Novel treatment

Abstract

The present invention provides methods of treating and / or managing obesity and / or overweight, methods of losing weight, methods of treating and / or managing metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction- associated steatohepatitis (MASH), and methods of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the methods comprise administering to a subject a THIK-1 modulator optionally in combination with a GLP-1 receptor agonist.

Description

[0001] Novel Treatment

[0002] Field of the invention

[0003] The present invention provides methods of treating and / or managing obesity and / or overweight, methods of losing weight, methods of treating and / or managing metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH), and methods of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the methods comprise administering to a subject a THIK-1 modulator optionally in combination with a GLP-1 receptor agonist.

[0004] Background of the invention

[0005] Obesity is a complex and multifactorial condition characterized by excessive body fat accumulation, which poses significant health risks, including cardiovascular diseases, diabetes, and certain cancers. Despite various available treatments, the prevalence of obesity continues to rise globally, highlighting the need for more effective and sustainable solutions.

[0006] Compared with normal weight, individuals with a body mass index (BMI) of 30-34.9 carry a 40% increased risk of overall premature mortality, rising to 100% with a BMI >40. The causes of obesity can be environmental, genetic or a combination of the two. The contribution of genetic factors to BMI is estimated to be about 40-70%.

[0007] Environmental factors accounting for the steep rise in global obesity include increased access to energy-dense food coupled with reduced physical activity, sleep deprivation, circadian desynchronization, chronic stress and use of certain prescribed drugs.

[0008] Monogenic obesity is observed in individuals with loss-of-function mutations in genes encoding for leptin, the leptin receptor (LEPR), pro-opiomelanocortin (POMC) and the melanocortin 4 receptor (MC4R). The most common polygenic risk factors for obesity include mutations in the fat mass and obesity-associated gene (FTO), MC4R, ADRB3, BDNF, CNR1, PCSK1 and PPARG. Notably, monogenic obesity affects only around 5% of the obesity population with the remaining 95% developing common polygenic obesity, which is multifactorial.

[0009] Physiologically we defend body weight both peripherally and centrally. Body weight control is based on the ability of the brain, hypothalamus in particular, to integratebehavioural, endocrine and autonomic responses via afferent and efferent pathways from and to the brainstem and peripheral organs. Communication between peripheral areas and the brain is mediated through afferent fibres of the vagus nerve projecting to the hindbrain or via the circulation by way of the median eminence of the hypothalamus or area postrema of the brainstem. Various intestinal signals are involved including GLP-1. Its ability to decrease food intake is mainly via direct activation of POMC / CART neurons but it also activates neurons in area postrema (AP) and nucleus tractus solitarius (NTS). GLP-1 receptor agonists can also modulate hedonic feeding by acting on dopaminergic neurons of the ventral tegmental area (VTA), nucleus accumbens (NAcc) and lateral septum.

[0010] Metabolic dysfunction-associated steatotic liver disease (MASLD) is an umbrella term for conditions caused by the build-up of extra fat in the liver that is not caused by alcohol intake. As fatty liver disease progresses, the liver can become inflamed (hepatitis) and damaged, which can lead to fibrosis or scarring of the liver. When people with MASLD reach this stage, it is known as metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), which is the most severe form of MASLD. After years of damage due to fibrosis, MASH can lead to cirrhosis, which is severe scarring of the liver that can lead to further complications such as loss of liver function, liver failure and liver cancer. The exact causes of MASLD and MASH are not known but it is well understood that obesity, type 2 diabetes or prediabetes, high levels of LDL cholesterol and metabolic syndrome are risk factors that make people more likely to develop these conditions. With the rising prevalence of obesity and type 2 diabetes, both strong risk factors for MASH, there is a growing number of people living with this serious chronic disease today.

[0011] KCNK13 (K2P13.1), or the potassium two-pore domain channel subfamily K member 13 gene, encodes for a two-pore forming domain potassium channel known as tandem pore domain halothane-inhibited K+channel 1 or THIK-1. KCNK13 together with KCNK12 are members of the leak or background K+channels (K2P) first cloned by Rajan et al (2001, J Biol Chem, 276, 7302-7311). KCNK12 encodes a closely related channel THIK-2 which is silent as a homodimer but can heterodimerise with THIK-1 to form an active channel, albeit with reduced function vs THIK-1 homodimer (Blin et al, 2014, J Biol Chem, 289, 28202-28212). Electrophysiological studies show that THIK-1 displays an outwardly rectifying current with a very small single-channel conductance (~5 pS at +100 mV) and short open time duration (<0.5 ms) (Kang et al, 2014, Pflugers Arch, 466(7), 1289-1300). THIK-1 K+channel conductance has been shown to play roles in modulating the biology of microglia and has a central role in mediatingthe proinflammatory response of microglia (Madry et al, 2018, Neuron, 97, 299-312). Example THIK-1 modulators, their biological activity and their route of synthesis are disclosed in International Patent Applications WO2022 / 167819, W02024 / 095003 and W02024 / 095005.

[0012] Glucagon-like peptide-1 (GLP-1) receptor agonists are glucose-lowering drugs that induce clinically significant reductions in body weight. However, GLP-1 receptor agonists not only reduce fat mass, but have also been shown to reduce lean mass and skeletal muscle mass. After treatment with GLP-1 receptor agonists is stopped, fat mass is typically regained faster than lean mass and skeletal muscle mass.

[0013] Improved treatments for obesity and / or overweight and methods of losing weight are therefore required, including improved treatments and methods that include GLP-1 receptor agonists, but prevent lean mass and skeletal muscle loss and / or limit the increase in fat mass following cessation of treatment with the GLP-1 receptor agonist. Such improved treatments and methods may also make a reduced dose or a reduced dosing frequency of the GLP-1 receptor agonist possible.

[0014] Summary of the invention

[0015] A first aspect of the present invention provides a method of treating or managing obesity or overweight, comprising administering to an obese or overweight subject a therapeutically effective amount of a THIK-1 modulator.

[0016] A second aspect of the present invention provides a THIK-1 modulator for use in the treatment or management of obesity or overweight. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for treating or managing obesity or overweight.

[0017] A third aspect of the present invention provides a method of treating or managing obesity or overweight, comprising administering to an obese or overweight subject: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

[0018] A fourth aspect of the present invention provides a THIK-1 modulator for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject the THIK-1 modulator in combination with a GLP-1 receptor agonist. The present invention alsoprovides use of a THIK-1 modulator in the manufacture of a medicament for treating or managing obesity or overweight, wherein the treating or managing comprises administering to an obese or overweight subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

[0019] A fifth aspect of the present invention provides a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject a THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing obesity or overweight, wherein the treating or managing comprises administering to an obese or overweight subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0020] A sixth aspect of the present invention provides a THIK-1 modulator and a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject the THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a THIK-1 modulator and a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing obesity or overweight, wherein the treating or managing comprises administering to an obese or overweight subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0021] A seventh aspect of the present invention provides a method of losing weight, comprising administering to a subject an effective amount of a THIK-1 modulator, preferably wherein the subject is obese or overweight.

[0022] An eighth aspect of the present invention provides a THIK-1 modulator for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator, preferably wherein the subject is obese or overweight. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator, preferably wherein the subject is obese or overweight.

[0023] A ninth aspect of the present invention provides a method of losing weight, comprising administering to a subject: (a) an effective amount of a THIK-1 modulator incombination with (b) an effective amount of a GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

[0024] A tenth aspect of the present invention provides a THIK-1 modulator for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist, preferably wherein the subject is obese or overweight. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

[0025] An eleventh aspect of the present invention provides a GLP-1 receptor agonist for use in a method of losing weight, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight. The present invention also provides use of a GLP-1 receptor agonist in the manufacture of a medicament for use in a method of losing weight, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

[0026] A twelfth aspect of the present invention provides a THIK-1 modulator and a GLP-1 receptor agonist for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight. The present invention also provides use of a THIK-1 modulator and a GLP-1 receptor agonist in the manufacture of a medicament for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

[0027] A thirteenth aspect of the present invention provides a method of treating or managing MASLD or MASH, comprising administering to a subject in need thereof a therapeutically effective amount of a THIK-1 modulator.

[0028] A fourteenth aspect of the present invention provides a THIK-1 modulator for use in the treatment or management of MASLD or MASH. The present invention also providesuse of a THIK-1 modulator in the manufacture of a medicament for treating or managing MASLD or MASH.

[0029] A fifteenth aspect of the present invention provides a method of treating or managing MASLD or MASH, comprising administering to a subject in need thereof: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

[0030] A sixteenth aspect of the present invention provides a THIK-1 modulator for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for treating or managing MASLD or MASH, wherein the treating or managing comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

[0031] A seventeenth aspect of the present invention provides a GLP-1 receptor agonist for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing MASLD or MASH, wherein the treating or managing comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0032] An eighteenth aspect of the present invention provides a THIK-1 modulator and a GLP-1 receptor agonist for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a THIK-1 modulator and a GLP-1 receptor agonist in the manufacture of a medicament for treating or managing MASLD or MASH, wherein the treating or managing comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0033] A nineteenth aspect of the present invention provides a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, comprising administering to a subject in need thereof a therapeutically effective amount of a THIK-1 modulator.A twentieth aspect of the present invention provides a THIK-1 modulator for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for reducing a cardiovascular risk factor and / or a risk of cardiovascular disease.

[0034] A twenty-first aspect of the present invention provides a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, comprising administering to a subject in need thereof: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

[0035] A twenty-second aspect of the present invention provides a THIK-1 modulator for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist. The present invention also provides use of a THIK-1 modulator in the manufacture of a medicament for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

[0036] A twenty-third aspect of the present invention provides a GLP-1 receptor agonist for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a GLP-1 receptor agonist in the manufacture of a medicament for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0037] A twenty-fourth aspect of the present invention provides a THIK-1 modulator and a GLP-1 receptor agonist for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist. The present invention also provides use of a THIK-1 modulator and a GLP-1 receptor agonist in the manufacture of a medicament for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the methodcomprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

[0038] A twenty-fifth aspect of the present invention provides a pharmaceutical composition or kit comprising a THIK-1 modulator and a GLP-1 receptor agonist.

[0039] The pharmaceutical composition of the twenty-fifth aspect provides the THIK-1 modulator and the GLP-1 receptor agonist together in one dosage form.

[0040] The kit of the twenty-fifth aspect provides the THIK-1 modulator and the GLP-1 receptor agonist in separate dosage forms. The kit may further comprise a device for separately retaining the THIK-1 modulator and the GLP-1 receptor agonist, such as a divided bottle or a divided foil packet. An example of such a kit is a blister pack used for the packaging of tablets or capsules. The kit can be suitable for administering different types of dosage forms (e.g., oral and subcutaneous), or suitable for administering different pharmaceutical compositions at separate dosing intervals, or suitable for titrating the different pharmaceutical compositions against one another. To assist with patient compliance, the kit typically comprises directions for administration and may be provided with a memory aid.

[0041] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is selected from:

[0042] 5-[[6,7-difluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0043] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-6,7-difluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0044] 4-[7-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0045] 4-[6-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0046] 4-[5-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0047] 4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0048] 3-[6,7-difluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0049] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-4-fluoro-benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;3-[4-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0050] 4-[7-fluoro-l-[(6-methoxypyridin-3-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0051] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl]pyrimidine-2-carbonitrile;

[0052] 4-[6-fl uoro-3-(pyrimidi n-5-yl methyl)imidazo[4, 5-b]pyrid in-2-yl]- 1,2,5-oxadiazol-3-amine;

[0053] 3-methyl-4-[3-(pyrimidin-5-ylmethyl)imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazole;

[0054] 4-[3-[(6-methoxypyridin-3-yl)methyl]imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazol-3-amine;

[0055] 4-[3-(pyrimidin-5-ylmethyl)imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazol-3-amine;

[0056] 3-[3-[(6-methoxypyridin-3-yl)methyl]imidazo[4,5-b]pyridin-2-yl]-4-methyl- 1.2.5-oxadiazole;

[0057] 3-methyl-4-[3-[[6-(trifluoromethyl)pyridin-3-yl]methyl]imidazo[4,5-b]pyridin- 2 -yl]- 1,2,5-oxadiazole;

[0058] 6-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl]pyridazine-3-carbonitrile;

[0059] 4-[3-[[6-(trifluoromethyl) pyrid in-3-yl]methyl]imidazo[4,5-b]pyridin-2-yl]- 1.2.5-oxadiazol-3-amine;

[0060] 3-methyl-4-[3-(pyridazin-3-ylmethyl)imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazole;

[0061] 4-[l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0062] 4-[4, 7-difluoro-l -(pyrid in-3-yl methyl) benzi midazol-2-yl]-l, 2, 5-oxadiazol-3-amine;

[0063] 4-[3-[(6-chloropyridin-3-yl)methyl]imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazol-3-amine;

[0064] 3-[3-[(6-chloropyrid in-3-yl) methyl] imidazo[4,5-b]pyridin-2-yl]-4-methyl-l, 2,5-oxadiazole;

[0065] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0066] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-4-fluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0067] 3-[5, 7-difluoro-l -(pyrid in-3-ylmethyl)benzimidazol-2-yl]-4-methyl- 1,2,5-oxadiazole;5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-4,7-difluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0068] 4-[3-[(6-chloropyridin-3-yl)methyl]-6-fluoro-imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazol-3-amine;

[0069] 3-[ 1- [dideuterio(pyrid in-3-yl) methyl ]-4- fl uoro-benzi midazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0070] 3-[ 1- [dideuterio(pyrid in-3-yl) methyl ]-7-fl uoro-benzi midazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0071] 4-[7-fluoro-l-(pyrazin-2-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[5-bromo-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0072] 4-[5-(d imethylamino)- l-(pyridi n-3-ylmethyl) benzi midazol-2-yl]- 1,2,5-oxadiazol-3-amine;

[0073] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl]methyl]pyrazine-2-carbonitrile;

[0074] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-4-fluoro-benzimidazol-l-yl]methyl]pyrazine-2-carbonitrile;

[0075] 5-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0076] 3-[l-[(6-chloropyridin-3-yl)methyl]-7-fl uoro-benzi midazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0077] 3-[l-[(6-chloropyridin-3-yl)methyl]-4-fl uoro-benzi midazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0078] 5-[[4-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0079] 5-[[7-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrazine-2-carbonitrile;

[0080] 5-[[4-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrazine-2-carbonitrile;

[0081] 3-[7-fluoro-l-[(6-methoxypyridin-3-yl)methyl]benzimidazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0082] 5-[[7-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0083] 5-[[4-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0084] 6-[[7-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridazine-3-carbonitrile;6-[[4-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridazine-3-carbonitrile;

[0085] 3-[l-[(6-ethoxypyridin-3-yl)methyl]-4-fluoro-benzimidazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0086] 3-[7-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0087] 5-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl]pyridine-2-carbonitrile;

[0088] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)imidazo[4,5-b]pyridin-3-yl]methyl]pyridine-2-carbonitrile;

[0089] 5-[[7-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0090] 3-[l-[(6-methoxypyridin-3-yl)methyl]benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0091] 5-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridin-2-ol; 5-[[6-fluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0092] 3-[6,7-difluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0093] 3-methyl-4-[l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]- 1,2,5-oxadiazole; 3-methyl-4-[l-[(6-(methylsulfonyl)pyridin-3-yl)methyl]benzimidazol-2-yl]-1,2,5-oxadiazole;

[0094] 4-[3-(pyridin-3-ylmethyl)imidazo[4,5-b]pyridin-2-yl]-l,2,5-oxadiazol-3-amine; 3-[l-[(6-chloropyridin-3-yl)methyl]benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0095] 5-[[4-chloro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0096] 5-[[7-chloro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0097] 3-methyl-4-[l-[(6-methylpyridin-3-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazole;

[0098] 3-methyl-4-[l-[(2-methylpyrimidin-5-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazole;

[0099] 3-[4,7-difluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl- 1,2,5-oxadiazole;

[0100] 3-[l-[(2-methoxypyridin-4-yl)methyl]benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;3-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0101] 5-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,3-thiadiazole;

[0102] 3-methyl-4-[l-[(3-methylpyridin-2-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazole;

[0103] 3-[7-ethoxy- 1-( pyrid in-4-yl methyl) benzi midazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0104] 4-[l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0105] 2-(4-methyl-l, 2, 5-oxadiazol-3-yl)-3-( pyrid in-3-ylmethyl) benzi midazol-4-amine;

[0106] N-methyl-5-[[2-(4-methyl-l,2,5-oxadiazol-3-yl) benzi midazol-1-yl]methyl]pyridin-2-amine;

[0107] 3-methyl-4-[l-[(2-methylpyridin-4-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazole;

[0108] 3-[l-[(4,6-di methyl pyridin-2-yl)methyl]benzimidazol-2-yl]-4-methyl-l, 2,5-oxadiazole;

[0109] 3-methyl-4-[l-[(l-oxidopyridin-l-ium-3-yl)methyl]benzimidazol-2-yl]- 1,2,5-oxadiazole;

[0110] 3-methyl-4-[l-[(l-oxidopyridin-l-ium-4-yl)methyl]benzimidazol-2-yl]- 1,2,5-oxadiazole;

[0111] 3-methyl-4-[l-[(6-methylpyridin-2-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazole;

[0112] 3-methyl-4-[l-(pyridin-2-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazole;

[0113] 5-[[6-fluoro-2-(4-methyl-l,2,5-thiadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;

[0114] N-methyl-2-(4-methyl-l,2,5-oxadiazol-3-yl)-3-(pyridin-3-ylmethyl)benzimidazol-4-amine;

[0115] 3-[l-[(3-fluoropyridin-2-yl)methyl]benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0116] 5-[[4,7-difluoro-2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0117] 3-[4,7-difluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0118] rac-4-[l-[l-(pyridin-3-yl)ethyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-(l-((6-bromopyridin-3-yl)methyl)benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;3-[ l-(pyridi n-3-yl methyl)benzi midazol-2-yl ]-4-vi nyl-1 ,2,5-thiadiazole;

[0119] 4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0120] 4-[6-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[5-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[l-[(2-methoxypyridin-4-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0121] 4-[l-[[2-(trifluoromethyl)pyridin-4-yl]methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0122] 4-[l-[[5-(trifluoromethyl)pyridin-3-yl]methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0123] N-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-thiadiazol-3-amine;

[0124] 4-[l-[[6-(trifluoromethyl)pyridin-3-yl]methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0125] 3-methyl-4-[l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazole;

[0126] 4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-thiadiazole-3-carbonitrile; 2-(3-methylthiophen-2-yl)-l-(pyridin-3-ylmethyl)benzi midazole;

[0127] 3-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazole;

[0128] 5-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,3-thiadiazole;

[0129] 5-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]oxazole;

[0130] 4-methyl-3-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]isoxazole;

[0131] 3-ethyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-thiadiazole;

[0132] 4-[l-(pyrimidin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0133] 4-[l-(pyridazin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0134] 3-fluoro-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-thiadiazole;

[0135] 4-[l-[[2-(trifluoromethyl)pyridin-3-yl]methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0136] 3-methyl-4-[3-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-l,2,5-oxadiazole;

[0137] 4,5-dimethyl-3-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]isoxazole;

[0138] 3-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]isoxazole;

[0139] 2-(l,4-dimethylpyrazol-3-yl)-l-(pyridin-3-ylmethyl)benzimidazole;

[0140] 2-(l-methylpyrazol-5-yl)-l-(pyridin-3-ylmethyl)benzimidazole;

[0141] 3-ethyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazole;

[0142] 2-(furan-2-yl)-l-(pyridin-4-ylmethyl)benzimidazole;

[0143] 4-[6-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[5-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;4-[4-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0144] 3-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0145] 3-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-thiadiazole;

[0146] 3-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-thiadiazole;

[0147] 3-bromo-4-(l-(pyridin-3-ylmethyl)benzimidazol-2-yl)-l,2,5-thiadiazole;

[0148] 3-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-thiadiazole;

[0149] 4-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-5-methyl-l,2,3-thiadiazole;

[0150] 4-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-5-methyl-l,2,3-thiadiazole;

[0151] 4-methyl-5-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]isoxazole;

[0152] 4-[4-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0153] 4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0154] 4-(4-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0155] 4-(7-fluoro-l-(pyrimidin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0156] 4-(4-fluoro-l-(pyrimidin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0157] 4-(5,7-difluoro-l-(pyridin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0158] 3-(7-fluoro-l-((6-(methylsulfonyl)pyridin-3-yl)methyl)-benzimidazol-2-yl)-4-methyl-l,2,5-oxadiazole;

[0159] 3-(4-fluoro-l-((6-(methylsulfonyl)pyridin-3-yl)methyl)-benzimidazol-2-yl)-4-methyl-l,2,5-oxadiazole;

[0160] 3-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-4-methyl-l,2,5-thiadiazole;

[0161] 3-(4-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-4-methyl-l,2,5-thiadiazole;

[0162] 4-(5,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(4,6-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0163] 4-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-N-methyl-l,2,5-thiadiazol-3-amine;

[0164] 4-(4-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-N-methyl-l,2,5-thiadiazol-3-amine;

[0165] 4-(6,7-difluoro-l-(pyridin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0166] 3-( 5, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0167] 3-(4, 6-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0168] 4-(l-((6-chloropyridazin-3-yl)methyl)-7-fluoro-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0169] 4-(l-((6-chloropyridazin-3-yl)methyl)-4-fluoro-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0170] 6-((2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl)methyl)pyridazin-3-ol;

[0171] 4-(l-((6-deuteriopyridazin-3-yl)methyl)-7-fluoro-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0172] 4-(7-fluoro-l-((6-methoxypyridazin-3-yl)methyl)-benzimidazol-2-yl)- 1,2,5-oxadiazol-3-amine;

[0173] 4-(4-fluoro-l-((6-methoxypyridazin-3-yl)methyl)-benzimidazol-2-yl)- 1,2,5-oxadiazol-3-amine;

[0174] 4-(4,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0175] 4-(4,7-difluoro-l-(pyridin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0176] 4-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-thiadiazol-3-amine;

[0177] 4-(4-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-thiadiazol-3-amine;

[0178] 4-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)isoxazol-3-amine; 4-(l-((6-chloropyridin-3-yl)methyl)-6-fluoro-l / 7-imidazo[4,5-b]pyridin-2-yl)-l,2,5-oxadiazol-3-amine;

[0179] 4-(6-fluoro-l-(pyrimidin-5-ylmethyl)-l / 7-imidazo[4,5-b]pyridin-2-yl)-l,2,5-oxadiazol-3-amine;(S)-4-(7-fluoro-l-(l-(pyridin-3-yl)ethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0180] 4-(6,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0181] 4-(4,5-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0182] N-methyl-5-((2-(4-methyl-l,2,5-oxadiazol-3-yl)-benzimidazol-l-yl)methyl)pyridine-2-sulfonamide;

[0183] 5-((2-(4-methyl-l,2,5-oxadiazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidine-2-carbonitrile;

[0184] 4-(7-fluoro-l-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0185] 4-(4-fluoro-l-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0186] 4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0187] 4-(4-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0188] 3-(6, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0189] 3-(4, 5-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0190] 4-(l-((6-(difluoromethyl)pyridazin-3-yl)methyl)-7-fluoro-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0191] 4-(l-((6-(difluoromethyl)pyridazin-3-yl)methyl)-4-fluoro-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0192] 6-((2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl)methyl)pyridazine-3-carbonitrile;

[0193] 6-((2-(4-amino-l,2,5-oxadiazol-3-yl)-4-fluoro-benzimidazol-l-yl)methyl)pyridazine-3-carbonitrile;

[0194] 4-(7-fluoro-l-((6-(trifluoromethoxy)pyridin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0195] 6-((2-(4-amino-l,2,5-oxadiazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazine-3-carbonitrile;

[0196] 4-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-N-methyl-l,2,5-oxadiazol-3-amine;

[0197] 4-(4-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;3-(l-((6-(ethylsulfonyl)pyridin-3-yl)methyl)-benzimidazol-2-yl)-4-methyl- 1,2,5-oxadiazole;

[0198] 3-methyl-4-(l-((6-(methylthio)pyridin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazole;

[0199] 3-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-4-methylisoxazole; 4-(7-fluoro-l-((2-methoxypyridin-4-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0200] 4-(4-fluoro-l-((2-methoxypyridin-4-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0201] 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0202] 3-(7-fluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)isoxazol-4-amine; 4-(7-fluoro-l-(pyridazin-3-ylmethyl)-lH-imidazo[4,5-c]pyridin-2-yl)-l,2,5-oxadiazol-3-amine;

[0203] 4-(7-fluoro-3-(pyridazin-3-ylmethyl)-3H-imidazo[4,5-c]pyridin-2-yl)-l,2,5-oxadiazol-3-amine;

[0204] N-benzyl-5-chloro-2-rnethoxy-N-methylnicotinarnide;

[0205] 5-chloro-N-(6-cyano-2,3-dihydro-lH-inden-l-yl)-2-methoxy-N-methylnicotinamide;

[0206] 5-chloro-N-(7-cyano-2,3-dihydro-lH-inden-l-yl)-2-methoxy-N-methylnicotinamide;

[0207] (5-fluoro-2-methoxypyridin-3-yl)(2-(3-fluorophenyl)piperidin-l-yl)methanone; 5-fluoro-N-(l-(2-fluorophenyl)ethyl)-2-rnethoxy-N-methylnicotinarnide;

[0208] 5-fluoro-N-(l-(3-fluorophenyl)ethyl)-2-rnethoxy-N-methylnicotinarnide;

[0209] 5-fluoro-N-(6-fluoro-2,3-dihyd ro-lH-inden-l-yl)-2-methoxy-N-methylnicotinamide;

[0210] N-(2,4-difluorobenzyl)-2-methoxy-N,6-di methyl nicotinamide;

[0211] 5-chloro-N-(2,3-dihyd ro-lH-inden-l-yl)-2-ethoxy-N-methyl nicotinamide; N-(chroman-4-yl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0212] N-(2, 3-dihydro-lH-inden-l-yl)-5-fluoro-2-methoxy-N-methylnicotinamide; 5-chloro-N-(chroman-4-yl)-2-methoxy-N-methyl nicotinamide;

[0213] 5-chloro-N-(6-fluoro-2,3-dihydro-lH-inden-l-yl)-2-methoxy-N-methylnicotinamide;

[0214] 5-chloro-N-(2,3-dihyd ro-lH-inden-l-yl)-2-methoxy-N-methylnicotinamide; 5-chloro-N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0215] 5-chloro-N-(2,3-dihyd robenzofuran-3-yl)-2-methoxy-N-methylnicotinamide; 5-chloro-N-(8-fluorochroman-4-yl)-2-methoxy-N-methylnicotinamide;

[0216] 5-fluoro-N-(8-fluorochroman-4-yl)-2-methoxy-N-methyl nicotinamide;N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0217] N-(2-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0218] 5-fluoro-N-(l-(3-fluorophenyl)cyclopropyl)-2-methoxy-N-methyl nicotinamide; 5-fluoro-N-(5-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;

[0219] N-(2-cyanobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0220] 5-fluoro-N-(2-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0221] N-(2,3-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0222] N-(2,4-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0223] 5-chloro-N-(2,3-difluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0224] 5-chloro-N-(3,5-difluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0225] 5-fluoro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;

[0226] 5-chloro-N-(7-fluorochroman-4-yl)-2-methoxy-N-methylnicotinamide;

[0227] 5-chloro-N-(3-chloro-5-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0228] 5-chloro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;

[0229] N-benzyl-5-chloro-N-ethyl-2-methoxynicotinamide;

[0230] 5-chloro-N-ethyl-N-(2-fluorobenzyl)-2-methoxynicotinamide;

[0231] 5-chloro-N-ethyl-N-(3-fluorobenzyl)-2-methoxynicotinamide;

[0232] 5-fluoro-N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0233] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-l,2,3,4-tetrahyd roisoqui noline; 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-l,2,3,4-tetrahyd roisoqui noline; 7-fluoro-4-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine;

[0234] 4-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine;

[0235] 7-fluoro-4-((2-methoxypyridin-3-yl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine;

[0236] methyl 4-fluoro-2-((5-fluoro-2-methoxy-N-methylnicotinamido) methyl) benzoate;

[0237] 5-chloro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methoxy-N-methylnicotinamide;

[0238] 5-chloro-N-(2-cyano-4-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0239] 5-chloro-N-(l-(2-cyano-5-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;

[0240] N-(2-cyano-4,6-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;N-(l-(2-cyano-5-fluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0241] N-(l-(2-cyano-4-fluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methylnicotinamide;

[0242] 5-chloro-N-(l-(2-cyano-4-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;

[0243] N-(l-(2,4-difluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methyl nicotinamide; 2-(difluoromethoxy)-5-fluoro-N-(l-(2-fluorophenyl)ethyl)-N-methylnicotinamide;

[0244] N-(2,4-difluorobenzyl)-2-methoxy-N,5-di methyl nicotinamide;

[0245] N-(2,4-difluorobenzyl)-2-methoxy-N,4-di methyl nicotinamide;

[0246] 2-(difluoromethoxy)-5-fluoro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;

[0247] 2-(difluoromethoxy)-5-fluoro-N-(7-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;

[0248] 5-chloro-2-(difluoromethoxy)-N-(3-fluoro-5-methylbenzyl)-N-methylnicotinamide;

[0249] 5-chloro-2-(difluoromethoxy)-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;

[0250] 5-chloro-N-(3,5-difluorobenzyl)-2-(difluoromethoxy)-N-methyl nicotinamide; 5-chloro-N-(3-chloro-5-fluorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;

[0251] 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-methyl benzyl) nicotinamide; 5-chloro-2-(difluoromethoxy)-N-(3-methoxybenzyl)-N-methylnicotinamide; 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-(trifluoromethyl)benzyl) nicotinamide;

[0252] 2-(difluoromethoxy)-5-fluoro-N-(l-(3-fluorophenyl)ethyl)-N-methylnicotinamide;

[0253] 5-chloro-N-(3-chlorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide; 2-(difluoromethoxy)-N-(2,3-dihyd robenzofuran-3-yl)-5-fluoro-N-methylnicotinamide;

[0254] 5-chloro-2-(difluoromethoxy)-N-(l-(3-fluorophenyl)ethyl)-N-methylnicotinamide;

[0255] 2-(difluoromethoxy)-5-fluoro-N-(l-(3-fluorophenyl)ethyl)-N-methylnicotinamide;

[0256] 5-chloro-N-(3-cyanobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide; 5-chloro-2-(difluoromethoxy)-N-(2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;5-chloro-2-(difluoromethoxy)-N-(7-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;

[0257] N-(2,3-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methyl nicotinamide; N-(2,4-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methyl nicotinamide; 2-(difluoromethoxy)-5-fluoro-N-(3-fluorobenzyl)-N-methyl nicotinamide; 2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methyl-5-(trifluoromethyl) nicotinamide;

[0258] 5-cyclobutyl-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methylnicotinamide; 5-chloro-2-(difluoromethoxy)-N-(3-(difluoromethoxy)benzyl)-N-methylnicotinamide;

[0259] 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-(trifluoromethoxy) benzyl) nicotinamide;

[0260] 5-chloro-N-(2,4-difluorobenzyl)-2-(difluoromethoxy)-N-methyl nicotinamide; 5-chloro-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methyl nicotinamide; 5-chloro-N-(2, 3-d ifluorobenzyl)-2-(difluoromethoxy)-N-methyl nicotinamide; N-(3,5-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;

[0261] ( / ?)-2-(difluoromethoxy)-5-fluoro-N-(l-(3-fluorophenyl)ethyl)-N-methylpyridine-3-sulfonamide;

[0262] (S)-2-(difluoromethoxy)-5-fluoro-N-(l-(3-fluorophenyl)ethyl)-N-methylpyridine-3-sulfonamide;

[0263] N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;

[0264] N-(2,3-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;

[0265] N-(3-chlorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;

[0266] 2-(difluoromethoxy)-N-ethyl-5-fluoro-N-(3-fluorobenzyl)pyridine-3-sulfonamide;

[0267] 2-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-l,2,3,4-tetrahydroisoquinoline;

[0268] 2-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-7-fluoro-l,2,3,4-tetrahydroisoquinoline;

[0269] 2-(difluoromethoxy)-5-fluoro-N-(3-fluorobenzyl)-N-methylpyridine-3-sulfonamide;

[0270] 5-chloro-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methylpyridine-3-sulfonamide;4-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine;

[0271] 4-((5-chloro-2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine;

[0272] 2-((5-chloro-2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-6,8-difluoro-l,2,3,4-tetrahydroisoquinoline;

[0273] 5-chloro-N-(2,6-difluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0274] 5-chloro-N-(2,6-dichlorobenzyl)-2-methoxy-N-methyl nicotinamide;

[0275] 5-chloro-2-(difluoromethoxy)-N-(l,l-dioxido-2,3-dihyd robenzo[b]thiophen-3-yl)-N-methyl nicotinamide;

[0276] 5-fluoro-2-((7-fluoro-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)sulfonyl)benzonitrile;

[0277] 5-chloro-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0278] 5-chloro-3-(5-(2-chlorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine;

[0279] 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-(2,2,2-trifluoroethoxy)pyridine;

[0280] 5-chloro-2-cyclopropoxy-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl) pyridi ne;

[0281] 5-chloro-3-(5-(3-chlorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-(difluoromethoxy)pyridine;

[0282] 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl) pyridi ne;

[0283] 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0284] 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0285] 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl) pyridi ne;

[0286] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(o-tolyl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0287] 2-(difluoromethoxy)-3-(5-(2,4-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-5-fluoropyridine;

[0288] 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-isopropoxypyridine;

[0289] 2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-5-methylpyridine;5-chloro-2-(difluoromethoxy)-3-(4-ethyl-5-(3-fluorophenyl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0290] 5-chloro-2-(difluoromethoxy)-3-(5-(3-(difluorornethoxy)phenyl)-4-methyl-4H- 1.2.4-triazol-3-yl) pyridine;

[0291] 5-bromo-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0292] 6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)nicotinonitrile;

[0293] 5-chloro-2-(difluoromethoxy)-3-(l-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-4-yl)pyrid ine;

[0294] 3-(5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1.2.4-triazole;

[0295] 3-(5-(2-bromophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-5-chloro-2-(difluoromethoxy)pyridine;

[0296] 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H-l,2,4-triazol-3-yl)benzonitrile;

[0297] 5-chloro-2-(difluoromethoxy)-3-(2-(2,6-difluorophenyl)-l-methyl-lH-imidazol-5-yl) pyridi ne;

[0298] 3-chloro-6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-methyl pyridine;

[0299] 6-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)benzo[c][l,2,5]thiadiazole;

[0300] 3-(5-chloro-2-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;

[0301] 5-chloro-2-(difluoromethoxy)-3-(4-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-1 -yl)pyrid ine;

[0302] 5-chloro-2-(difluoromethoxy)-3-(3-(2,6-difluorophenyl)-5-methoxy-lH-pyrazol-l-yl)pyridine;

[0303] 3-(5-chloro-2-(trifluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole;

[0304] 3-(4-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole;

[0305] 3-(3-bromo-5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;

[0306] 3-(5-chloro-2-(difluoromethoxy)-3-methylphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;

[0307] 3-(5-chloro-2-(difluoromethoxy)-3-fluorophenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;3-(5-chloro-2-(difluoromethoxy)-4-fluorophenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;

[0308] 3-(4,5-dichloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl- 4H-l,2,4-triazole;

[0309] 4-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-6-methoxypyrimidine;

[0310] 2-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-5-methoxypyridine;

[0311] 2-chloro-5-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0312] 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-6-isopropoxypyridine;

[0313] 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-6- (methylthio)pyridine;

[0314] 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-3- (methylthio)pyridine;

[0315] 3-chloro-2-(4-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-l-yl)-6-methoxypyridine;

[0316] 3-chloro-6-(difluoromethoxy)-2-(4-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-1 -yl)pyrid ine;

[0317] 3-(2-chloro-5-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole;

[0318] 3-(2-chloro-5-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1.2.4-triazole;

[0319] 3-chloro-2-(2-(2,6-difluorophenyl)-l-methyl-lH-imidazol-5-yl)-6-methoxypyridine;

[0320] 3-chloro-6-(difluoromethoxy)-2-(2-(2,6-difluorophenyl)-l-methyl-lH-imidazol- 5-yl) pyridi ne;

[0321] 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluoro-6-methylphenyl)-4-methyl-4H- 1.2.4-triazol-3-yl) pyridine;

[0322] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(methylsulfonyl)phenyl)-4H- 1, 2, 4-triazol-3-yl) pyridine;

[0323] 3-chloro-6-(difluoromethoxy)-2-(l-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-4-yl)pyrid ine;

[0324] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,3,6-trifluorophenyl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0325] 2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-6-methoxynicoti nonitrile;5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-N-methylpyridin-2-amine;

[0326] 4-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl) phenol; 3-chloro-2-(l-(2,6-difluorophenyl)-5-methyl-lH-l,2,3-triazol-4-yl)-6-methoxypyridine;

[0327] 3-chloro-6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0328] 6-chloro-3-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0329] 5-chloro-2-(difluoromethoxy)-3-(5-(2-methoxyphenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0330] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(trifluoromethyl)phenyl)-4H- 1, 2, 4-triazol-3-yl) pyridine;

[0331] 5-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-methoxypyridine;

[0332] 5-chloro-2-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0333] 6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-3-fluoropyridine;

[0334] 2-(5-(5-c loro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H-l,2,4-triazol-3-yl)a nil ine;

[0335] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,4,6-trifluorophenyl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0336] 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-6-(methoxy-d3)pyridine;

[0337] 3,5-bis(4-chloro-2-(difluoromethoxy)phenyl)-4-methyl-4H-l,2,4-triazole; 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluoropyridin-4-yl)-4-methyl-4H- 1, 2, 4-triazol-3-yl) pyridine;

[0338] 5-chloro-3-(5-(2-chloropyridin-3-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine;

[0339] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-4H- 1, 2, 4-triazol-3-yl) pyridine;

[0340] 5-chloro-3-(5-(3-chloropyridin-2-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-2-(difluoromethoxy)pyridine;

[0341] 5-chloro-3-(5-(3-chloropyridin-4-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine;

[0342] 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihyd robenzofu ran-7-yl)-4-methyl-4H- 1, 2, 4-triazol-3-yl) pyridine;5-chloro-3-(5-(4-chloropyridin-3-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine;

[0343] 3-(5-(benzo[d][l,3]dioxol-4-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-5-chloro-2-(difluoromethoxy)pyridine;

[0344] 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihyd robenzofu ran-4-yl)-4-methyl-4H- 1.2.4-triazol-3-yl) pyridine;

[0345] 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-4-yl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0346] 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-methylpyridin-3-yl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0347] 5-chloro-2-(difluoromethoxy)-3-(5-(5-fluorobenzo[d][l,3]dioxol-4-yl)-4-methyl-4H-l,2,4-triazol-3-yl)pyridine;

[0348] 5-chloro-2-(d ifluoromethoxy)-3-( 5-(6-fluoro-2, 3-di hydro benzo[b][l,4]dioxin-5-yl)-4-methyl-4H-l,2,4-triazol-3-yl)pyridine;

[0349] 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-2-yl)-4-methyl-4H-l,2,4-triazol-3-yl)pyrid ine;

[0350] 5-chloro-2-(difluoromethoxy)-3-(5-(3-(difluoromethoxy)pyridin-2-yl)-4-methyl-4H- 1, 2, 4-triazol-3-yl) pyridine;

[0351] 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)chroman-4-one;

[0352] 3-(6-chlorochroman-5-yl)-5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazole; 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)-2,3-dihydrofuro[2,3-b]pyridine;

[0353] 4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)thieno[2,3-b]pyridine-5-carbonitrile;

[0354] 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)thieno[2,3-c]pyridine;

[0355] 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)thieno[2,3-b]pyridine;

[0356] 3-( 5-chloro-2, 3-d ihyd robenzofu ran-4-yl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1.2.4-triazole;

[0357] 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)quinoline; 3-chloro-6-methoxy-2-(4-methyl-5-(2-methylpyridin-3-yl)-4H-l,2,4-triazol-3-yl)pyrid ine;

[0358] 3-chloro-2-(5-(3-chloropyridin-2-yl)-4-methyl-4H-l,2,4-triazol-3-yl)-6-(difluoromethoxy)pyridine;

[0359] 3-chloro-2-[5-(3-chloro-6-methoxy-2-pyridyl)-4-methyl-l,2,4-triazol-3-yl]-6-methoxy-pyridine;5-chloro-3-[5-[5-chloro-2-(difluoromethoxy)-3-pyridyl]-4-methyl-l,2,4-triazol- 3-yl]-2-(difluoromethoxy)pyridine;

[0360] or an enantiomer of any of the foregoing;

[0361] or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

[0362] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is selected from:

[0363] 4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0364] 4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0365] 4-(4,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0366] 4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0367] 4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0368] 4-[l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0369] 4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0370] 4-[l-[(2-methoxypyridin-4-yl)methyl]benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0371] 4-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[5-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[6-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[5-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 4-[6-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-methyl-4-[l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazole;

[0372] 3-[7-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0373] 3-[4-fluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0374] 3-[5,7-difluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0375] 5-[[2-(4-methyl-l,2,5-oxadiazol-3-yl)benzimidazol-l-yl]methyl]pyridine-2-carbonitrile;4-[4,7-difluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0376] 3-[4,7-difluoro-l-(pyridin-3-ylmethyl)benzimidazol-2-yl]-4-methyl-l,2,5-oxadiazole;

[0377] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0378] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-4,7-difluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0379] 4-[l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0380] 4-[7-fluoro-l-(pyrazin-2-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl]methyl]pyrazine-2-carbonitrile;

[0381] 4-[7-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0382] 4-[6-fluoro-l-(pyrimidin-5-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;

[0383] 5-[[2-(4-amino-l,2,5-oxadiazol-3-yl)-6,7-difluoro-benzimidazol-l-yl]methyl]pyrimidine-2-carbonitrile;

[0384] 6-((2-(4-amino-l,2,5-oxadiazol-3-yl)-7-fluoro-benzimidazol-l-yl)methyl)pyridazine-3-carbonitrile;

[0385] 4-(7-fluoro-l-(pyrimidin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0386] 4-(6,7-difluoro-l-(pyridin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0387] 4-(7-fluoro-l-((6-methoxypyridazin-3-yl)methyl)-benzimidazol-2-yl)- 1,2,5-oxadiazol-3-amine;

[0388] 5-chloro-N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;

[0389] 5-chloro-N-(3,5-difluorobenzyl)-2-(difluoromethoxy)-N-methyl nicotinamide; 5-chloro-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-l,2,4-triazol-3-yl)pyridine;

[0390] or an enantiomer of any of the foregoing;

[0391] or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

[0392] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is selected from:

[0393] 4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;

[0394] 4-(4,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0395] 4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0396] 4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;

[0397] or an enantiomer of any of the foregoing;

[0398] or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

[0399] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is 4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0400] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is formulated as a pharmaceutical composition comprising the THIK-1 modulator and one or more pharmaceutically acceptable carriers or excipients.

[0401] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735. In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is selected from Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide, or Tirzepatide.

[0402] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is formulated as a pharmaceutical composition comprising the GLP-1 receptor and one or more pharmaceutically acceptable carriers or excipients.

[0403] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is administered orally or subcutaneously. In one embodiment ofany of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is administered orally.

[0404] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is administered once or twice per day.

[0405] In one embodiment of any of the first to twenty-fifth aspects of the present invention, the THIK-1 modulator is administered in an amount of from about 10 mg to about 1,000 mg per day.

[0406] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is administered orally or subcutaneously.

[0407] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

[0408] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

[0409] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, the THIK-1 modulator and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

[0410] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, administration of the THIK-1 modulator is initiated on the same day as administration of the GLP-1 receptor agonist.

[0411] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, administration of the THIK-1 modulator is initiated one or more days (such as one, two, three, four, five, six, seven, eight, nine, ten or more days, or one, two, three,four, five, six, seven, eight, nine, ten or more weeks, or one, two, three, four, five, six or more months) after administration of the GLP-1 receptor agonist. Optionally the administration amount and / or the administration frequency of the GLP-1 receptor agonist is reduced when administration of the THIK-1 modulator is initiated.

[0412] Weight loss effected by GLP-1 receptor agonists tends to plateau after a few months of treatment (such as one, two, three, four, five, six or more months). Therefore, in one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, administration of the THIK-1 modulator is initiated after administration of the GLP-1 receptor agonist when weight loss effected by the GLP-1 receptor agonist has plateaued. Optionally the administration amount and / or the administration frequency of the GLP-1 receptor agonist is reduced when administration of the THIK-1 modulator is initiated.

[0413] In one embodiment of any of the third to sixth, ninth to twelfth, fifteenth to eighteenth, and twenty-first to twenty-fifth aspects of the present invention, administration of the THIK-1 modulator is continued after administration of the GLP-1 receptor agonist has ceased.

[0414] In the first to sixth aspects of the present invention, the subject is obese or overweight. In one embodiment of any of the seventh to twenty-fourth aspects of the present invention, the subject is obese or overweight.

[0415] Generally, subjects are considered overweight if they have a BMI of 25 or greater, and obese if they have a BMI of 30 or greater. Although weight loss therapies provide a treatment of weight-gain induced comorbidities, such as obesity-associated comorbidities, weight loss therapies can have an impact on body composition. Body composition includes free mass, fat free mass, lean mass, skeletal muscle mass, bone mineral content, and total body water. Free mass is a mass of all adipose tissue; fat free mass is total body mass minus total fat mass; lean mass includes organs, skin, bones, total body water, and muscle mass minus total fat mass; skeletal muscle mass includes lean mass minus connective tissue, skin, and other organs; and total body water includes intra- and extracellular water. A GLP-1 receptor agonist used to induce weight loss in a subject, can also induce loss of lean mass and / or skeletal muscle mass which can make the subject susceptible to muscle atrophies, sarcopenia, and physical frailty. A subject who is overweight and recommended for weight loss therapy may already have an increased risk of conditions such as diabetes, insulin resistance, muscle atrophies, sarcopenia, and physical frailty.The present inventors discovered that administration of a THIK-1 modulator can induce and co-administration of a THIK-1 modulator with a GLP-1 receptor agonist can increase total weight loss (e.g., fat mass loss) but also preserve muscle function and muscle mass, and thus reduce or prevent the loss of skeletal muscle mass and / or lean mass that usually follows treatment with a GLP-1 receptor agonist. The present inventors discovered that the combination therapy can lead to increased total weight loss, reduction of fat mass percentage, increase in lean mass percentage, and / or improvement in body composition (higher lean mass / fat mass ratio) relative to that caused by administration of the GLP-1 receptor agonist alone.

[0416] Definitions

[0417] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, and other publications are incorporated by reference in their entirety.

[0418] The THIK-1 potassium channel is a protein encoded by the KCNK13 gene. The term "THIK-1 modulator" includes compounds (including but not limited to small molecules, peptides, proteins, and siRNA) which act on THIK-1, for example, by inhibiting, reducing, blocking or antagonising THIK-1 function or by reducing the expression level of THIK-1. Methods for determining THIK-1 modulatory activity are described in the supplementary data of ACS Med. Chem. Lett., 2024, 15(5), 646-652 (https: / / pubs.acs.org / doi / 10.1021 / acsmedchemlett.4c00035).

[0419] The term "GLP-1 receptor agonist" includes compounds which act only as GLP-1 receptor agonists (such as Semaglutide) as well as compounds that have a mixed pharmacology which includes GLP-1 receptor agonism (such as Tirzepatide which is a mixed GIP / GLP-1 receptor agonist). A protocol of how to measure GLP-1 receptor agonism can be found in Willard et al, JCI Insight, 2020 (https: / / doi.org / 10.1172 / jci.insight.140532).

[0420] The term "solvate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0421] The term "pharmaceutically acceptable salt" encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acid addition salts includethose derived from organic and inorganic acids known in the art, see for example, Remington's Pharmaceutical Sciences, 18thed, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19thed, Mack Publishing, Easton PA (1995). Base addition salts may be alkali metal or alkaline earth metal salts or salts with suitable organic bases.

[0422] The term "subject" or "patient" refers to an animal, including but not limited to a mammal, including a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0423] The terms "treat", "treating" and "treatment" refer to the eradication or amelioration of a disease, disorder or condition, or of one or more symptoms associated with the disease, disorder or condition. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease, disorder or condition.

[0424] The terms "manage", "managing" and "management" refer to preventing or slowing the progression or worsening of a disease, disorder or condition, or of one or more symptoms thereof. Often, the beneficial effects that a patient derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder or condition.

[0425] The term "cardiovascular risk factor" includes, but is not limited to, being obese or overweight, having a high cholesterol level (including a high total cholesterol level or a high LDL cholesterol level), having a high triglyceride level, having high blood pressure, having diabetes, having a high blood glucose level, having a high insulin level, having a high C-reactive protein (CRP) level, and having a high glycosylated haemoglobin (HbAlc) level. The term "reducing a cardiovascular risk factor" refers to, for example, reducing a subject's weight, cholesterol level (including total cholesterol level or LDL cholesterol level), triglyceride level, blood pressure, blood glucose level, insulin level, CRP level, or HbAlc level. Protocols for measurement of the above cardiovascular risk factors in blood can be found here: (1) Glucose: The use of mice in diabetes research: The impact of experimental protocols, Matilda R. Kennard et al, Diabetic Medicine, 2021 (https: / / doi.org / 10.llll / dme.14705); (2) HbAlc: Evaluation of diagnostic reliability of DCA 2000 for rapid and simple monitoring of HbAlc, Arsie MP et al, Acta Diabetol, 37(1-7), 2000 (doi: 10.1007 / s005920070028); (3) Plasma / serum levels of cholesterol and triglyceride: Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia, Wu Yinet al, J Lipid Res, 2012 (doi: 10.1194 / jlr.M019927); (4) CRP: Elevated C-Reactive Protein Levels in Overweight and Obese Adults, Marjolein Visser et al, JAMA, 1999; (5) Insulin: Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions, Kirk M. Habegger et al, Diabetes, 2013 (https: / / doi.org / 10.2337 / dbl2-1116).

[0426] The term "cardiovascular disease" includes, but is not limited to, atherosclerosis, coronary heart disease, angina, heart attack, heart failure, stroke, transient ischaemic attack, and peripheral arterial disease. The term "reducing a risk of cardiovascular disease" refers to reducing a subject's risk of suffering from a cardiovascular disease.

[0427] A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A "therapeutically effective amount" of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease, disorder or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0428] The terms "combination therapy" and "in combination with" refer to the use of more than one therapeutic agent to treat a particular disease, disorder or condition. The terms are not intended to imply that the therapeutic agents must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. A therapeutic agent (such as a THIK-1 modulator) can be administered concurrently with, prior to, or subsequent to, one or more other additional agents (such as a GLP-1 receptor agonist). The administration of a therapeutic agent (such as a THIK-1 modulator) "in combination with" another therapeutic agent (such as a GLP-1 receptor agonist) includes, but is not limited to, simultaneous, separate and sequential administration of the two agents. In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent.

[0429] Subjects are considered "obese" if they have a body mass index (BMI) of 30 or greater. Obese subjects suffer from the disease, disorder or condition known as "obesity". Obesity is classified by the World Health Organization (WHO) as a chronic, relapsing disease arising from complex interactions between genetics, neurobiology,eating behaviours, access to healthy diet, market forces, and the broader environment.

[0430] Subjects are considered "overweight" if they have a body mass index (BMI) of 25 or greater. Overweight subjects suffer from the condition known as "overweight".

[0431] Overweight is a condition of excessive fat deposits.

[0432] Subjects are considered to suffer from metabolic dysfunction-associated steatotic liver disease (MASLD) if they have a build-up of extra fat in the liver that is not caused by alcohol intake. Subjects are considered to suffer from metabolic dysfunction-associated steatohepatitis (MASH) if their liver has become inflamed and damaged leading to fibrosis of the liver. Elevated levels of liver enzymes, in particular alanine aminotransferase (ALT), are used as a part of diagnostic tools for both MASLD and MASH, for example, see Annals of Hepatology, 2024, 29(2), 101280 (https: / / doi.Org / 10.1016 / j.aohep.2023.101280).

[0433] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, disintegrating agent, binding agent, lubricating agent, solvent, adjuvant, sweetening agent, flavouring agent, colouring agent, encapsulating material, or preservative. In one embodiment, each ingredient is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. (See, Remington: The Science and Practice of Pharmacy, 21sted, Lippincott Williams 8i Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5thed, Rowe et al., The Pharmaceutical Press and The American Pharmaceutical Association: 2005; Handbook of Pharmaceutical Additives, 3rded, Ash and Ash, Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, Gibson, CRC Press LLC: Boca Raton, FL, 2004).

[0434] Brief description of the figures

[0435] Figure 1 is a bar chart showing body weight of all groups on Day -1 before the start of the study.Figure 2A is a graph showing body weight of all groups over the course of the study.

[0436] Figure 2B is a bar chart showing the percentage change in body weight from baseline.

[0437] Figures 3A and 3B are bar charts showing the percentage change from baseline for fat mass and lean mass respectively, as measured by Echo MRI.

[0438] Figure 4A is a graph showing the food intake over the course of the study. Figures 4B and 4C are bar charts showing the average daily food intake by weight (g) and calories (kcal) respectively.

[0439] Figure 5 is a bar chart showing total cholesterol levels on Day 29 in each group.

[0440] Figure 6 is a bar chart showing blood glucose levels on Day 23 in each group.

[0441] Figure 7 is a bar chart showing plasma insulin levels on Day 29 in each group.

[0442] Figures 8A and 8B are bar charts showing ALT and AST levels respectively on Day 29 in each group.

[0443] Example

[0444] 4-[7-Fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine (Compound 1) was tested alone and in combination with Semaglutide, a GLP-1 receptor agonist, in a mouse model of obesity.

[0445] OBJECTIVE

[0446] The objective of this preclinical study was to measure the changes in body weight and body fat composition following treatment with 4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine (Compound 1) and / or Semaglutide when given via subcutaneous injection to C57BL / 6J and C57BL / 6J DIO (diet induced obesity) male mice.

[0447] TEST MATERIALS

[0448] The following test articles were used:

[0449] • Vehicle consisting of 5% Kolliphor EL and 95% saline

[0450] • Compound 1 as a suspension in Vehicle

[0451] • Semaglutide as a solution in 5mM sodium phosphate, 5% mannitol, pH 8.0ANIMALS

[0452] Species: Mouse

[0453] Strain: C57BL / 6J C57BL / 6J DIO

[0454] Number of males: 24 48

[0455] Age at pre-dose

[0456] assessments: 15-17 weeks

[0457] FOOD

[0458] Diet: Control Mice

[0459] PMI Nutrition International Certified Rodent Chow No. 5CR4 (14% kcal from fat)

[0460] DIO Mice

[0461] Research Diet: D12492 (high fat diet - 60% kcal from fat) DIO Mice fed on high fat diet from 6 weeks

[0462] Diet Frequency: Ad libitum, except during designated procedures.

[0463] EXPERIMENTAL DESIGN

[0464] Table - Experimental Design

[0465]

[0466] No. = number; QD = once daily; SC = subcutaneous injection

[0467] Administration of Test Articles (Semaalutide, Compound 1 and Vehicle)

[0468] Route of Administration: Subcutaneous bolus

[0469] Treatment Frequency per day: All groups 1-6: QD (lx)

[0470] Treatment Duration: 28 days

[0471] MEASUREMENTS AND RESULTS

[0472] Body Weight

[0473] Individual body weights were recorded three times weekly from Week -1 and throughout the study. Figure 1 shows body weight of all groups before the start of the study.Figures 2A and 2B show that by the end of the study, administration of Compound 1 led to a statistically significant decrease in body weight, whilst a combination of Compound 1 and Semaglutide led to a statistically significant additional decrease in body weight compared to all other DIO groups including Semaglutide alone.

[0474]

[0475] Body composition was analysed on Days -1 and 27. The animals were taken from their home cage and placed into a plastic restrainer compatible with the body composition analysis machine (Echo MRI). The restrainer was placed into the Echo MRI and body composition was assessed.

[0476] Figure 3A shows that whilst administration of Semaglutide alone or Compound 1 alone led to a statistically significant decrease in percentage fat mass, the administration of a combination of Compound 1 and Semaglutide led to a statistically significant additional decrease in the percentage fat mass.

[0477] Figure 3B shows that administration of Semaglutide led to a statistically significant decrease in the percentage lean mass, whereas administration of Compound 1 led to an increase in the percentage lean mass. The difference between Semaglutide and Compound 1 was statistically significant. Moreover, administration of a combination of Compound 1 and Semaglutide reduced the negative effect of lean mass loss seen with Semaglutide alone.

[0478] Food Consumption

[0479] Food consumption was recorded twice weekly from Week -1 and throughout the study. Food consumption was measured quantitatively with food spillage being recorded.

[0480] Figure 4A shows that mice treated with Semaglutide alone initially consumed less food, but that this did not last beyond 9 days, whereas mice treated with a combination of Compound 1 and Semaglutide consumed less food throughout the study period of 28 days. Hence administration of a combination of Compound 1 and Semaglutide led to a superior reduction in food intake. Figures 4B and 4C show that administration of a combination of Compound 1 and Semaglutide led to a statistically significant reduction of the average daily food intake (measured by weight and by calories) compared to Vehicle.Figure 5 shows that whilst Semaglutide alone is able to reduce total cholesterol levels, Compound 1 alone and Compound 1 in combination with Semaglutide led to an additional, statistically significant decrease in total cholesterol levels.

[0481] Figure 6 shows that administration of a combination of Compound 1 and Semaglutide led to a statistically significant reduction of blood glucose levels.

[0482] Figure 7 shows that administration of Semaglutide alone, Compound 1 alone, and a combination of Compound 1 and Semaglutide led to a statistically significant reduction of insulin levels.

[0483] Figures 8A and 8B show that both ALT and AST were elevated in the diet induced obesity (DIO) model relative to animals fed with normal chow and that ALT and AST levels were statistically significantly reduced in all treatment groups by administration of Semaglutide alone, Compound 1 alone, and a combination of Compound 1 and Semaglutide.

[0484] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

Claims1. A method of treating or managing obesity or overweight, comprising administering to an obese or overweight subject a therapeutically effective amount of a THIK-1 modulator.

2. A method of losing weight, comprising administering to a subject an effective amount of a THIK-1 modulator, preferably wherein the subject is obese or overweight.

3. A method of treating or managing MASLD or MASH, comprising administering to a subject in need thereof a therapeutically effective amount of a THIK-1 modulator.

4. A method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, comprising administering to a subject in need thereof a therapeutically effective amount of a THIK-1 modulator.

5. A method of treating or managing obesity or overweight, comprising administering to an obese or overweight subject: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

6. A method of losing weight, comprising administering to a subject: (a) an effective amount of a THIK-1 modulator in combination with (b) an effective amount of a GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

7. A method of treating or managing MASLD or MASH, comprising administering to a subject in need thereof: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

8. A method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, comprising administering to a subject in need thereof: (a) a therapeutically effective amount of a THIK-1 modulator in combination with (b) a therapeutically effective amount of a GLP-1 receptor agonist.

9. The method of any one of claims 1 to 8, wherein the THIK-1 modulator is selected from:4-[7-fluoro-l-(pyridazin-3-ylrnethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;4-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzimidazol-2-yl)- 1,2, 5-oxadiazol-3-amine;4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;or an enantiomer of any of the foregoing;or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

10. The method of any one of claims 1 to 9, wherein the THIK-1 modulator is administered orally or subcutaneously.

11. The method of any one of claims 1 to 10, wherein the THIK-1 modulator is administered once or twice per day.

12. The method of any one of claims 1 to 11, wherein the THIK-1 modulator is administered in an amount of from about 10 mg to about 1,000 mg per day.

13. The method of any one of claims 5 to 12, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

14. The method of any one of claims 5 to 13, wherein the GLP-1 receptor agonist is administered orally or subcutaneously.

15. The method of any one of claims 5 to 14, wherein the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

16. The method of any one of claims 5 to 15, wherein the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

17. The method of any one of claims 5 to 16, wherein the THIK-1 modulator and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

18. The method of any one of claims 5 to 17, wherein administration of the THIK-1 modulator is initiated on the same day as administration of the GLP-1 receptor agonist.

19. The method of any one of claims 5 to 17, wherein administration of the THIK-1 modulator is initiated one or more days after administration of the GLP-1 receptor agonist.

20. The method of any one of claims 5 to 19, wherein administration of the THIK-1 modulator is continued after administration of the GLP-1 receptor agonist has ceased.

21. A THIK-1 modulator for use in the treatment or management of obesity or overweight.

22. A THIK-1 modulator for use in a method of losing weight.

23. A THIK-1 modulator for use in the treatment or management of MASLD or MASH.

24. A THIK-1 modulator for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease.

25. A THIK-1 modulator for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

26. A THIK-1 modulator for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP- 1 receptor agonist, preferably wherein the subject is obese or overweight.

27. A THIK-1 modulator for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

28. A THIK-1 modulator for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject the THIK-1 modulator in combination with a GLP-1 receptor agonist.

29. A GLP-1 receptor agonist for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

30. A GLP-1 receptor agonist for use in a method of losing weight, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

31. A GLP-1 receptor agonist for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

32. A GLP-1 receptor agonist for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject a THIK-1 modulator in combination with the GLP-1 receptor agonist.

33. A THIK-1 modulator and a GLP-1 receptor agonist for use in the treatment or management of obesity or overweight, wherein the treatment or management comprises administering to an obese or overweight subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

34. A THIK-1 modulator and a GLP-1 receptor agonist for use in a method of losing weight, wherein the method comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist, preferably wherein the subject is obese or overweight.

35. A THIK-1 modulator and a GLP-1 receptor agonist for use in the treatment or management of MASLD or MASH, wherein the treatment or management comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

36. A THIK-1 modulator and a GLP-1 receptor agonist for use in a method of reducing a cardiovascular risk factor and / or a risk of cardiovascular disease, wherein the method comprises administering to a subject the THIK-1 modulator in combination with the GLP-1 receptor agonist.

37. The THIK-1 modulator for use of any one of claims 21-28, the GLP-1 receptor agonist for use of any one of claims 29-32, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-36, wherein the THIK-1 modulator is selected from:4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;4-(4,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;or an enantiomer of any of the foregoing;or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

38. The THIK-1 modulator for use of any one of claims 21-28 or 37, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-37, wherein the THIK-1 modulator is administered orally or subcutaneously.

39. The THIK-1 modulator for use of any one of claims 21-28 or 37-38, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-38, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-38, wherein the THIK-1 modulator is administered once or twice per day.

40. The THIK-1 modulator for use of any one of claims 21-28 or 37-39, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-39, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-39, wherein the THIK-1 modulator is administered in an amount of from about 10 mg to about 1,000 mg per day.

41. The THIK-1 modulator for use of any one of claims 25-28 or 37-40, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-40, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-40, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

42. The THIK-1 modulator for use of any one of claims 25-28 or 37-41, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-41, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-41, wherein the GLP-1 receptor agonist is administered orally or subcutaneously.

43. The THIK-1 modulator for use of any one of claims 25-28 or 37-42, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-42, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-42, wherein the GLP-1 receptor agonist is administered once per month, twice per month, once per week, twice per week, once per day, or twice per day.

44. The THIK-1 modulator for use of any one of claims 25-28 or 37-43, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-43, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-43, wherein the GLP-1 receptor agonist is administered in an amount of from about 0.1 mg to about 200 mg per administration dose.

45. The THIK-1 modulator for use of any one of claims 25-28 or 37-44, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-44, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-44, wherein the THIK-1 modulator and the GLP-1 receptor agonist are administered simultaneously, separately or sequentially.

46. The THIK-1 modulator for use of any one of claims 25-28 or 37-45, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-45, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-45, wherein administration of the THIK-1 modulator is initiated on the same day as administration of the GLP-1 receptor agonist.

47. The THIK-1 modulator for use of any one of claims 25-28 or 37-45, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-45, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-45, wherein administration of the THIK-1 modulator is initiated one or more days after administration of the GLP-1 receptor agonist.

48. The THIK-1 modulator for use of any one of claims 25-28 or 37-47, the GLP-1 receptor agonist for use of any one of claims 29-32 or 37-47, or the THIK-1 modulator and the GLP-1 receptor agonist for use of any one of claims 33-47, wherein administration of the THIK-1 modulator is continued after administration of the GLP-1 receptor agonist has ceased.

49. A pharmaceutical composition or kit comprising a THIK-1 modulator and a GLP-1 receptor agonist.

50. The pharmaceutical composition or kit of claim 49, wherein the THIK-1 modulator is selected from:4-[7-fluoro-l-(pyridazin-3-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine;4-[7-fluoro-l-(pyridin-4-ylmethyl)benzimidazol-2-yl]-l,2,5-oxadiazol-3-amine; 3-(4, 7-difluoro- l-(pyridazi n-3-yl methyl)-benzi midazol-2-yl)-4- methyl- 1,2,5-oxadiazole;4-(4,7-difluoro-l-(pyridazin-3-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(7-fluoro-l-(pyridazin-4-ylmethyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;4-(7-fluoro-l-((6-methylpyridazin-3-yl)methyl)-benzimidazol-2-yl)-l,2,5-oxadiazol-3-amine;or an enantiomer of any of the foregoing;or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing.

51. The pharmaceutical composition or kit of claim 49 or 50, wherein the GLP-1 receptor agonist is selected from AMG 133, Amycretin (NNC0487-0111), CagriSema, CT-388, CT-996, Danuglipron, Dapiglutide, Dulaglutide, Efinopegdutide, Exenatide, HM15211, Liraglutide, Lixisenatide, Mazdutide, Orforglipron, Pemvidutide, Retatrutide, SCO-094, Semaglutide, Survodutide, Tirzepatide, or VK2735.

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