Reducing body weight and / or induction of satiety by triazolo compounds

Abstract

The present invention relates to a compound of Formula (I), in particular, the compound of Formula (II) or an isotopic variant, a pharmaceutically acceptable salt or solvate thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof.

Description

[0001] Reducing body weight and / or induction of satiety by triazolo compounds

[0002] SUMMARY OF THE INVENTION

[0003] The present invention relates to a compound of Formula (I), in particular, a compound of Formula (II) or an isotopic variant, a pharmaceutically acceptable salt or solvate thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof.

[0004] BACKGROUND

[0005] Obesity has emerged as a major public health crisis worldwide, with prevalence rates escalating at an alarming pace over the past few decades. According to the World Health Organization (WHO), obesity has nearly tripled since 1975, and it is now recognized as a significant risk factor for a variety of chronic diseases, including type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis of the knee, sleep apnea, and some cancers (Circulation 2004;110:e476; N. Engl. J. Med. 1999;341:1097). The condition is characterized by excessive fat accumulation that presents a risk to health, and it is commonly measured by the body mass index (BMI), where a BMI of 30 or above is categorized as obese. The relationships between BMI and risks for death and major comorbidities vary by age, sex, race, and smoking status, but, in general, are lowest in individuals with BMIs of 18.5 kg / m2to 24.9 kg / m2and increase in a curvilinear or linear manner with BMIs of 25 kg / m2to approximately 40 kg / m2(FDA Guidance for Industry. Developing Products for Weight Management. February 2007). The rising incidence of obesity is not only a health concern but also imposes substantial economic burdens due to increased healthcare costs and loss of productivity.

[0006] Current treatment options for obesity include lifestyle interventions such as diet and exercise, pharmacotherapy, and surgical procedures. Lifestyle interventions, while essential, often have limited long-term success due to issues with adherence and behavioral change. Pharmacological treatments can be effective but are frequently associated with side effects and contraindications, limiting their suitability for all patients. Bariatric surgery, although effective, is invasive and carries significant risks, making it an option only for individuals with severe obesity. There remains a critical need for more effective, safe, and accessible treatments that can provide sustainable weight loss and improve overall health outcomes for obese individuals.

[0007] Recent advancements in our understanding of the biological mechanisms underlying obesity have opened new avenues for potential treatments. It is now understood that obesity is a complex interplay of genetic, metabolic, environmental, and behavioral factors. Research has highlighted the role of hormones, such as leptin and ghrelin, in regulating appetite and energy balance. Additionally, the gut microbiome has been identified as a crucial player in metabolism and weight regulation. These insights have paved the way for novel therapeutic strategies that target specific pathways involved in weight regulation, offering hope for more personalized and effective interventions. Given the multifaceted nature of obesity, there is a growing recognition of the need for innovative therapeutic approaches that go beyond conventional methods. The development of new treatments that can effectively reduce body weight and maintain weight loss over time is imperative to combat the obesity epidemic and its associated health complications. This patent application aims to address this unmet need by presenting a novel therapeutic strategy for the treatment of obesity and the reduction of body weight, offering a promising addition to the current arsenal of obesity management tools.

[0008] Glucagon-like peptide-1 (GLP-1) is an incretin hormone primarily secreted by the intestinal L-cells in response to nutrient intake. It plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, and delaying gastric emptying. Beyond its well- established function in the regulation of glucose metabolism, GLP-1 has emerged as a key therapeutic target for managing obesity due to its ability to influence appetite and energy intake. The physiological effects of GLP-1 receptor activation on appetite suppression and satiety underscore its significance in addressing the global challenge of obesity.

[0009] Obesity is a major health concern worldwide, closely associated with comorbidities such as type 2 diabetes, cardiovascular disease, and certain cancers. Current therapeutic strategies often struggle to balance efficacy and safety, emphasizing the need for novel interventions that effectively promote weight loss with minimal adverse effects. GLP-1 receptor agonists have demonstrated significant promise in preclinical and clinical studies, showcasing their dual benefits of weight reduction and improved metabolic parameters. These agents not only reduce caloric intake through appetite suppression but may also increase energy expenditure, highlighting their multifaceted approach to weight management.

[0010] Recent advances in the pharmacological development of GLP-l-based therapies have expanded beyond receptor agonists to include compounds that stimulate the natural secretion of GLP-1, offering a novel approach to enhancing therapeutic efficacy. By promoting endogenous GLP-1 release, these compounds leverage the body's natural regulatory mechanisms to optimize the physiological effects of GLP-1, such as appetite suppression, improved glucose control, and metabolic balance, while potentially reducing side effects associated with direct receptor agonists. The present invention introduces a novel class of compounds designed to stimulate GLP-1 secretion, achieving effective and sustained weight reduction. This innovative approach not only facilitates weight loss but also supports metabolic equilibrium, addressing a critical unmet need in the treatment of obesity and related metabolic disorders.

[0011] Baseline endogenous GLP-1 levels are typically in the range of 5-15 pmol / L in fasted and with postprandial peaks of up to 50 pmol / L in healthy individuals. Increased GLP-1 may have beneficial effects, e.g. cardioprotective (e.g. atherosclerosis, restenosis, cardiac remodeling or inflammation), in addictive disorders (e.g. substance use disorder, alcohol use disorder, gambling addiction, compulsive buying disorder, cocaine use disorder or tobacco use disorder), in CNS disorders (e.g. Alzheimer's disease or Parkinson's disease), as well as on kidney outcomes, including reduced progression to end-stage kidney disease. Concerns about pancreatitis and tumors have not been substantiated in human studies.

[0012] DETAILED DESCRIPTION OF THE INVENTION

[0013] In one aspect, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof, wherein:

[0014] R1is selected from the group consisting of hydrogen, carboxyl, cyano, fluorine, chlorine, methyl, isopropyl, t-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl methoxy, l,l-difluoro-2- methylpropyl, l,l-difluoro-2,2-dimethylpropyl, 1-methyl-l-cyclobutyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 1-hydroxy-l-methylethyl, azetidine-l-carbonyl, 3- methyloxetan-3-yl, 4,5-dihydrooxazol-2-yl and cyclopropylcarbonyl;

[0015] R2is hydrogen or methyl;

[0016] A1is =N- or =CH-;

[0017] X is benzene, pyridine or cyclohexane;

[0018] J is any ring selected from the group

[0019] Y is selected from the group consisting of phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, piperidinyl, azetidinyl, tetrahydropyranyl, morpholinyl and tetrahydropyridinyl, optionally substituted with 1, 2 or 3 groups selected from Y1, or alternatively Y is amino, optionally substituted with 1 or 2 groups selected from Y1;

[0020] Y1is selected from the group consisting of hydroxy, cyano, fluorine, amino, methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, , wherein amino is optionally substituted with 1 or 2 groups selected from Y2and methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, are optionally substituted with 1, 2 or 3 groups selected from Y2;

[0021] Y2is selected from the group consisting of hydroxyl, fluorine, amino, methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, wherein amino is optionally substituted with 1 or 2 groups selected from Y3and methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, is optionally substituted with 1, 2 or 3 groups selected from Y3,

[0022] Y3is hydroxyl, fluorine, cyano, methyl or methoxy, wherein methyl or methoxy are optionally substituted with fluorine.

[0023] In some embodiments of a the compound of Formula (I),

[0024] X is cyclohexane; and

[0025] Y is selected from or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from the following group: or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a a pharmacologically acceptable salt thereof.

[0026] In some embodiments, the compound of Formula (I) is selected from the following group: or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a a pharmacologically acceptable salt thereof.

[0027] It has been surprisingly found that the compound of Formula (I), in particular the compound of Formula (II), stimulates the release of GLP-1 from L-Cells. The effect results in the compound of Formula (I) of being suitable for use in a method of inducing satiety and / or reducing body weight. In addition, this effect results in the compound of Formula (I), in particular the compound of Formula (II), of being suitable for use in a method there a cardiovascular disease (e.g. atherosclerosis, restenosis, cardiac remodeling or inflammation) is ameliorated.

[0028] In addition, this effect results in the compound of Formula (I), in particular the compound of Formula (II), of being suitable for use in a method there an addictive disorder (e.g. substance use disorder, alcohol use disorder, gambling disorder / addiction, cocaine use disorder or tobacco use disorder (tobacco addiction, nicotine dependence), compulsive buying disorder) is ameliorated.

[0029] In addition, this effect results in the compound of Formula (I), in particular the compound of Formula (II), of being suitable for use in a method of ameliorating a CNS disorder (e.g. Alzheimer's disease, dementia or Parkinson's disease).

[0030] In addition, this effect results in the compound of Formula (I), in particular the compound of Formula (II), of being suitable for use in a method of treating an end-stage kidney disease.

[0031] In addition, this effect results in the compound of Formula (I), in particular the compound of Formula (II), of being suitable for use in a method of reducing muscle loss.

[0032] In summary, compounds of Formula (I), in particular the compound of Formula (II) modulates GLP-l-related activity by enhancing the secretion of GLP-1, thereby promoting a physiological effect associated with reduced body weight, e.g. cardioprotection, mitigation of addictions and CNS disorders.

[0033] In some embodiments, the compound of Formula (II) is or an isotopic variant, a pharmaceutically acceptable salt or solvate thereof.

[0034] In some embodiments, the compound of Formula (II) is

[0035] In some embodiments, said subject suffers from overweight or obesity.

[0036] In some embodiments, said subject suffers from a disease selected from diabetes, a cardiovascular disease, hypertension, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction, hypothalamic amenorrhea, metabolic syndrome, obstructive sleep apnoea syndrome (OSAS), chronic kidney disease (CKD), metabolic associated fatty liver disease (MAFLD), and depression.

[0037] In some embodiments, said subject suffers from a disease selected from type 2 diabetes, hyperglycemia, bulimia, genetically induced obesity or overweight, metabolic syndrome, NASH / MASH, impaired glucose tolerance, non-insulin dependent diabetes, female fertility disorders associated with overweight or obesity, or obesity or overweight particularity in preparation of a bariatric surgical intervention.

[0038] In some embodiments, said subject suffers from an addictive disorder (e.g. substance use disorder, alcohol use disorder, gambling disorder / addiction, cocaine use disorder, cannabis use disorder, opioid use disorder, stimulant use disorder, compulsive buying disorder or tobacco use disorder (tobacco addiction, nicotine dependence)).

[0039] In some embodiments, said subject suffers from a CNS disorders (e.g. Alzheimer's disease, dementia or Parkinson's disease).

[0040] In some embodiments, said subject suffers from a cardiovascular disease (e.g. atherosclerosis, restenosis, cardiac remodeling or inflammation).

[0041] In some embodiments, said subject suffers from a circulatory disorder (e.g. acute pulmatory embolism, cardiac arrest, chronic phlebitis, deep vein thrombosis, gangrene, heart failure, hemorrhagic stroke, ischemic stroke, myocardial infarction, post thrombotic sequelae or thromboembolic disorders).

[0042] In some embodiments, said subject suffers from hepatic failure.

[0043] In some embodiments, said subject suffers from bulemia.

[0044] In some embodiments, said subject suffers from an end-stage kidney disease, acute kidney injury or chronic kidney disease.

[0045] In some embodiments, said subject suffers from urinary tract infection, bacterial infection or septicemia.

[0046] In some embodiments, said subject suffers from a mental disorder, e.g. schizophrenia, suicidal ideation.

[0047] In some embodiments, said subject suffers from a musculoskeletal disorder, e.g. muscle pain, osteomyelitis.

[0048] In some embodiments, said subject suffers from neoplasms, e.g. liver cancer.

[0049] In some embodiments, said subject suffers from a nervous disorder, e.g. neurocognitive disorder, seizures.

[0050] In some embodiments, said subject suffers from a respiratory disorder, e.g. aspiration pneumonitis, COPD, pleural effusion, phneuminia, pneumonitis, respiratory complications, respiratory failure.

[0051] In some embodiments, said subject suffers from anemia or clotting disorders.

[0052] In some embodiments, said subject suffers from fever or shock.

[0053] In some embodiments, said subject suffers from muscle loss.

[0054] In some embodiments, said subject is at risk of loosing muscle mass.

[0055] In some embodiments, said subject is human.

[0056] In some embodiments, said subject has BMI equal or higher than 25 kg / m2.

[0057] In some embodiments, said subject has BMI equal or higher than 27 kg / m2.

[0058] In some embodiments, said subject has BMI equal or higher than 30 kg / m2.

[0059] In some embodiments, said subject has BMI equal or higher than 35 kg / m2.

[0060] In some embodiments, said subject has BMI equal or higher than 40 kg / m2. In some embodiments, said male subject has a waist circumference (WC), equal or higher than 100 cm.

[0061] In some embodiments, said male subject has a waist circumference (WC), equal or higher than 110 cm.

[0062] In some embodiments, said female subject has a waist circumference (WC), equal or higher than 90 cm.

[0063] In some embodiments, said female subject has a waist circumference (WC), equal or higher than 105 cm.

[0064] In some embodiments, said male subject has a waist-to-hip ratio (WHR), equal or higher than 0.90.

[0065] In some embodiments, said male subject has a waist-to-hip ratio (WHR), equal or higher than 1.00.

[0066] In some embodiments, said female subject has a waist-to-hip ratio (WHR), equal or higher than 0.85.

[0067] In some embodiments, said female subject has a waist-to-hip ratio (WHR), equal or higher than 0.90.

[0068] In some embodiments, said male subject has a percent body fat (%BF), equal or higher than 20%. In some embodiments, said male subject has a percent body fat (%BF), equal or higher than 25%. In some embodiments, said female subject has percent body fat (%BF), equal or higher than 32%. In some embodiments, said female subject has percent body fat (%BF), equal or higher than 35%. In some embodiments, the GLP-1 level in serum is increased by about 1.2-, about 1.3-, about 1.4- , about 1.5-, about 1.7-, about 2-, about 2.5-, about 3-, about 4-, about 5- or more, compared to normal population and / or baseline level under the same measurement conditions (e.g. fasted). In some embodiments, the GLP-1 level in serum is increased by at least 1.2-, at least 1.3-, at least 1.4-, at least 1.5-, at least 1.7-, at least 2-, at least 2.5-, at least 3-, at least 4-, at least 5-, compared to normal population and / or baseline level under the same measurement conditions (e.g. fasted).

[0069] In some embodiments, the level of GLP-1 level in serum in the subject is increased by about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50%, about 100%, about 150%, about 200% or more compared to the level at beginning of treatment under the same measurement conditions (e.g. fasted).

[0070] In some embodiments, the level of GLP-1 level in serum in the subject is increased by at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, at least 150%, at least 200% or more compared to the level at beginning of treatment under the same measurement conditions (e.g. fasted).

[0071] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in the treatment of obesity or overweight.

[0072] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in the treatment of obesity or overweight, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0073] In some embodiments, the present invention relates to a compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for regulating appetite, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0074] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for inducing satiety, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0075] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for preventing weight gain after successfully having lost weight, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0076] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for treating a disease or state related to overweight or obesity, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0077] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for treating bulimia, comprising administering to a patient in need thereof an effective amount of the compound according to Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.

[0078] In some embodiments, the present invention relates to a compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for the manufacture of a medicament for use in the treatment of obesity or overweight.

[0079] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in the treatment of obesity or overweight.

[0080] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in the treatment of obesity or overweight, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0081] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for regulating appetite, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0082] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for inducing satiety, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0083] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for preventing weight gain after successfully having lost weight, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0084] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for treating a disease or state related to overweight or obesity, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0085] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for treating bulimia, comprising administering to a patient in need thereof an effective amount of this compound, optionally in combination with one or more additional therapeutically active compounds.

[0086] In some embodiments, the present invention relates to compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for the manufacture of a medicament for use in the treatment of obesity or overweight.

[0087] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose of 34 pmol to 1370 pmol, preferably of about 137 pmol to about 512 imol, more preferably of about 137 imol to about 411 imol, and even more preferably of about 137 pmol to about 273 imol.

[0088] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose from about 20 mg to about 800 mg, or from about 80 mg to about 320 mg, from about 60 mg to about 240 mg, or from about 60 mg to about 160 mg. Exemplary unit doses include about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 500 mg, or about 600 mg.

[0089] In case the compound of Formula (I), in particular the compound of Formula (II), is present as an isotopic variant, a salt or a solvate, the daily dose is based on the active moiety, e.g. the free base for the the compound of Formula (II).

[0090] In the following table the daily dose in pmol is converted into mg for of the active moiety of the compound of Formula (II), i.e. IMU-856 (molecular weight: 585.68): mg 20 40 60 80 100 120 150 160 200 240 280 300 320 400 480 500 600 pmol 34 68 102 137 171 205 256 273 341 410 478 512 546 683 820 854 1024

[0091] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof result in a plasma trough level which is above 20 ng / mL at a steady state. For example, administration the compound of Formula (II) may result in a plasma trough level above 20 ng / mL, above 40 ng / mL, above 60 ng / mL, above 80 ng / mL, above 100 ng / mL, above 120 ng / mL, above 140 ng / mL, above 160 ng / mL, above 180 ng / mL, above 200 ng / mL, above 240 ng / mL, above 280 ng / mL, above 320 ng / mL, above 400 ng / mL, or above 500 ng / mL.

[0092] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof result in a plasma trough level, which is above 20 ng / mL at a steady state. For example, administration of the compound of Formula (II) may result in a plasma trough level range from about 20 ng / mL to 1000 ng / mL, from about 40 ng / mL to 500 ng / mL, from about 60 ng / mL to 320 ng / mL, from about 60 ng / mL to 200 ng / mL, from about 60 ng / mL to 200 ng / mL, from about 160 ng / mL to 320 ng / mL, from about 60 ng / mL to 90 ng / mL, from about 70 ng / mL to 85 ng / mL, from about 140 ng / mL to 200 ng / mL, or from about 150 ng / mL to 190 ng / mL.

[0093] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, the steady state is achieved between about 3 to 14 days, about 5 to 10 days, or about 8 days after periodic or regular administration to a optionally once-a-day dosing of the drug, therapeutic combination or pharmaceutical dosage form.

[0094] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, the plasma concentration for the drug, therapeutic combination or pharmaceutical dosage form is: (a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or (b) determined from blood samples taken between about 2 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours, after the last dose or administration of the drug, therapeutic combination or pharmaceutical dosage form.

[0095] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, favorably alters the BML For example, administration of the compound of Formula (II) may reduce the BMI by at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0096] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, favorably alters the body weight. For example, administration of the compound of Formula (II) may reduce the body weight by at least about 5%, at least about 7%, at least about 9%, at least about 10%, at least about 13%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0097] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, favorably alters the waist circumference. For example, administration of the compound of Formula (II) may reduce the waist circumference by at least about 5%, at least about 7%, at least about 9%, at least about 10%, at least about 13%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0098] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, favorably alters the waist-to-hip ratio. For example, administration of the compound of Formula (II) may reduce the waist-to-hip ratio by at least about 3%, at least about 5%, at least about 7%, at least about 10%, at least about 13%, at least about 15%, or at least about 20% compared to untreated patients or compared to before the start of treatment.

[0099] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof, favorably alters the percent body fat. For example, administration of the compound of Formula (II) may reduce the percent body fat by at least about 3%, at least about 5%, at least about 7%, at least about 9%, at least about 10%, at least about 13%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0100] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject with at least one additional therapeutic target.

[0101] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject for a period of at least 12 weeks, preferably at least 26 weeks, more preferably at least 52 weeks, and most preferably longer.

[0102] In some emdodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered orally.

[0103] In some embodiments, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof may be administered for a prolonged period, for example, for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, or at least about 26 weeks. For example, the compound of Formula (II) may be administered for about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, or at least about 12 weeks. In some embodiments, the compound of Formula (II) is administered for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, or longer.

[0104] In another aspect, the present invention relates to a method of inducing satiety and / or reducing body weight, comprising administering to a subject in need thereof an effective among of the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof to a subject in need thereof.

[0105] In another aspect, the present invention relates to a method of treating overweight or obesity, comprising administering to a subject in need thereof an effective among of the compound of Formula (I), in particularthe compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof to a subject in need thereof.

[0106] In another aspect, the present invention relates to a method of treating a disease or state related to overweight or obesity, comprising administering to a subject in need thereof an effective among of the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof to a subject in need thereof, wherein the disease is selected from the group comprising diabetes, a cardiovascular disease, hypertension, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction, hypothalamic amenorrhea, metabolic syndrome, obstructive sleep apnoea syndrome (OSAS), chronic kidney disease (CKD), metabolic associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH) and depression.

[0107] In another aspect, the present invention relates to a method of treating a disease or state related to overweight or obesity, comprising administering to a subject in need thereof an effective among of the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof to a subject in need thereof, wherein the disease is genetically induced obesity or overweight, e.g. by a mutation in the leptin receptor gene.

[0108] In some embodiments of said methods, said subject is human.

[0109] In some embodiments of said methods, said subject has BMI equal or higher than 25 kg / m2.

[0110] In some embodiments of said methods, said subject has BMI equal or higher than 27 kg / m2.

[0111] In some embodiments of said methods, said subject has BMI equal or higher than 30 kg / m2.

[0112] In some embodiments of said methods, said subject has BMI equal or higher than 35 kg / m2.

[0113] In some embodiments of said methods, said subject has BMI equal or higher than 40 kg / m2.

[0114] In some embodiments of said methods, said male subject has a waist circumference (WC), equal or higher than 100 cm.

[0115] In some embodiments of said methods, said male subject has a waist circumference (WC), equal or higher than 110 cm.

[0116] In some embodiments of said methods, said female subject has a waist circumference (WC), equal or higher than 90 cm.

[0117] In some embodiments of said methods, said female subject has a waist circumference (WC), equal or higher than 105 cm.

[0118] In some embodiments of said methods, said male subject has a waist-to-hip ratio (WHR), equal or higher than 0.90.

[0119] In some embodiments of said methods, said male subject has a waist-to-hip ratio (WHR), equal or higher than 1.00.

[0120] In some embodiments of said methods, said female subject has a waist-to-hip ratio (WHR), equal or higher than 0.85.

[0121] In some embodiments of said methods, said female subject has a waist-to-hip ratio (WHR), equal or higher than 0.90.

[0122] In some embodiments of said methods, said male subject has a percent body fat (%BF), equal or higher than 20%.

[0123] In some embodiments of said methods, said male subject has a percent body fat (%BF), equal or higher than 25%.

[0124] In some embodiments of said methods, said female subject has percent body fat (%BF), equal or higher than 32%.

[0125] In some embodiments of said methods, said female subject has percent body fat (%BF), equal or higher than 35%. In some embodiments of said methods, the GLP-1 level in serum is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 1.7-, about 2-, about 2.5-, about 3-, about 4-, about 5-fold or more, compared to normal population and / or baseline level under the same measurement conditions (e.g. fasted, age, gender and / or BMI).

[0126] In some embodiments of said methods, the GLP-1 level in serum is increased by at least 1.2-, at least 1.3-, at least 1.4-, at least 1.5-, at least 1.7-, at least 2-, at least 2.5-, at least 3-, at least 4-, at least 5-fold, compared to normal population and / or baseline level under the same measurement conditions (e.g. fasted, age, gender and / or BMI).

[0127] In some embodiments of said methods, the level of GLP-1 level in serum in the subject is increased by about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50%, about 100%, about 150%, about 200% or more compared to the level at beginning of treatment under the same measurement conditions (e.g. fasted, age, gender and / or BMI).

[0128] In some embodiments of said methods, the level of GLP-1 level in serum in the subject is increased by at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, at least 150%, at least 200% or more compared to the level at beginning of treatment under the same measurement conditions (e.g. fasted, age, gender and / or BMI).

[0129] In some embodiments, the present invention relates to a method of treating obesity or overweight, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0130] In some embodiments, the present invention relates to a method of regulating appetite, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0131] In some embodiments, the present invention relates to a method of inducing satiety, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds. In some embodiments, the present invention relates to a method of inducing satiety, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0132] In some embodiments, the present invention relates to a method of preventing weight gain after successfully having lost weight, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0133] In some embodiments, the present invention relates to a method of treating a disease or state related to overweight or obesity, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0134] In some embodiments, the present invention relates to a method of treating bulimia, comprising administering to a subject in need thereof an effective among of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0135] In some embodiments, the present invention relates to a method of treating obesity or overweight, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds. In some embodiments, the present invention relates to a method of regulating appetite, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0136] In some embodiments, the present invention relates to a method of inducing satiety, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0137] In some embodiments, the present invention relates to a method of inducing satiety, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0138] In some embodiments, the present invention relates to a method of preventing weight gain after successfully having lost weight, comprising administering to a subject in need thereof an effective among of compound , or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0139] In some embodiments, the present invention relates to a method of treating a disease or state related to overweight or obesity, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0140] In some embodiments, the present invention relates to a method of treating bulimia, comprising administering to a subject in need thereof an effective among of compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, optionally in combination with one or more additional therapeutically active compounds.

[0141] In some embodiments of said methods, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose of 34 imol to 1370 imol, preferably of about 137 imol to about 512 pmol, more preferably of about 137 imol to about 411 pmol, and even more preferably of about 137 pmol to about 273 imoL

[0142] In some embodiments of said methods, the compound of Formula (I), in particularthe compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose from about 20 mg to about 800 mg, or from about 80 mg to about 320 mg, from about 60 mg to about 240 mg, or from about 60 mg to about 160 mg. Exemplary unit doses include about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 500 mg, or about 600 mg.

[0143] In some embodiments of said methods, the compound of Formula (I), in particularthe compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof result in a plasma trough level which is above 20 ng / mL at a steady state. For example, administration the compound of Formula (II) may result in a plasma trough level above 20 ng / mL, above 40 ng / mL, above 60 ng / mL, above 80 ng / mL, above 100 ng / mL, above 120 ng / mL, above 140 ng / mL, above 160 ng / mL, above 180 ng / mL, above 200 ng / mL, above 240 ng / mL, above 280 ng / mL, above 320 ng / mL, above 400 ng / mL, or above 500 ng / mL.

[0144] In some embodiments of said methods, treating the subject with the compound of Formula (II) resulted in a plasma trough level, which is above 20 ng / mL at a steady state. For example, administration of the compound of Formula (II) may result in a plasma trough level range from about 20 ng / mL to 1000 ng / mL, from about 40 ng / mL to 500 ng / mL, from about 60 ng / mL to 320 ng / mL, from about 60 ng / mL to 200 ng / mL, from about 60 ng / mL to 200 ng / mL, from about 160 ng / mL to 320 ng / mL, from about 60 ng / mL to 90 ng / mL, from about 70 ng / mL to 85 ng / mL, from about 140 ng / mL to 200 ng / mL, or from about 150 ng / mL to 190 ng / mL. In some embodiments of said methods, the steady state is achieved between about 3 to 14 days, about 5 to 10 days, or about 8 days after periodic or regular administration to a optionally once- a-day dosing of the drug, therapeutic combination or pharmaceutical dosage form.

[0145] In some embodiments of said methods, the plasma concentration for the drug, therapeutic combination or pharmaceutical dosage form is: (a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or (b) determined from blood samples taken between about 2 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours, after the last dose or administration of the drug, therapeutic combination or pharmaceutical dosage form.

[0146] In some embodiments of said methods, the BMI is favorably altered. For example, said method may improve the BMI by at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0147] In some embodiments of said methods, the body weight favorably altered. For example, said method may improve the body weight by at least about 5%, at least about 7%, at least about 9%, at least about 10%, at least about 13%, at least about 15%, at least about 20%, or at least about 30% compared to untreated patients or compared to before the start of treatment.

[0148] In some embodiments of said methods, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject with at least one additional therapeutic target.

[0149] In some embodiments of said methods, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject for a period of at least 12 weeks, preferably at least 26 weeks, more preferably at least 52 weeks. In some emdodiments of said methods, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered orally.

[0150] In some embodiments of said methods, the compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof may be administered for a prolonged period, for example, for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, or at least about 26 weeks. For example, the compound of Formula (II) may be administered for about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, or at least about 12 weeks. In some embodiments, the compound according to Formula (II) is administered for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

[0151] The present invention further relates relates to use of the compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, for manufacturing a medicament for treatment of any of the above defined diseases, in particular obesity or overweight, optionally in combination with one or more additional therapeutically active compounds.

[0152] The present invention further relates relates to use of the compound of Formula (II) Formula (II) , or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof, for manufacturing a medicament for treatment of any of the above defined diseases, in particular obesity or overweight, optionally in combination with one or more additional therapeutically active compounds.

[0153] It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure:

[0154] 1. A compound of Formula (I) Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof, wherein:

[0155] R1is selected from the group consisting of hydrogen, carboxyl, cyano, fluorine, chlorine, methyl, isopropyl, t-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl methoxy, 1,1- difluoro-2-methylpropyl, l,l-difluoro-2,2-dimethylpropyl, 1-methyl-l-cyclobutyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 1-hydroxy-l-methylethyl, azetidine- 1-carbonyl, 3-methyloxetan-3-yl, 4,5-dihydrooxazol-2-yl and cyclopropylcarbonyl; R2is hydrogen or methyl;

[0156] A1is =N- or =CH-;

[0157] X is benzene, pyridine or cyclohexane;

[0158] J is any ring selected from the group

[0159] Y is selected from the group consisting of phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, piperidinyl, azetidinyl, tetrahydropyranyl, morpholinyl and tetrahydropyridinyl, optionally substituted with 1, 2 or 3 groups selected from Y1, or alternatively Y is amino, optionally substituted with 1 or 2 groups selected from Y1;

[0160] Y1is selected from the group consisting of hydroxy, cyano, fluorine, amino, methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, , wherein amino is optionally substituted with 1 or 2 groups selected from Y2and methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, are optionally substituted with

[0161] 1, 2 or 3 groups selected from Y2;

[0162] Y2is selected from the group consisting of hydroxyl, fluorine, amino, methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, wherein amino is optionally substituted with 1 or 2 groups selected from Y3and methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl, is optionally substituted with 1, 2 or

[0163] 3 groups selected from Y3,

[0164] Y3is hydroxyl, fluorine, cyano, methyl or methoxy, wherein methyl or methoxy are optionally substituted with fluorine. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to embodiment 1, wherein the compound is selected from the following group:

[0165] A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to embodiment 1 or 2, wherein the compound is Formula (II). A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 3, wherein said subject suffers from overweight or obesity. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 4, wherein said subject suffers from a disease selected from diabetes, a cardiovascular disease, hypertension, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction, hypothalamic amenorrhea, metabolic syndrome, obstructive sleep apnoea syndrome (OSAS), chronic kidney disease (CKD), metabolic associated fatty liver disease (MAFLD), and depression. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 4, wherein said subject suffers from a disease selected from type 2 diabetes, hyperglycemia, bulimia, genetically induced obesity or overweight, metabolic syndrome, NASH / MASH, impaired glucose tolerance, non-insulin dependent diabetes, female fertility disorders associated with overweight or obesity, or obesity or overweight particularity in preparation of a bariatric surgical intervention. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 6, wherein said subject is human. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 7, wherein said subject has BMI equal or higher than 27 kg / m2. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 7, wherein said subject has BMI equal or higher than 30 kg / m2. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 9, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose of 34 pmol to 1370 pmol, preferably of about 137 pmol to about 411 pmol, and more preferably of about 137 pmol to about 273 pmol. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 10, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject with at least one additional therapeutic target.

[0166] 12. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety in a subject in need thereof according to any of embodiments 1 to 11, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject for a period of at least 12 weeks, preferably at least 26 weeks, more preferably at least 52 weeks.

[0167] 13. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 12, wherein said method modulates GLP-l-related activity.

[0168] 14. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 12, wherein said method enhances secretion of GLP- 1.

[0169] 15. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of embodiments 1 to 12, wherein said method causes GLP-1 increase.

[0170] DEFINITIONS

[0171] An "isotopic variant" refers within the scope of the invention to deuterated variations of compounds of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof. Usually, each molecule in the proportion of the population is substituted with a deuterium atom at the same position. The proportion of molecules of the population that comprise a deuterium atom at a specific atomic position can be represented by an isotopic enrichment factor ep / s, where ep / s = (Rp / Rs - 1) x 1000, where Rp is the abundance of deuterium at that position within the population of molecules, and Rs is the natural abundance of deuterium at the position. The proportion of molecules of the population that comprise a deuterium atom at a specific atomic position can alternatively be represented by the molar percent of the population that is substituted with deuterium at that atomic position (i.e., % deuterium incorporation). Nonlimiting examples of an isotopic enrichment factor include at least 835 (12.5% deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Non-limiting examples of an abundance of deuterium in a sample of a compound herein include a natural abundance, and abundance that is at least 3340 times of the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 times of the natural abundance of deuterium (52.5% deuterium incorporation), at least 4500 times of the natural abundance of deuterium (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 times of the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times of the natural abundance of deuterium (90% deuterium incorporation), at least 6333.3 times of the natural abundance of deuterium (95% deuterium incorporation), at least 6466.7 times of the natural abundance of deuterium (97% deuterium incorporation), at least 6600 times of the natural abundance of deuterium (99% deuterium incorporation), at least 6633.3 times of the natural abundance of deuterium (99.5% deuterium incorporation), or any other abundance. When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or (II), or a pharmaceutically acceptable salt and / or solvate thereof) is designated specifically by name or structure as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. The percentage of deuterium incorporation can be obtained by quantitative analysis using, for example, mass spectroscopy (peak area) or by quantifying the remaining residual 1H-NMR signals of the specific deuteration site compared to signals from internal standards or other, non-deuterated 1H signals in the compound.

[0172] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Thus, the compound of the present disclosure contains a basic group and can be used according to the disclosure, for example, as hydrochloride, aspartate, glutamate, L-tatrate, malonate, fumarate, citrate, malate, maleate, lactate, gluconate, benzoate, succinate, acetate, phosphate, sulfate, napsylate, besylate, tosylate or mesylate salt. The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid in a solvent or dispersant, or by anion exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0173] "Pharmaceutically acceptable" means suitable for use in a human subject. The term "solvate" refers to a crystalline form of a molecule that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. Thus, the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A stoichiometric or non-stoichiometric amount of solvent is bound by non-covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate." It is understood, that a "pharmaceutically acceptable salts" can in addition optionally contain a "solvate".

[0174] "A week" preferably refers to a period of time of or about 5, about 6 or about 7 days. It may be about 5-8 days.

[0175] "A month" preferably refers to a period of time of or about 28, about 29, about 30 or about 31 days. It may be about 26-33 days.

[0176] The term "treating" or "treatment" means an alleviation of symptoms associated with a disease, disorder or condition, or halt of further progression or worsening of those symptoms. Depending on the disease and condition of the subject, the term "treatment" as used herein may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the present invention in combination with other therapies.

[0177] "Daily dose" preferably refers to the total dose of a compound according to Formula (I) or (II) or an isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, preferably orally administered to the subject or patient each day of administration. The daily dose can be reached through a single or several administrations per day, such as for example once a day, twice a day or three times a day. Preferably, it is reached or achieved by single administration per day, preferably consisting of one or more tablets or capsules, preferably tablets or capsules as described herein.

[0178] As used herein, the term "effective amount" includes a dosage sufficient to produce a desired result with respect to the indicated disorder, condition, or mental state. The desired result may comprise a subjective or objective improvement in the recipient of the dosage.

[0179] As used herein, the term "administering" includes activities associated with providing a patient an amount of a compound according to Formula (I) or (II) or an isotopic variant, a pharmaceutically acceptable salt or a solvate thereof. Administering includes providing unit dosages of compositions set forth herein to a patient in need thereof. Administering includes providing effective amounts of compounds, e.g. the compound of Formula (II) or an isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, for a specified period of time, e.g. for about 6, 9, 12, 15 or more months, or about 1, 2, 3, 4, 5 or more years.

[0180] As used herein, the term "patient" or "subject" refers to refers to a living mammalian organism. In one embodiment the patient is a human subject.

[0181] As used herein, the term "administered as adjunct therapy" or "administered with at least one additional therapeutic target" includes sequential or simultaneous administration of two or more structurally different compounds. For example, two or more structurally different pharmaceutically active compounds can be co-administered by administering a pharmaceutical composition adapted for oral administration that contains two or more structurally different active pharmaceutically active compounds. As another example, two or more structurally different compounds can be co-administered by administering one compound and then administering the other compound. In some instances, the co-administered compounds are administered by the same route. In other instances, the co-administered compounds are administered via different routes. For example, one compound can be administered orally, and the other compound can be administered, e.g. sequentially or simultaneously, via intravenous or intraperitoneal injection.

[0182] The term "about" as used herein with respect to numbers, figures, ranges and / or amounts is preferably meant to mean "circa" and / or "approximately". The meaning of those terms is well known in the art and preferably includes a variance, deviation and / or variability of the respective number, figure, range and / or amount of plus / minus 15% and especially of plus / minus 10%.

[0183] The term "obesity" implies an excess of adipose tissue. When energy intake exceeds energy expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity. In this context, obesity is best viewed as any degree of excess adipose tissue that imparts a health risk. The distinction between normal and obese individuals can only be approximated, but the health risk imparted by obesity is probably a continuum with increasing adipose tissue. However, in the context of the present invention, individuals with a body mass index (BMI = body weight in kilograms divided by the square of the height in meters) between 25 and 30 are to be regarded as overweight, above 30 are to be regarded as obese, above 35 are to be regarded as adipositas grade 2 and above 40 are to be regarded as adipositas grade 3 (or adipositas permagna). There are additional parameters to asses obesity, e.g. waist circumference (WC), waist-to-hip ratio (WHR) or percent body fat (%BF) according to Nat. Rev. Endocrinol. 2020;16:177. The term "modulates GLP-l-related activity" refers to the ability of a compound of the present invention to either enhance or inhibit the biological activity or signaling pathways associated with GLP-1 (glucagon-like peptide-1). GLP-1 is a hormone that plays a critical role in regulating insulin secretion, glucose homeostasis, and appetite control, among other physiological processes. Preferably the compound of the present invention enhances secretion of GLP-1 as determined in Example 4 with IMU-856, leading to weight loss probably due to appetite suppression.

[0184] Metabolic dysfunction-associated steatohepatitis (MASH) is also known as nonalcoholic steatohepatitis (NASH). Non-alcoholic fatty liver disease (NAFLD) refers to conditions where there is an accumulation of excess fat in the liver of people who drink little or no alcohol. The most common form of NAFLD is a non-serious condition called hepatic steatosis (fatty liver), sometimes referred to as NAFL, in which fat accumulates in the liver cells: NASH, as the extreme form of NAFLD, is a leading cause of end-stage liver disease; while NAFL, and to a greater degree NASH, and the cardiovascular complications associated with them, are intimately related to states of the metabolic syndrome, including insulin resistance (pre-diabetes) and type 2 diabetes mellitus (T2DM), and abdominal obesity. Obesity is thought to be the most common cause of NAFL and is also linked to the other risk factors of the metabolic syndrome; and some experts estimate that about two-thirds of obese adults and one-half of obese children may have NAFL.

[0185] Variations in genes, many of them highly expressed in the central nervous system, may predispose to common obesity or overweight. Genetically induced obesity or overweight can be e.g. due to gene variations of one or more of the following genes: leptin, leptin receptor, ghrelin, ghrelin receptor, prohormone convertase-1, proopiomelanocortin, melanocortin-4 receptor polymorphism (MC4R), body mass index quantitative trait (BMIQ) 1 to 6, insulin induced gene 2 (INSIG2), fat mass and obesity-associated gene (FTO), transmembrane protein 18 (TMEM18), glucosamine-6-phosphate deaminase 2 (GNPDA2), neuronal growth regulator 1 (NEGRI), brain derived neurotrophic factor (BDNF), potassium channel tetramerization domain containing 15 (KCTD15), KLF transcription factor 14 (KLF14), Src homology 2B family member 1 (SH2B1), mitochondrial carrier 2 (MTCH2), proprotein convertase subtilisin / kexin type 1 (PCSK1), NPC intracellular cholesterol transporter 1 (NPC1), lysophospholipase-like protein 1 (LYPLAL1), cannabinoid receptor (CB) or neuropeptide Y receptor 5 (NPY5R).

[0186] Both obesity and overweight are increasing worldwide and have detrimental influences on several human body functions including the reproductive health. In particular, obese women undergo perturbations of the 'hypothalamic pituitary ovarian axis', and frequently suffer of menstrual dysfunction. In obesity the adipocytes act as endocrine organ leading often to anovulation and infertility. The adipose tissue indeed, releases a number of bioactive molecules, namely adipokines, that variably interact with multiple molecular pathways of insulin resistance, inflammation, hypertension, cardiovascular risk, coagulation, and oocyte differentiation and maturation. Moreover, endometrial implantation and other reproductive functions are affected in obese women with complications including delayed conceptions, increased miscarriage rate, reduced outcomes in assisted conception treatments. The term „female fertility disorders" comprises thus anovulation, infertility, polycystic ovary syndrome (PCOS), increased miscarriage rate, and / or reduced outcomes in assisted conception treatments.

[0187] Compositions may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.

[0188] Compositions may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants and wetting agents. Binding agents include, but are not limited to, syrup, acacia, gelatine, sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, maize starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycollate. Wetting agents include, but are not limited to, sodium lauryl sulfate). Tablets may be coated according to methods well known in the art.

[0189] Compositions may also be liquid formulations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use, such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, nonaqueous vehicles and preservatives. Suspending agent include, but are not limited to, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatine, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Nonaqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl p-hydroxybenzoate and sorbic acid.

[0190] Combination treatments:

[0191] As already indicated, in all of the therapeutic methods or indications disclosed above, the compound of the present invention may be administered alone. However, it may also be administered in combination with one or more additional therapeutically active agents, substances or compounds, either sequentially or concomitantly.

[0192] As described above, compounds of the present invention may be administered or applied in combination with one or more additional therapeutically active compounds or substances, and suitable additional compounds or substances may be selected, for example, from antiobesity agents, antidiabetic agents, anti-hyperlipidemic agents, or anti-hypertensive agents for promoting fertility agents or with compouds suitable for the purpose of achieving weight loss or preventing weight gain, e.g. in combination with bariatric surgical intervention.

[0193] Examples of suitable additional therapeutically active substances include: a-glucosidase inhibitors, e.g. voglibose, emiglitate, miglitol or acarbose; glycogen phosphorylase inhibitors, e.g. the compounds described in W097 / 09040 (Novo Nordisk NS); glucokinase activators; agents acting on the ATP-dependent potassium channel of the pancreatic P-cells, e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

[0194] Other suitable additional therapeutically active substances include anti-hyperlipidemic agents and anti-lipidemic agents, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

[0195] Further agents which are suitable as additional therapeutically active substances include antiobesity agents and appetite-regulating agents. Such substances may be selected from the group consisting of

[0196] CART (cocaine amphetamine regulated transcript) agonists;

[0197] NPY (neuropeptide Y receptor 1 and / or 5) antagonists;

[0198] MC3 antagonists; orexin receptor antagonists;

[0199] TNF (tumor necrosis factor) agonists;

[0200] CRF (corticotropin releasing factor) agonists;

[0201] CRHR2 (Corticotropin-releasing hormone receptor 2) agonists, e.g. COR-1389, HM17321;

[0202] CRF BP (corticotropin releasing factor binding protein) antagonists; urocortin agonists; neuromedin U analogues (agonists on the neuromedin U receptor subtypes 1 and 2); p3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140;

[0203] MCH (melanocyte-concentrating hormone) antagonists;

[0204] CCK (cholecystokinin) agonists; serotonin reuptake inhibitors e.g. fluoxetine, seroxat or citalopram; serotonin and norepinephrine reuptake inhibitors;

[0205] 5HT (serotonin) agonists;

[0206] 5HT6 agonists;

[0207] 5HT2c agonists such as APD356 (U.S. Pat. No. 6,953,787); bombesin agonists; galanin antagonists; growth hormone; growth factors such as prolactin or placental lactogen; growth hormone releasing compounds; growth differentiation factor-15 (GDF15) analogues, e.g. CIN-109;

[0208] TRH (thyrotropin releasing hormone) agonists;

[0209] UCP 2 or 3 (uncoupling protein 2 or 3) modulators; chemical uncouplers; leptin agonists;

[0210] DA (dopamine) agonists (bromocriptin, doprexin); lipase / amylase inhibitors;

[0211] TR P agonists; adrenergic CNS stimulating agents;

[0212] AGRP (agouti-related protein) inhibitors; histamine H3 receptor antagonists such as those disclosed in WO00 / 42023, WO00 / 63208 and WO 00 / 64884, the contents of all of which are incorporated herein by reference; exendin-4 analogues; glucagon-like peptide-1 (GLP-1) analogues; glucagon-like peptide-1 (GLP-1) receptor agonists, e.g. exenatide, danuglipron, liraglutide, semaglutide, ecnoglutide, orfoglipron, efpeglenatide, RG6652 (CT-996), aleniglipron, GS-4571, TERN-601, MET-097, HM11260C, XW014;

[0213] GLP-1 receptor partial agonists, e.g. orforglipron; glucose-dependent insulinotropic peptide (GIP) receptor agonists, e.g. AT-7687; glucagon (GCG) receptor agonists;

[0214] GLP-1R / GIP dual agonists e.g. tirzepatide, maridebart cafraglutide, RG6640 (CT-388), NN9542, VK2735, BGM0504, HRS9531;

[0215] GLP-lR / glucagon agonists e.g. mazdutide, survodutide;

[0216] GLP-lR / GIP / glucagon triple agonists e.g. retatrutide, HM15275;

[0217] GLP-1, GIP, amylin and calcitonin receptor four-way agonist; tachykinin receptor 2 (Tacr2) agonists e.g. EMB2; sodium-glucose cotransporter 2 (sGLT2) inhibitors e.g. bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, luseogliflozin, remogliflozin etabonate, sotagliflozin, tofogliflozin, henagliflozin; ciliary neurotrophic factor; amylin analogues, e.g. pramlintide, cagrilintide, NN1213; amylin and GLP-1 co-agonists, e.g. NN9487 (amycretin); amylin receptor agonists e.g. pramlintide; dual-acting amylin and calcitonin receptor agonists (DACRA); calcitonin receptor agonists (CALCR); microsomal triglyceride transfer protein (MTTP) inhibitors, e.g. RDX-002; controlled metabolic accelerators (CMAs), e.g. HU6; mitochondrial protonophores, e.g. TLC-6740; silencer of inhibin PE (INHBE) gene expression, e.g. WVE-007; peptide YY3-36 (PYY3-36) (Batterham et al. Nature 2002;418:650-65); targeting activin receptors peptide YY (PYY) analogues, e.g. CIN-110;

[0218] PYY3-36 analogues;

[0219] NPY Y2 receptor agonists;

[0220] NPY Y4 receptor agonists and substances acting as combined NPY Y2 and NPY Y4 agonists;

[0221] FGF21 and analogues thereof; p-opioid receptor antagonists; oxyntomodulin or analogues thereof; neurokinin 2 receptor (NK2R) agonists, e.g. EB1002;

[0222] NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) Inhibitors e.g. VTX3232 or NT-0796;

[0223] NIMA related kinase 7 (NEK7) inhibitors or molecular glue degraders e.g. HT-6184, MRT-8102; gastric / pancreatic lipase inhibitor or fatty acid synthase (FAS) inhibitors e.g. orlistat monoacylglycerol acyltransferase-2 (MGAT2) inhibitors e.g. S-309309; cannabinoid receptor 1 (CB1) inhibitors, antagonists or inverse agonists e.g. INV-202 (monlunabant), INV-347 or INV-101 (zevaquenabant); capsaicin inhibitors; anti-activin type HA and IIB (ACVR2A and ACVR2B) monoclonal antibodies e.g. bimagrumab; constitutive androstane receptor (CAR) modulators; apelin receptor (APJ) agonists e.g. azelaprag (BGE-105); targeting anti-latent myostatin e.g. apitegromab (SRK-439), RG6237 (gym 329);

[0224] DPP-IV (dipeptidyl peptidase-IV) inhibitors, e.g. linagliptin, vildagliptin, sitagliptin, saxagliptin; inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and / or glycogenolysis; glucose uptake modulators; compounds modifying the lipid metabolism such as antihyperlipidemic agents as HMG CoA inhibitors (statins), e.g. lovastatin, pravastatin, simvastatin; retinoid X receptor (RXR) modulators or agonists;

[0225] P-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol;

[0226] ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopril, quinapril and ramipril; calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil; a-blockers such as doxazosin, urapidil, prazosin and terazosin; selective androgen receptor modulator (SARM), e.g. enobosarm; meglitinides, e.g. neteglinide, repaglinide; topical gel therapy, e.g. GDD3898; anti-miR-22 oligonucleotides, e.g. RES-O1O, RES-020;

[0227] AMP-activated protein kinase activators, e.g. ATX-304; biguanides; sulphonylureas; insulin; setmelanotide;

[0228] Further suitable antiobesity agents are bupropion (antidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1 / D5 antagonist) and naltrexone (opioid antagonist), and combinations thereof. Combinations of these anti-obesity agents would be e.g.: phentermine+topiramate, bupropion sustained release (SR)+naltrexone SR, zonisamide SR and bupropion SR. Among embodiments of suitable anti-obesity agents for use in a method of the invention as additional therapeutically active substances in combination with a compound of the invention are leptin and analogues or derivatives of leptin.

[0229] Additional embodiments of suitable anti-obesity agents are serotonin and norepinephrine reuptake inhibitors, e.g. sibutramine.

[0230] Other embodiments of suitable anti-obesity agents are lipase inhibitors, e.g. orlistat.

[0231] Still further embodiments of suitable anti-obesity agents are adrenergic CNS stimulating agents, e.g. dexamphetamine, amphetamine, phentermine, mazindol, phendimetrazine, diethylpropion, fenfluramine or dexfenfluramine.

[0232] Other examples of suitable additional therapeutically active compounds include antihypertensive agents. Examples of anti-hypertensive agents are 0-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin.

[0233] In certain embodiments of the uses and methods of the present invention, the compound of the present invention may be administered or applied in combination with more than one of the above-mentioned, suitable additional therapeutically active compounds or substances, e.g. in combination with: metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin.

[0234] In the case, in particular, of administration of a compound of the invention, optionally in combination with one or more additional therapeutically active compounds or substances as disclosed above, for a purpose related to treatment or prevention of obesity or overweight, i.e. related to reduction or prevention of excess adiposity, it may be of relevance to employ such administration in combination with surgical intervention for the purpose of achieving weight loss or preventing weight gain, e.g. in combination with bariatric surgical intervention. The administration of a compound of the invention (optionally in combination with one or more additional therapeutically active compounds or substances as disclosed above) may take place for a period prior to carrying out the bariatric surgical intervention in question and / orfor a period of time subsequent thereto. In many cases it may be preferable to begin administration of a compound of the invention after bariatric surgical intervention has taken place.

[0235] DESCRIPTION OF FIGURES

[0236] Figure 1 illustrates the results from 6-month study in Wistar Han rats where animals have been treated daily by oral gavage with compound 1 in 0.5% methylcellulose (Example 2). Change of body weight from control group (0 mg / kg / day, vehicle control). Anova & Dunnett: *= p <0.05; **= p <0.01. A reduced food intake was observed in rats in the active treatment arms.

[0237] Figure 2 shows the GLP-1 change from baseline in pg / mL serum as mean (black line) with error bars (SEM) from Example 4. y-axis Iog2 scale, statistics: two-sided Mann-Whitney U - treatment vs placebo at Day 14 and Day 29. *= p <0.05; **= p <0.01.

[0238] Figure 3 highlights the increase of GLP-1 in serum in % change from baseline (N= 11 (placebo), N= 13 (80 mg of compound 1) and N=13 (160 mg of compound 1)) in a Phase 1 study in celiac disease patients according Example 4 (Day 1: baseline (N = 37); Day 14: before start of gluten challenge (N = 36); Day 29: last treatment day (N = 32)).

[0239] EXAMPLES

[0240] Example 1: Chemical synthesis of the compound according to Formula (II)

[0241] Step 1: Methyl trans-4-(methylcarbamoyl)cyclohexane-l-carboxylate (II) trans-4-(Methoxycarbonyl)cyclohexane carboxylic acid (25.3 g) was dissolved in CH2CI2 (400 mL). To this, NEta (56.6 mL), methylamine hydrochloride (18.4 g), 3H-l,2,3-triazolo[4,5-b]pyridin-3-ol (0.93 g) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.5 g) were added and the mixture was stirred at room temperature (rt) for 70 h. To the mixture, water and IN HCI was added, and the mixture was extracted with CH2CI2. The organic layer was dried over anhydrous MgSO4. The resultant solution was concentrated under reduced pressure and the precipitated solid was diluted with hexane. The obtained solid was collected by filtration to yield II as a white solid.TH NMR (CDCI3) 6 (ppm) 1.38-1.58 (m, 4H), 1.92-1.98 (m, 2H), 2.01-2.09 (m, 3H), 2.27-2.34 (m, 1H), 2.81 (d, J = 4.9 Hz, 3H), 3.67 (s, 3H), 5.40-5.48 (m, 1H).

[0242] Step 2: Methyl trans-4-(methylcarbamothioyl)cyclohexane-l-carboxylate (Ik)

[0243] Compound II (19 g) was dissolved in toluene (400 mL). To this, Lawesson's reagent (21.3 g) was added and the mixture was stirred at 90°C for 8 h. To the mixture, saturated aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSOzi. The residue obtained by concentration under reduced pressure was purified by NH silica gel column chromatography (CHzCh / EtOAc = 9:1 to 1:1 (v / v)) to obtain compound Ik as a white solid.1H NMR (CDCh) 6 (ppm) 1.44-1.54 (m, 2H), 1.69-1.79 (m, 2H), 1.93-1.98 (m, 2H), 2.07-2.12 (m, 2H), 2.31-2.38 (m, 1H), 2.41-2.48 (m, 1H), 3.19 (d, J = 4.9 Hz, 3H), 3.67 (s, 3H), 7.26-7.31 (m, 1H).

[0244] Step 3: 2-((4-(Trifluoromethyl)pyridin-2-yl)oxy)acetohydrazide (Ij)

[0245] Methyl 2-((4-(trifluoromethyl)pyridin-2-yl)oxy)acetate (111 g) was dissolved in EtOH (2.4 L). To this, hydrazine monohydrate (177 g) was added and the mixture was stirred at 90°C for 3 h. The resultant solution was concentrated under reduced pressure to obtain compound Ij as a white solid.

[0246] Step 4: Methyl trans-4-((methylimino)(methylthio)methyl)cyclohexane-l-carboxylate (li)

[0247] <1 i)

[0248] Compound Ik (1.5 g) was dissolved in acetone (400 mL). To this, K2CO3 (26.5 g) and methyl iodide (15.9 mL) were added and the mixture was stirred for 5 h under reflux with heating. After the reaction temperature was allowed to reach rt, concentrated under reduced pressure and diluted CH2CI2. The precipitated solid was collected by filtration to obtain compound li as a white solid.2H NMR (CDCh) 6 (ppm) 1.44-1.56 (m, 4H), 1.7 9-1.85 (m, 0.7H), 1.88-1.97 (m,1.3H), 2.04-2.11 (m, 2H), 2.20 (s, 1H), 2.29-2.36 (m, 1H), 2.42 (s, 2H), 2.47-2.53 (m, 0.7H), 2.80-2.87 (m, 0.3H), 3.17 (s, 2H), 3.26 (s, 1H), 3.67 (s, 1.3H), 3.67 (s, 0.7H).

[0249] Step 5: Methyl trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4- triazol-3-yl)cyclohexane-l-carboxylate (Ih) Compound li (20 g) was dissolved in EtOH (200 mL). To this, compound Ij (20.5 g) was added and the mixture was stirred at 90°C for 4 h. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (MeOH / CH2Cl2 = 0:1 to 1:9 (v / v)) to obtain compound Ih as a white solid.1H NMR (CDCI3) 6 (ppm) 1.52-1.64 (m, 2H), 1.87-1.98 (m, 2H), 2.06-2.14 (m, 2H), 2.16-2.23 (m, 2H), 2.47 (dt, J = 12.2, 3.4 Hz, 1H), 2.75 (dt, J = 12.2, 3.4 Hz, 1H), 3.70 (s, 3H), 3.78 (s, 3H), 5.40 (s, 2H), 7.22-7.32 (m, 3H), 7.45 (t, J = 7.8 Hz, 1H).

[0250] Step 6: (trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4F / -l,2,4-triazol-3- yl)cyclohexyl)methanol

[0251] Compound Ih (19.7 g) was dissolved in THF (250 mL). To this, a LiAIH4-THF solution (2.5M, 20 mL) was added under ice-cooling and the mixture was stirred at rt for 25 minutes. To the mixture, water (1.9 mL), a 15% aqueous NaOH solution (1.9 mL) and water (5.7 mL) were sequentially added under ice-cooling and the mixture was diluted with EtOAc and then filtered with celite. The filtrate was concentrated under reduced pressure to obtain compound 1g as a light yellow oily substance.TH NMR (CDCI3) 6 (ppm) 1.08-1.20 (m, 2H), 1.34 (d, J = 5.4 Hz, IH), 1.55-1.72 (m, IH), 1.76-1.89 (m, 2H), 1.94-2.11 (m, 4H), 2.62 (dt, J = 12.2, 3.4 Hz, IH), 3.53 (t, J = 5.9 Hz, 2H), 3.66 (s, 3H), 5.29 (s, 2H), 7.22-7.29 (m, 3H), 7.42 (t, J = 7.8 Hz, IH).

[0252] Step 7: trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4-triazol-3- yl)cyclohexane-l-carbaldehyde (If)

[0253] Compound 1g (17.9 g) was dissolved in CH2CI2 (300 mL). To this, Dess-Martin periodinane (22.4 g) was added under ice-cooling and the mixture was stirred for 5 minutes under ice-cooling and at rt for 40 minutes. The solution was ice-cooled. To this, a IN NaOH solution (230 mL) and a 10% aqueous sodium thiosulfate solution were added and stirred, and then the mixture was extracted with CH2CI2. The organic layer was dried over anhydrous Na2SO4. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (MeOH / EtOAc = 0:1 to 1:9 (v / v)) to obtain compound If as a white solid.TH NMR (CDCI3) 6 (ppm) 1.36-1.47 (m, 2H), 1.82-1.92 (m, 2H), 2.09-2.16 (m, 2H), 2.18-2.25 (m, 2H), 2.36-2.44 (m, IH), 2.64 (dt, J = 12.2, 3.4 Hz, IH), 3.67 (s, 3H), 5.30 (s, 2H), 7.22-7.31 (m, 3H), 7.43 (t, J = 7.8 Hz, IH), 9.70 (s, IH).

[0254] Step 8: 2-(trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4-triazol-3- yl)cyclohexyl)acetaldehyde (le)

[0255] (Methoxymethyl)triphenylphosphonium chloride (13.2 g) was suspended in THF (100 mL). To this, potassium tert-butoxide (4.31 g) was added under ice-cooling and the mixture was stirred for 20 minutes. The resultant solution was added dropwise using a cannula to a solution of compound If (9.44 g) in THF (150 mL). After 45 minutes, to a suspension of (methoxymethyl)triphenylphosphonium chloride (8.79 g) in THF (100 mL), potassium tert- butoxide (2.88 g) was added under ice-cooling and the mixture was stirred for 5 minutes. The obtained solution was added dropwise again to the reaction solution using a cannula. After 10 minutes, water was added to the reaction mixture and the mixture was concentrated under reduced pressure and extracted with EtOAc. The organic layer was washed with brine and then dried over anhydrous NazSCU. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (EtOAc / hexane / MeOH = 1:1:1 to 1:0:0 to 9:0: 1 (v / v / v)). The obtained methoxyethenyl intermediate was dissolved by adding THF (100 mL) and IN HCI (70 mL) was added. Then the mixture was stirred at rt for 2.5 h. The solution was ice-cooled and 2N NaOH (35 mL) was added thereto and the mixture was extracted with EtOAc. The organic layer was washed with brine and then dried over anhydrous NazSOzi. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (MeOH / EtOAc = 0:1 to 1:9 (v / v)) to obtain compound le as a colorless oily substance.TH NMR (CDCI3) 6 (ppm) 1.13-1.22 (m, 2H), 1.61-2.06 (m, 7H), 2.36 (dd, J = 6.6, 2.2 Hz, 2H), 2.57-2.64 (m, 1H), 3.61 (s, 3H), 5.55 (s, 2H), 6.98-6.99 (m, 1H), 7.12-7.14 (m, 1H), 8.33 (d, J = 5.4 Hz, 1H), 9.76 (t, J = 2.2 Hz, 1H).

[0256] Step 9: 2-(trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4-triazol-3- yl)cyclohexyl)acrylaldehyde

[0257] Compound le (6.87 g) was dissolved in A / ,A / -dimethylformamide (40 mL). To this, a formaldehyde solution (37%) (6.6 mL) and L-proline (618 mg) were added and the mixture was stirred at rt for 14 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (EtOAc / hexane / MeOH = 1:2:0 to 1:0:0 to 9:0:1 (v / v / v)) to obtain compound Id as a white solid.XH NMR (CDCI3) 6 (ppm) 1.34-1.44 (m, 2H), 1.85-1.98 (m, 4H), 2.03-2.08 (m, 2H), 2.56-2.63 (m, 1H), 2.64-2.71 (m, 1H), 3.62 (s, 3H), 5.55 (s, 2H), 5.98 (s, 1H), 6.25 (s, 1H), 6.99 (s, 1H), 7.13 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 9.52 (s, 1H). Step 10: 2-(trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4-triazol- 3-yl)cyclohexyl)oxirane-2-carbaldehyde (1c)

[0258] Compound Id (3.68 g) was dissolved in MeOH (60 mL). To this, a hydrogen peroxide solution (30%) (1.33 mL) and a 5N aqueous NaOH solution (0.47 mL) were sequentially added under icecooling and the mixture was stirred for 1 h. To the mixture, a 10% aqueous sodium thiosulfate solution was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, and then dried over anhydrous Na2SO4. The mixture was concentrated under reduced pressure, then CH2CI2 was added. The mixture was azeotropically concentrated to obtain compound 1c as a white solid.1H NMR (CDCI3) 6 (ppm) 1.30-1.39 (m, 1H), 1.44-1.53 (m, 1H), 1.76- 1.93 (m, 4H), 2.00-2.12 (m, 3 H ), 2.58-2.64 (m, 1H), 2.98 (d, J = 4.4 Hz, 1H), 3.10 (d, J = 4.4 Hz, 1H), 3.61 (s, 3H), 5.55 (s, 2H), 6.98-6.99 (m, 1H), 7.12-7.14 (m, 1H), 8.33 (d, J = 4.9 Hz, 1H), 8.85 (s, 1H).

[0259] Step 11: Benzyl (trans-4-(4-(trans-4-(4-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)- 4H-l,2,4-triazol-3-yl)cyclohexyl)-lH-pyrazol-l-yl)cyclohexyl)carbamate (lb)

[0260] Benzyl (trans-4-hydrozinylcyclohexyl)carbamate hydrochloride (442 mg) was suspended in EtOH (10 mL). To this, compound 1c (504 mg) was added and the mixture stirred at rt for 43 h. The solvent was distilled away under reduced pressure and the resultant residue was purified by NH silica gel column chromatography (hexane / C^Ch / EtOAc = 1:4:0 to 0:1:4 (v / v / v)). The resultant crude product was washed with EtOAc to afford compound lb as a white solid.XH NMR (CDCI3) 6 (ppm) 1.29-1.39 (m, 2H), 1.42-1.53 (m, 2H), 1.80-1.99 (m, 4H), 2.03-2.25 (m, 9H), 2.58-2.73 (m, 2H), 3.66 (s, 3H), 4.02-4.11 (m, 1H), 4.61-4.69 (m, 1H), 5.10 (s, 2H), 5.59 (s, 2H), 7.02 (s, 1H), 7.16 (d, J = 5.4 Hz, 1H), 7.22 (s, 1H), 7.30-7.39 (m, 6H), 8.36 (d, J = 5.4 Hz, 1H).

[0261] Step 12: trans-4-(4-(trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H-l,2,4- triazol-3-yl)cyclohexyl)-lH-pyrazol-l-yl)cyclohexan-l-amine (la)

[0262] Compound lb (300 mg) was dissolved in meOH (6 mL) and CH2CI2 (1 mL). To this, acetic acid (0.14 mL) and 10% palladium on carbon (150 mg) were added at room temperature and the mixture was stirred at rt for 4 h under a H2 atmosphere. Then the catalyst was filtered off and the mixture was washed with CH2CI2. The resultant filtrate was concentrated under reduced pressure and the solvent was azeotropically concentrated with ethanol and toluene. The resultant residue was purified by silica gel column chromatography (MeOH / CH2Cl2 = 0:1 to 1:19 (v / v)) to obtain compound la as a white solid.TH NMR (CDCI3) 6 (ppm) 1.25-1.35 (m, 2H), 1.43-1.54 (m, 2H), 1.75- 2.24 (m, 14H), 2.59- 2.73 (m, 3H), 3.66 (s, 3H), 4.02-4.09 (m, 1H), 5.59 (s, 2H), 7.02 (s, 1H), 7.16 (d, J = 5.4 Hz, 1H), 7.23 (s, 1H), 7.38 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H).

[0263] Step 13: 6-(trans-4-(4-(trans-4-(4-Methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-4H- l,2,4-triazol-3-yl)cyclohexyl)-lH-pyrazol-l-yl)cyclohexyl)-l-oxa-6-azaspiro[3.3]heptane (1)

[0264] Compound of oxetane-2,2-diyldimethanol (75 mg) and A / ,A / -diisopropylethylamine (0.72 mL) were dissolved in CH2CI2 (1.5 mL). The mixture was cooled to -78°C, then trifluoromethanesulfonic acid anhydride (0.21 mL) was added dropwise thereto. The mixture was stirred at -78°C for 15 minutes. To this, a solution of compound la (213 mg) in CH2CI2 (5 mL) was added at 0°C and the mixture was stirred at 0°C for 15 minutes and then stirred at rt for 18 h. The residue obtained by concentration under reduced pressure was purified by NH silica gel column chromatography (MeOH / CH2Cl2 = 0:1 to 1:99 (v / v)). To the obtained crude product, diethyl ether was added, and the precipitated solid was collected by filtration to obtain title compound 1 as a white solid. NMR (CDCI3) 6 (ppm) 1.16-1.26 (m, 2H), 1.42-1.53 (m, 2H), 1.70-1.80 (m, 2H), 1.89- 2.19 (m, 11H), 2.58-2.72 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.11-3.16 (m, 2H), 3.64-3.68 (m, 2H), 3.65 (s, 3H), 3.99-4.07 (m, 1H), 4.53 (t, J = 7.5 Hz, 2H), 5.59 (s, 2H), 7.01-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.21 (s, 1H), 7.37 (s, 1H), 8.36 (d, J = 5.1 Hz, 1H). MS (APCI) m / z: 586 [M+H]+.

[0265] Example 2: Preclinical rationale for the development of compound according to Formula (II) as a weight loss treatment

[0266] The compound of Formula (II) was administered for 26 weeks to Wistar Han rats by daily oral gavage in three dose groups (10; 25 and 75 mg / kg / day). A control group received the vehicle control: 0.5% (w / v) Methylcellulose 400cps in drinking water (0 mg / kg / day). 20 males and 20 females were included in each of the dose groups and the control group, test item and vehicle were dosed at a volume of 10 mL / kg. Individual body weights were recorded for all animals weekly throughout the study.

[0267] Result: After 6-month treatment with the test item, significantly reduced body weight gain relative to vehicle control group (0 mg / kg / day) was observed showing clear dose dependency. The body weight change in the high dose group (75 mg / kg / day) was reduced up to -22.1% in males and -16.2% in females without impacting the general wellbeing of the animals. A compound of Formula (I), in particular the compound of Formula (II), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is advantageous in the prevention or treatment of obesity or overweight, type 2 diabetes, hyperglycemia, bulimia, regulating appetite, genetically induced obesity or overweight, metabolic syndrome, NASH / MASH, impaired glucose tolerance or non-insulin dependent diabetes, reducing body weight and / or food intake, inducing satiety, female fertility disorders associated with overweight or obesity and / or for the purpose of achieving weight loss or preventing weight gain, e.g. in combination with bariatric surgical intervention.

[0268] Example 3: Exemplary clinical Phase 2

[0269] According to FDA Guidance for Industry. Developing Products for Weight Management. (February 2007)

[0270] Phase 2 study will be a randomized, double-blind placebo-controlled clinical trial assessing different dose levels of the compound of Formula (II) versus placebo. Patients included in an early phase 2 safety and efficacy study with the compound of Formula (II) will have a BMIs greater than or equal to 30 kg / m2or greater than or equal to 27 kg / m2if accompanied by comorbidities. Efficacy endpoints will be a comparison of the mean absolute or percent change in body weight between the active-product and placebo-treated groups and the proportion of patients in each treatment group who lose greater than or equal to 5 percent of baseline weight. The effects by dose of the weight-management product on common weight related comorbidities will also be examined and taken into account when choosing the most appropriate dose for the phase 3 studies. The duration of the phase 2 trials will be 12 weeks main treatment period with an optional extended treatment period up to 40 weeks.

[0271] Example 4: Measurement of total GLP-1 protein levels in human plasma or serum samples

[0272] Samples were from the phase lb celiac disease clinical trial of IMU-856 (with 15 days with 6 g daily gluten challenge). Patients measured post hoc for plasma GLP-1 concentrations. To test, whether IMU-856 has an influence on the protein expression levels of total GLP-1 in humans, 50 iL of serum from celiac disease patients treated with either placebo, 80 mg or 160 mg IMU-856 once daily, was used as input for the glucagon-like peptide-1 (GLP-1) Total ELISA KIT (Cat. # EZGLP1T-36K, EZGLP1T-36BK, EMD Millipore Corporation, St. Louis, Missouri, USA). The assay was performed according to the manufacturer's instruction. Results were reported as GLP-1 concentration in pg / mL serum (see Figure 2 and 3).

Claims

CLAIMS1. A compound of Formula (I)Formula (I), or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof, wherein:R1is selected from the group consisting of hydrogen, carboxyl, cyano, fluorine, chlorine, methyl, isopropyl, t-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl methoxy, 1,1- difluoro-2-methylpropyl, l,l-difluoro-2,2-dimethylpropyl, 1-methyl-l-cyclobutyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 1-hydroxy-l-methylethyl, azetidine- 1-carbonyl, 3-methyloxetan-3-yl, 4,5-dihydrooxazol-2-yl and cyclopropylcarbonyl;R2is hydrogen or methyl;A1is =N- or =CH-;X is benzene, pyridine or cyclohexane;J is any ring selected from the groupY is selected from the group consisting of phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,piperidinyl, azetidinyl, tetrahydropyranyl, morpholinyl and tetrahydropyridinyl, optionally substituted with 1, 2 or 3 groups selected from Yl, or alternatively Y is amino, optionally substituted with 1 or 2 groups selected from Yl;Y1is selected from the group consisting of hydroxy, cyano, fluorine, amino, methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl,, wherein amino is optionally substituted with 1 or 2 groups selected from Y2and methyl, ethyl, isopropyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl,are optionally substituted with1, 2 or 3 groups selected from Y2;Y2is selected from the group consisting of hydroxyl, fluorine, amino, methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl,wherein amino is optionally substituted with 1 or 2 groups selected from Y3and methyl, methoxy, azetidinyl, pyrrolidinyl, morpholinyl,is optionally substituted with 1, 2 or3 groups selected from Y3,Y3is hydroxyl, fluorine, cyano, methyl or methoxy, wherein methyl or methoxy are optionally substituted with fluorine.

2. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to claim 1, wherein the compound is selected from the following group:

3. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to claim 1 or 2, wherein the compound isFormula (II).

4. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 3, wherein said subject suffers from overweight or obesity.

5. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 4, wherein said subject suffers from a disease selected from diabetes, a cardiovascular disease, hypertension, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gall stone, osteoarthritis, cancer, sexual dysfunction, hypothalamic amenorrhea, metabolic syndrome, obstructive sleep apnoea syndrome (OSAS), chronic kidney disease (CKD), metabolic associated fatty liver disease (MAFLD), and depression.

6. A compound of Formula (I) or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 4, wherein said subject suffers from a disease selected from type 2 diabetes, hyperglycemia, bulimia, genetically induced obesity or overweight, metabolic syndrome, NASH / MASH, impaired glucose tolerance, non-insulin dependent diabetes, female fertility disorders associated with overweight or obesity, or obesity or overweight particularity in preparation of a bariatric surgical intervention.

7. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 6, wherein said subject is human.

8. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 7, wherein said subject has BMI equal or higher than 27 kg / m2.

9. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 7, wherein said subject has BMI equal or higher than 30 kg / m2.

10. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 9, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject in a daily dose of34 pmol to 1370 imol, preferably of about 137 pmolto about 411 imol, and more preferably of about 137 imol to about 273 imol.

11. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 10, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject with at least one additional therapeutic target.

12. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety in a subject in need thereof according to any of claims 1 to 11, wherein said compound or an isotopic variant, a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof is administered to said subject for a period of at least 12 weeks, preferably at least 26 weeks, more preferably at least 52 weeks.

13. A compound of Formula (I) an isotopic variant, or a pharmacologically acceptable salt thereof or a solvate thereof or a solvate of a pharmacologically acceptable salt thereof for use in a method of inducing satiety and / or reducing body weight in a subject in need thereof according to any of claims 1 to 12, wherein said method causes GLP-1 increase.

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