment of the number of premature responses they made during training. Experiments were performed in cross-over such that all experiment subjects received both vehicle and compound, on separate days, with each administration separated by~2 weeks. The order of vehicle and compound administration was randomized withinexperimental subjects, while a third group was administered Atomoxetine on both experimental days as a technical control. As a standardized numerical threshold for impulsivity levels, animals with >40 and <40 premature responses (out of 200 initiated trials) in vehicle were labeled as high and low impulsive, respectively. Importantly, this numerical threshold-based labeling overlapped >80% with the longitudinal analysis of the training data (described above). The high convergence of these two approaches towards stratification allowed us torobustly compare compound effects in stably high- vs stably low- impulsive rats in the5-CSRTT.Table 1: Test results (example 70 was used as the test compound “cpd”)Impulsivity Impulsivity (Premature Counts) level of animal group Vehicle cpd 0.15 mg / kg cpd 0.5 mg / kg cpd 1.5 mg / kgHigh 32 ± 3 19 ± 3 19 ± 2 16 ± 3Low 11 ± 1 15 ± 2 17 ± 2 16 ± 2The above data of table 1 shows that the compound of example 70 significantlyreduces the impulsivity in high impulsive rats at all three tested doses. The psychological and neural basis of impulsivity can be studied and experimentally translated from humans to rodents. Striking parallels can be observed in the underlyingneurobehavioral systems, which enable both macro- and micro-definition of functionalcircuits (Dalley JW, Robbins TW. Fractionating impulsivity: neuropsychiatricimplications. Nat Rev Neurosci 2017; 18: 158-171). Boehringer Ingelheim 01-3614 ff -42 -In vivo, the compound of example 70 significantly reduced acylated ghrelin in plasmain rats. Treatment of rats with example 70 significantly reduced impulsive behavior inhigh impulsive animals in a translatable behavioral task (5-choice serial reaction time task) without observable confounding factors.Early Real World Evidence suggests that improving impulsivity may translate to animprovement in addiction outcomes. Methods and scales to measure impulsivity in humansTo assess impulsivity, there are several objective measures that have a long history inexperimental neuroscience and strong data to support the linkage of task behavior withspecific corticostriatal brain circuits (Dalley JW, Robbins TW. Fractionating impulsivity:neuropsychiatric implications. Nat Rev Neurosci 2017; 18: 158-171). An objectivemeasure of impulsivity (DDT) is proposed to assess the effect of example 70 in humanswith additional exploratory measures of efficacy (e.g., craving, BIS-11, S-UPPS-P, the4-CSRTT, cue reactivity test) also collected after 8 days of treatment. Considering theincreased risk of negative addiction outcomes posed by heightened impulsivity as wellas emerging Real World Evidence, it is considered that a significant reduction ofimpulsivity may suffice to demonstrate a meaningful improvement over available therapies. 4-Choice Serial Reaction Time Test (4-CSRTT) The 4-CSRTT task is a computerized task of waiting impulsivity that was developed based on the rodent 5-CSRTT (Voon V, Irvine MA, Derbyshire K, et al. Measuring “waiting” impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task. Biol Psychiatry 2014; 75:148-155). Participants are required to press and hold down the space bar with their dominant index finger while four boxes are presented on the screen. After a specified period(cue-target interval), a green circle target appears briefly and randomly in 1 of the 4boxes. Participants are instructed to release the space bar and touch the box in which the target appeared. Baseline blocks without monetary reward feedback are used to individualize subsequent blocks based on the individual’s mean reaction time (RT) andstandard deviation (SD). The subsequent 4 test blocks with monetary feedback are Boehringer Ingelheim 01-3614 ff -43 -optimized to increase premature responding. This includes variation of target duration, variability of the cue-target interval, and the presence of distractors. Responses are followed by outcome feedback depending on performance. The task duration is 10-15 mins. The main outcome measure, premature responding, is defined as a release ofthe space bar before target onset. The short version consists of 2 trials blocks and apractice run. The standard version consists of 1 baseline block and 4 test blocks. Delay Discounting Task (DDT) In the DDT, participants make choices on the screen between a smaller, immediate amount of money and a larger, delayed amount. Steep discounting of delayed rewards is indicative of cognitive impulsivity. A behavioral version of the task incudes that theamount of the delayed option is reduced in a stepwise manner after 2 successivechoices of the delayed reward and increased in a stepwise manner after 2 successivechoices of the immediate reward. The key outcome variable for this task is the discount rate (k) or rate at which delayed rewards lose their value. The DDT task duration is 10-15 mins. An MRI compatible version of the DDT can be completed in the scanner. By analyzing the neural correlates of decision-making in this task, researchers can gain insights into the brain processes underlying impulsive behavior and self-control.Barratt Impulsiveness Scale version 11 (BIS-11)The Barratt Impulsiveness Scale version 11 (BIS-11) is described in Vasconcelos, A.G., Malloy-Diniz, L., & Correa, H. (2012). Systematic review of psychometric proprieties of Barratt Impulsiveness Scale Version 11 (BIS-11). Clinical Neuropsychiatry: Journal of Treatment Evaluation, 9(2), 61–74. Short Urgency, Premeditation, Perseverance, Sensation Seeking, PositiveUrgency Impulsive Behavior Scale (S-UPPS-P)The Short Urgency, Premeditation, Perseverance, Sensation Seeking, PositiveUrgency Impulsive Behavior Scale (S-UPPS-P) is described in Whiteside, S.P. andLynam, D.R., The Five Factor Model and Impulsivity: Using a Structural Model of Personality to Understand Impulsivity. Personality and Individual Differences 2001, 30(4), 669-689. Boehringer Ingelheim 01-3614 ff -44 -Opioid Craving Visual Analog Scale (OC-VAS)The Opioid Craving Visual Analog Scale (OC-VAS) is described in Boynett et al., DrugAlcohol Depend (2021). Assessment of craving in opioid use disorder: Psychometric evaluation and predictive validity of the opioid craving VAS (DOI: 10.1016 / j.drugalcdep.2021.109057. Cue Reactivity test An increased neural response to drug-related cues has been well documented in substance use disorder patients and is associated with drug craving, drug seeking, andrelapse (Ekhtiari H, Kuplicki R, Aupperle RL, et al. It is never as good the second timearound: brain areas involved in salience processing habituate during repeated drug cue exposure in treatment engaged abstinent methamphetamine and opioid users. Neuroimage; 2021; 238; 118180). In this task, participants will be presented with 4 blocks of drug-related pictures and 4 blocks of neutral pictures while undergoing fMRI scanning. After every block, participants are asked to rate their current urge to use drug on a one to four scale, with 1 being “No Urge” and 4 being “Strong Urge” using a4 key response box. Opioid-related pictures are selected from the methamphetamineand opioid cue database provided by the Laureate Institute for Brain Research (Tulsa, OK, USA). Pharmaceutical CompositionsThe dose range of the compounds of general formula I applicable per day is usuallyfrom 0.001 to 10 mg per kg body weight, for example from 0.01 to 8 mg per kg body weight of the patient. Each dosage unit may conveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.The preferred dose range of compounds of general formula I including example 70applicable per day is from 0.5 to 20 mg per day and patient.The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a Boehringer Ingelheim 01-3614 ff -45 -therapeutically effective amount to be delivered based upon patient’s unique condition. The compounds, compositions, including any combinations with one or more additional therapeutic agents, according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route. Of the possible methods ofadministration, oral or intravenous administration is preferred. Most preferred is oraladministration.Suitable preparations for administering the compounds of formula I including example70, optionally in combination with one or more further therapeutic agents, will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for examplefrom 1 to 70 wt.-% of the composition as a whole.Suitable tablets may be obtained, for example, by mixing one or more compoundsaccording to formula I with known excipients, for example inert diluents, carriers,disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablets may also consist of several layers. The particular excipients, carriers and / or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge. The preferred ones are those that are suitable for the particular formulation and method of administration that are desired. The preparations or formulations according to the invention may be prepared using methods known perse that are familiar to the skilled man, such as for example by mixing or combining atleast one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, carriers and / or diluents. Combination Therapy A compound of the invention may be administered as part of a combination therapy together with another active agent for the treatment of the disease or disorder in Boehringer Ingelheim 01-3614 ff -46 -question, e.g. buprenorphine, methadone, L-methadone, naltrexone and / or naloxonesubstitution therapy. In such cases, the two active agents may be given together or separately, e.g. as constituents in the same pharmaceutical composition or formulation, or as separate formulations. The dosage for the combination partners mentioned above is usually 1 / 5 of the lowest dose normally recommended up to 1 / 1 of the normally recommended dose. Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment of diseases or conditions as described hereinbefore and hereinafter. In yet another aspect the present invention relates a method for treating a disease orcondition as described herein in a patient that includes the step of administering to thepatient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter. The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times. The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so- called kit-of-parts. Consequently, in another aspect, this invention relates to a pharmaceutical com- position which comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and / or diluents. Boehringer Ingelheim 01-3614 ff -47 -Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention.

[0003] Boehringer Ingelheim 01-3614 ff -48 -Examples Example I A Phase Ib trial is conducted to evaluate the effects on impulsivity, pharmacokinetics,safety, and tolerability of compound 70, given orally, in patients with opioid use disordertaking background buprenorphine treatment.The original purpose of the trial was to examine preliminary efficacy of oral compound70 in treating impulsivity by comparing the mean change from baseline in both the k parameter of the Delay Discounting Task (DDT) and the total number of premature responses in the 4 Choice Serial Reaction Time Test (4-CSRTT) at Day 8. Theamended purpose of the trial is to examine preliminary efficacy of oral compound 70in treating impulsivity by comparing the mean change from baseline in the k parameter of the Delay Discounting Task (DDT) at Day 8. The primary treatment comparison will be on treatment, which will assume all participants took randomized treatment.Participants are put in 2 groups, one receiving the compound of example 70 (alsocalled “example 70” or “ compound 70”), the other receiving placebo. After a screening period, participant are randomized. Trial designThe trial is a randomized, double-blind (participant and investigator),placebo-controlled, parallel group trial to examine the preliminary efficacy and safetyof oral compound 70 once daily over an 8-day treatment period in adult maleparticipants with moderate to severe OUD and impulsivity that are on stable background buprenorphine-based medication for OUD (MOUD) treatment. Trial medicationCompound 70 in an amount of 2.5 mg and matching placebo are supplied as film-coated tablets. Four of these tablets are admininstered once daily, resulting in atreatment dose of 10 mg qd. Boehringer Ingelheim 01-3614 ff -49 -Standard pharmaceutical excipients are selected for the manufacture of example 70 film-coated tablets which are commonly used in oral dosage forms. The tablet cores of the formulation include lactose monohydrate (filler), microcrystalline cellulose (filler), hydroxypropylcellulose (binder), crospovidone (disintegrant), and magnesium stearate (lubricant); purified water is used as a processing aid (solvent) for the manufacture of the tablet cores and for film-coating of the cores (film-coatingsolvent). The film-coating mixture consists of hypromellose, macrogol, talc, titaniumdioxide, and iron oxide red. Trial population In total, about 90 participants currently engaged in medications for opioid use disorder (MOUD) treatment based on buprenoprphine / naloxone administration are randomized into the trial. Main Inclusion Criteria / Diagnosis: ^Male participants, 18 to 65 years of age^ Meet current DSM-5 diagnostic criteria for OUD, of at least moderate severity withinthe 12 months prior to screening^ Currently engaged in medications for opioid use disorder (MOUD) treatment at abuprenorphine / naloxone sublingual film total daily dose ranging from 8 mg / 2 mg to24 mg / 6 mg or buprenorphine / naloxone sublingual tablet from 5.7 mg / 1.4 mg to17.1 mg / 4.3 mg daily, or buprenorphine sublingual tablet from 8 mg to 24 mg totaldaily dose for at least 2 weeks at screening OR on a stable dose of depot injectablebuprenorphine for at least 5 weeks at screening, with at least 1 week since lastdepot buprenorphine injection ^Have a current MOUD prescription and a positive urine drug screen to documentbuprenorphine use ^Willingness to abstain from using alcohol for 24 h and all other drugs of abuse for72 h prior to Day 1 and through discharge from the trial site on Day 9As used herein “current” in connection with DSM-5 diagnostic criteria for OUD means as of September 2024. Boehringer Ingelheim 01-3614 ff -50 -Main Exclusion Criteria: ^Lifetime diagnosis of schizophrenia, schizoaffective disorder, schizophreniformdisorder, bipolar I disorder, delusional disorder, or autism spectrum disorder^ Moderate or severe substance use disorder other than OUD within the 6 monthsprior to screening (excluding tobacco, caffeine, and moderate stimulant use) ^Severe stimulant use disorder within the 6 months prior to screening^ Any other psychiatric disorder that is not currently stable in symptoms andtreatment. Stable is defined as having no significant changes in symptom acuity or treatment (medication or psychotherapy treatment) in the 6 weeks prior torandomization ^Currently experiencing a moderate to severe major depressive episode^ Positive results on a urine drug screen for 3 or more drugs at screening (notcounting buprenorphine) ^Any positive result on a urine drug screen upon admission to the trial site (excludingbuprenorphine and cannabis) ^Intoxication at screening or randomization^ Participants deemed to be at significant risk of serious violence or suicide^ Concomitant use of psychotropic medication except for:o Buprenorphine-based MOUDo A single SSRI or SNRI antidepressant that has been stable in agent, dose, andfrequency for more than 6 weeks prior to randomizationo Quetiapine (at a daily dose not exceeding 200 mg) and / or gabapentin, providedthey have been stable in dose and frequency for more than 6 weeks prior torandomization oA single sleep medication given as a nightly scheduled medication that has beenstable in agent, dose, and frequency for more than 6 weeks prior torandomization. Allowed sleep medications include: non-benzodiazepine sleep medications (i.e. “Z-drugs”), antihistamines, melatonin, trazodone, or doxepin ^Current Type 1 or Type 2 diabetes mellitus^ History of seizure disorders, stroke, brain tumor, or any other major neurologicalillness Boehringer Ingelheim 01-3614 ff -51 -^ Any contraindication to undergo magnetic resonance imaging (MRI) radiography(e.g. history of surgery involving metal implants) or that could interfere with the performance of behavioral or functional MRI tasks, including the following: oParticipants who have undergone operations to the heado Participants with significant hearing impairmentso Participants with a significant visual impairment, or history of oculartreatment including corrective laser eye surgery oParticipants with a weight or body circumference that exceeds MRIscanner capabilities or a BMI of ≥35 kg / m2^A positive result for an active hepatitis B or C infectionTrial endpointsPrimary endpoint: ^Change from baseline in k parameter of the DDTThere are no secondary endpoints for this trial.Further endpoints: Efficacy ^Change from baseline in total number of premature responses in the 4-CSRTTat Day 8^ Change from baseline in the Opioid Craving Visual Analog Scale (OC-VAS)^ Change from baseline in the Barratt Impulsiveness Scale (BIS-11) total score^ Change from baseline in the Short Urgency, Premeditation, Perseverance,Sensation Seeking, Positive Urgency Impulsive Behavior Scale (S-UPPS-P) total score Biomarkers Change from baseline of acylated ghrelin (AG), unacylated ghrelin (UAG), and the AG / UAG ratio in plasma following administration of compound 70. Boehringer Ingelheim 01-3614 ff -52 -Statistical methods ANCOVA will be used for the analysis of the primary endpoint. These models will include fixed effects for treatment, and baseline value of the relevant endpoint.

Claims

1. Boehringer Ingelheim 01-3614 ff -53 -Patent Claims1. A compound of formulawhereinX is CH or N;R1is selected from the group consisting of CH3, -CH2OH and Cl;R2 is independently of each other selected from the group consisting of H, F, Cl,Br, I, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, -O-(C1-6-alkyl), -O-(C3-7-cycloalkyl), -O-(C1-3-alkyl)-(C3-7-cycloalkyl), -O-heterocyclyl, -O-(C1-3-alkyl)-heterocyclyl, -O-aryl, -O-heteroaryl, -S-(C1-3-alkyl), -SO-(C1-3-alkyl), -SO2-(C1-3-alkyl), -NH2, - NH-(C1-6-alkyl), -NH-(C3-6-cycloalkyl), -NH-(C1-3-alkyl)-heterocyclyl, -NH-(C1-6- alkyl)-C(=O)-NH2, -C(=O)-NH2, -C(=O)-NH-(C1-3-alkyl), -C(=O)-N(C1-3-alkyl)2, - C(=O)OH, -C(=O)-O-(C1-4-alkyl), -C(=O)-(C1-4-alkyl), -C1-3-alkyl-C(=O)-O-(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and wherein each heterocyclyl group is selected from a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C=O, andBoehringer Ingelheim 01-3614 ff -54 -wherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and C1-3- alkyl, wherein each aryl group is selected from a group consisting of phenyl and naphthyl, and wherein each heteroaryl group is selected from a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F, CN and C1-3-alkyl, which is optionally substituted with one or more F; or, if two groups R2are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a –O-CH2-O-, -O-CH2-CH2-O- or –O-CH2-CH2-CH2-O- bridge, in which 1 or 2 H atoms may be replaced withF or C1-3-alkyl; and n is 1, 2 or 3;wherein each of the above-mentioned alkyl groups may be substituted with one ormore F; or a salt thereof, for use in the treatment of substance use disorder (SUD) in patients with high impulsivity.

2. A compound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof, for use in^ Improving impulse control,Boehringer Ingelheim 01-3614 ff -55 -^ Normalizing impulsivity, particularly in substance use disorder patients with highimpulsivity, ^Improving the results of impulsivity tasks or scales such as the DelayDiscounting Task (DDT), the 4-Choice Serial Reaction Time Test (4-CSRTT), the Barratt Impulsiveness Scale, version 11 (BIS-11), the Short Urgency,Premeditation, Perseverance, Sensation Seeking, Positive Urgency Impulsive Behavior Scale (S-UPPS-P) and / or the Opioid Craving Visual Analog Scale(OC-VAS), ^Reducing or normalizing cue reactivity, particularly in substance use disorderpatients with high impulsivity, ^Reducing or normalizing addictive behaviors, particularly in substance usedisorder patients with high impulsivity, ^Reducing relapse after abstinence,^ Reducing drug intake,^ Improving quality of life,^ Improving adherence and compliance with medications,^ Improving adherence and compliance to psychotherapy,^ Decreasing overall mortality and overdose mortality,^ Reducing criminal behavior to satisfy drug consumption, and / or^ Reducing craving, reducing drug use or abstaining from drug use or changingdrug use pattern, wherein drug includes opioids and stimulants, in SUD, OUD or StimUD patients with high impulsivity.

3. A compound of formula (I) for use according to claim 1 or 2, whereinR1 is -CH3; andn is 1 or 2.

4. A compound of formula (I) for use according to claim 1 or 2, whereinR2 is independently of each other selected from the group consisting of H, F, Cl, Br,CN, C1-6-alkyl, C3-7-cycloalkyl, OH, -O-(C1-6-alkyl), -O-(C1-3-alkyl)-(C3-7-cycloalkyl), -O- heterocyclyl, -O-(C1-3-alkyl)-heterocyclyl, -O-aryl, -O-heteroaryl, -S-(C1-3-alkyl), -SO2- (C1-3-alkyl), -NH2, -NH-(C1-6-alkyl), -NH-(C3-6-cycloalkyl), -NH-(C1-3-alkyl)-heterocyclyl,Boehringer Ingelheim 01-3614 ff -56 --NH-(C1-6-alkyl)-C(=O)-NH2, -C(=O)-NH2, -C(=O)-NH-(C1-3-alkyl), -C(=O)-(C1-4-alkyl), -C1-3-alkyl-C(=O)-O-(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and wherein each heterocyclyl group is selected from a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C=O, and wherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and C1-3- alkyl, wherein each aryl group is selected from a group consisting of phenyl and naphthyl, and wherein each heteroaryl group is selected from a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F and C1-3-alkyl, which is optionally substituted with one or more F; or, if two groups R2are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a –O-CH2-O-, -O-CH2-CH2-O- or –O-CH2-CH2-CH2-O- bridge.

5. A compound of formula (I) for use according to claim 1 or 2, whereinBoehringer Ingelheim 01-3614 ff -57 -R2 is independently of each other selected from the group consisting of F, Cl, Br, CN,C1-3-alkyl, C3-6-cycloalkyl, -O-(C1-4-alkyl), -O-CH2-cyclopropyl, -O-CH2-heterocyclyl, -O-phenyl, -O-heteroaryl, -S-CH3, -NH2, -NH-(C1-4-alkyl), -NH-(C3-5-cycloalkyl), -NH-(CH2- heterocyclyl), -NH-(C1-4-alkyl)-C(=O)-NH2, -C(=O)-NH-(C1-3-alkyl), -C(=O)-(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, andwherein each heterocyclyl group is selected from a group consisting ofoxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4- diazepan-5-one, and wherein each heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from F, OH and CH3,wherein each heteroaryl group is selected from a group consisting of furanyl, isoxazolyl, thiazolyl and pyrazolyl, and wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from a group consisting of F, CH3and CF3.

6. A compound of formula (I) for use according to claim 1 or 2, whereinR2 is independently of each other selected from the group consisting of F, Cl, Br, CN,CH3, C3-5-cycloalkyl, -O-(C1-4-alkyl), -O-CH2-heterocyclyl, -O-phenyl, -S-CH3, -NH2, - NH-(C1-4-alkyl), -NH-(C3-5-cycloalkyl), -NH-(CH2-heterocyclyl), -NH-(C1-4-alkyl)-C(=O)-NH2, heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, andBoehringer Ingelheim 01-3614 ff -58 -wherein each heterocyclyl group is selected from a group consisting of oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently selected from F, OH and CH3, andwherein each heteroaryl group is selected from a group consisting of furanyl and thiazolyl.

7. A compound of formula (I) for use according to claim 1 or 2, whereinR2is independently selected from the group consisting of:Boehringer Ingelheim 01-3614 ff -59 -8. A compound of formula (I) for use according to any one of the previousclaims, wherein X is CH.

9. A compound of formula (I) for use according to any one of the previousclaims, wherein X is N.

10. A compound for use according to claim 1 or 2 having the formulawherein R1is CH3;R2a and R2b are each independently selected from the group consisting of:Boehringer Ingelheim 01-3614 ff -60 -or a salt thereof.

11. A compound for use according to claim 1 or 2 selected from:Boehringer Ingelheim 01-3614 ff -61 -,or a salt thereof.

12. The compound for use according to claim 1 or 2, wherein said compound is:Boehringer Ingelheim 01-3614 ff -62 -.

13. The compound for use according to claim 1 or 2, wherein said compound is:.

14. The compound for use according to claim 1 or 2, wherein said compound is:.

15. The compound for use according to claim 1 or 2, wherein said compound is:.

16. The compound for use according to claim 1 or 2, wherein said compound is:.

17. The compound for use according to claim 1 or2, wherein said compound is:Boehringer Ingelheim 01-3614 ff -63 -.

18. The compound for use according to claim 1 or 2, wherein said compound is:.

19. The compound for use according to claim 1 or 2, wherein said compound is:.

20. The compound for use according to claim 1 or 2, wherein said compound is:.

21. The compound for use according to claim 1 or 2, wherein said compound is:.Boehringer Ingelheim 01-3614 ff -64 -22. The compound for use according to claim 1 or 2, wherein said compound is:.

23. The compound for use according to claim 1 or 2, wherein said compound is:.

24. The compound for use according to claim 1 or 2, wherein said compound is:.

25. The compound for use according to claim 1 or 2, wherein said compound is:.

26. The compound for use according to claim 1 or 2, wherein said compound is:Boehringer Ingelheim 01-3614 ff -65 -.

27. The compound for use according to claim 1 or 2, wherein said compound is:.

28. The compound for use according to claim 1 or 2, wherein said compound is:.

29. The compound for use according to claim 1 or 2, wherein said compound is:.

30. A pharmaceutically acceptable salt of a compound for use according toany one of claims 1 to 29.

31. A compound or salt according to any one of claims 1 to 30 for use in thetreatment of opioid use disorder (OUD) in patients with high impulsivity.

32. A compound or salt according to any one of claims 1 to 30 for use in thetreatment of stimulant use disorder (StimUD) in patients with high impulsivity.Boehringer Ingelheim 01-3614 ff -66 -33. A method for treating substance use disorder (SUD) ) including opioiduse disorder (OUD) and stimulant use disorder (StimUD) in patients with highimpulsivity, characterized in that a compound according to any one of claims 1 to 29or a pharmaceutically acceptable salt thereof is administered to a patient in needthereof.

34. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating substance usedisorder (SUD) including opioid use disorder (OUD) and stimulant use disorder(StimUD) in patients with high impulsivity.

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