Aryl sulfone and sulfanone derivatives as orexin receptor modulators

Abstract

The present invention relates to novel aryl sulfone and sulfanone derivatives of Formula (I) wherein R1, R2, RB1, RB3, X1, X2, X3, X4, Ring A, and Ring B are as described in the description, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and their use as agonists of the orexin-2 receptor (hereinafter also referred to as OX2R), and particularly as agonists of the human orexin-2 receptor (hereinafter also referred to as hOX2R).

Description

[0001] ID 407 A

[0002] Aryl sulfone and sulfanone derivatives as orexin receptor modulators

[0003] The present invention relates to novel aryl sulfone and sulfanone derivatives of Formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and their use as agonists of the orexin-2 receptor (hereinafter also referred to as OX2R), and particularly as agonists of the human orexin-2 receptor (hereinafter also referred to as hOX2R).

[0004] The orexin system (also known as hypocretin system) was discovered in 1998 by two independent research groups and is composed of 2 neuropeptides and 2 receptors (de Lecea L et al.; The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity; Proc Natl Acad Sci U S A. 1998, 95(1 ):322-7; Sakurai T et al.; Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior; Cell. 1998, 92(5): 1 page following 696). Orexin A (OX-A) and orexin B (OX-B) are neuropeptides specifically expressed in a small population of neurons of the lateral, dorsomedial and perifornical hypothalamus. They are proteolytically derived from a single precursor prepro-orexin peptide. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide. Orexins bind to two G-protein-coupled receptors (orexin- 1 receptor (OX1R) and orexin-2 receptor (OX2R)) widely expressed throughout the brain. While OX-A binds to both receptors with similar affinity, OX-B binds preferentially to OX2R. The wide distribution of orexin fibers and receptors in many parts of the brain suggests that orexins have multiple functions.

[0005] The orexin system is recognized as being crucial for the stability of wakefulness and the regulation of vigilance in accordance with various physiological processes (de Lecea L; Hypocretins and the neurobiology of sleep-wake mechanisms; Prog Brain Res. 2012, 198: 15-24; Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci. 2007, 8(3): 171 -81 ; Scammell TE et al.; Neural Circuitry of Wakefulness and Sleep; Neuron. 2017, 93(4):747-765). Orexin neurons are primarily active during wakefulness (Lee MG et al.; Discharge of identified orexin / hypocretin neurons across the sleep-waking cycle; J Neurosci. 2005, 25(28):6716- 20). They send excitatory projections to wake-promoting neuronal populations such as the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons in the ventral tegmental area and cholinergic neurons in the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei. Different wake-promoting regions of the brain predominantly express OX1R or OX2R, or both (for review see (Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci. 2007, 8(3): 171 -81)). OX-A levels in the brain extracellular and cerebrospinal fluid (CSF) follow a circadian rhythm: they rise during the wake period and drop rapidly during sleep. Increasing orexin levels are necessary to compete with the increasing sleep pressure that builds up during long periods of wakefulness, preventing from falling asleep (Gotter AL et al.; The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold; BMC Neurosci. 2013, 14:90; Modirrousta M et al.; Orexin and MCH neurons express c-Fos differently after sleep deprivation vs. recovery and bear different adrenergic receptors; Eur J Neurosci. 2005, 21 (10):2807-16; Zeitzer JM et al.; Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness; J Neurosci. 2003, 23(8):3555-60).

[0006] Moreover, orexin neurons integrate a variety of signals related to internal or external environment (e.g. emotion, light / dark cycles, sleep pressure, energy balance) and send information to a variety of neuronal systems to adjust the arousal level to the one necessary for an appropriate behavioral response (Inutsuka A et al.; The physiological role of orexin / hypocretin neurons in the regulation of sleep / wakefulness and neuroendocrine functions; Front Endocrinol (Lausanne). 2013, 4: 18). For this purpose, they do not only follow a circadian related pattern of activation, but also a behaviour-related burst of firing and are, for example, particularly active in periods of heightened arousal associated with emotion and social interaction (Blouin AM et al.; Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction; Nat Commun. 2013, 4:1547).

[0007] Evidences from human and animal studies have demonstrated that narcolepsy type 1 , a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions), is linked to a deficiency in the orexin system (Chemelli RM et al.; Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation; Cell. 1999, 98(4):437-51 ; Lin L et al.; The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene; Cell. 1999, 98(3):365-76; Peyron C et al.; A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains; Nat Med. 2000, 6(9):991 -7; Thannickal TC et al.; Reduced number of hypocretin neurons in human narcolepsy; Neuron. 2000, 27 (3): 469-74). In human, narcolepsy type 1 has been shown to be caused by the loss of orexin-producing neurons (Peyron C et al.; A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains; Nat Med. 2000, 6(9):991 -7) and low OX-A level in the CSF can be used as specific biological measure for the diagnosis (Dauvilliers Y et al.; Narcolepsy and Other Central Hypersomnias; Continuum (Minneap Minn). 2017, 23(4, Sleep Neurology):989-1004). Several genetic animal models (in both mice and dogs) showed that disruption of orexin signaling leads to a narcoleptic phenotype with excessive daytime sleepiness (fragmented wakefulness) and cataplexy (Lin L et al.; The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene; Cell. 1999, 98(3):365-76; Willie JT et al.; Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes; Neuron. 2003, 38(5):715-30). Central administration of OX-A or ectopic expression of the prepro-orexin transgene in the brain of orexin neuron-ablated mice are able to reversed the narcoleptic phenotype (Mieda M et al.; Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice; Proc Natl Acad Sci U S A. 2004, 101 (13): 4649-54). Those data suggest that an orexin receptor agonist would be an appropriate treatment for narcoleptic patients. In addition, intracerebroventricular (i.c.v.) injections of OX-A in rats or mice increased wakefulness and markedly reduced both non-rapid eye movement (NREM) and REM sleep (Piper DC et al.; The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats; Eur J Neurosci. 2000, 12(2)726-30; Huang ZL et al.; Arousal effect of orexin A depends on activation of the histaminergic system; Proc Natl Acad Sci U S A. 2001 , 98(17):9965- 70). Furthermore, optogenetic or chemogenetic studies showed that stimulation of orexin neurons reduced the latency in sleep-to-wake transition from both NREM and REM sleep and induced wakefulness with a very short latency (Adamantidis AR et al.; Neural substrates of awakening probed with optogenetic control of hypocretin neurons; Nature. 2007, 450(7168): 420-4; Sasaki K et al.; Pharmacogenetic modulation of orexin neurons alters sleep / wakefulness states in mice; PLoS One. 2011 , 6(5):e20360).

[0008] Altogether, it suggests that activation of orexin receptors is a promising therapeutic approach for disease associated with difficulties maintaining wakefulness with patients complaining of: feelings of excessive sleepiness; episodes of inadvertently falling asleep, including sleep attacks (episodes of falling asleep without prodromal symptoms of drowsiness); a prolonged main sleep episode that is unrefreshing; recurrent naps in the same day; and sleep inertia (prolonged difficulty waking up, with irritability, automatic behavior, or confusion).

[0009] These can be seen in sleep disorders such as the disorders of hypersomnolence. Based on the international classification of sleep disorders, 3rdedition (ICSD-3) (Sateia MJ; International classification of sleep disorders-third edition: highlights and modifications; Chest. 2014, 146(5): 1387-1394), central disorders of hypersomnolence include narcolepsy (including narcolepsy type 1 and narcolepsy type 2), idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, hypersomnia associated with psychiatric disorder and insufficient sleep syndrome.

[0010] Narcolepsy is supposed to be the result of an autoimmune disorder which specifically destroy orexin-producing neurons. However, symptoms of narcolepsy (or secondary narcolepsy) can occur during the course of other neurologic disorders and be caused by the underlying condition, e.g. inherited disorders (such as Prader-Willi syndrome, Niemann-Pick C disease, or myotonic dystrophy), tumors or head trauma (particularly when the hypothalamus area is involved) (Kanbayashi T et al.; The pathophysiologic basis of secondary narcolepsy and hypersomnia; Curr Neurol Neurosci Rep. 2011 , 11 (2):235-41; Nishino S et al.; Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin / orexin system; Sleep Med Rev. 2005, 9(4):269-310). Reduced orexin levels in CSF were often seen in those symptomatic narcolepsy and EDS cases.

[0011] Other immune-mediated disorders can show a disruption of orexin neurotransmission with patients presenting symptoms reminiscent of narcolepsy (Fronczek R et al.; The orexin / hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms; Handb Clin Neurol. 2021 , 180:343-358). For some of them, destruction of part of the orexin neurons on top of other cell types have been demonstrated. For example, orexin deficiency in the CSF and narcolepsy-like symptoms have been observed in patients with neuromyelitis optica, multiple sclerosis (Kanbayashi T et al.; The pathophysiologic basis of secondary narcolepsy and hypersomnia; Curr Neurol Neurosci Rep. 2011, 11 (2):235-41 ; Kanbayashi T et al.; Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications; Arch Neurol. 2009, 66(12): 1563-6), Guillain- Barre syndrome (Nishino S et al.; CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies; Neurology. 2003, 61 (6):823-5), or anti-Ma2 encephalitis (Overeem S et al.; Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis; Neurology. 2004, 62(1): 138-40).

[0012] In neurodegenerative disease, EDS and other sleep disturbances are commonly reported. Loss of orexin neurons has been described in several neurodegenerative disease and is suggested to contribute to EDS and the sleep disturbances, including Alzheimer's (Fronczek R et al.; Hypocretin (orexin) loss in Alzheimer's disease; Neurobiol Aging. 2012, 33(8): 1642-50), Parkinson's (Fronczek R et al.; Hypocretin (orexin) loss in Parkinson's disease; Brain. 2007, 130(Pt 6): 1577-85; Fronczek R et al.; Hypocretin (orexin) loss and sleep disturbances in Parkinson's Disease; Brain. 2008, 131 (Pt 1):e88), Lewy body dementia (Kasanuki K et al.; Neuropathological investigation of hypocretin expression in brains of dementia with Lewy bodies; Neurosci Lett. 2014, 569:68-73), Perry syndrome (Mishima T et al.; Reduced orexin immunoreactivity in Perry syndrome and multiple system atrophy; Parkinsonism Relat Disord. 2017, 42:85-89), multiple system atrophy (Benarroch EE et al.; Involvement of hypocretin neurons in multiple system atrophy; Acta Neuropathol. 2007, 113(1)75-80) and Huntington's diseases (Petersen A et al.; Orexin loss in Huntington's disease; Hum Mol Genet. 2005, 14(1 ):39-47).

[0013] EDS can also be observed in circadian rhythm sleep-wake disorders such as for example delayed sleep-wake phase disorder, shift work or jet lag disorder and result from a misalignment between the body clock and social requirements (Sateia MJ; International classification of sleep disorders-third edition: highlights and modifications; Chest. 2014, 146(5): 1387-1394; Gandhi KD et al.; Excessive Daytime Sleepiness: A Clinical Review; Mayo Clin Proc. 2021 , 96(5): 1288-1301 ). It is specially the case when the patient needs to be awake but their alertness level secondary to their internal body clock is at its nadir.

[0014] Likewise, EDS is accompanying disorders such as obesity, diabetes, depression and objective sleep disturbances such as sleep apnea (Fernandez-Mendoza J et al.; Natural history of excessive daytime sleepiness: role of obesity, weight loss, depression, and sleep propensity; Sleep. 2015, 38(3):351-60). Taking in particular the example of obstructive sleep apnea (OSA), it is suggested that dysregulation of the orexin system could play a role in the pathogenesis of this disorder (Wang W et al.; Orexin: a potential role in the process of obstructive sleep apnea; Peptides. 2013, 42:48-54). Low levels of OX-A in plasma were reported in patients suffering from OSA (Busquets X et al.; Decreased plasma levels of orexin-A in sleep apnea; Respiration. 2004, 71 (6):575-9). In addition, in the orexin knockout narcolepsy mouse model, the frequency of spontaneous sleep apneas increased (Nakamura A et al.; Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice; J Appl Physiol (1985). 2007, 102(1 ):241 -8).

[0015] Different from EDS, fatigue is a lack of energy ("an overwhelming sense of tiredness, a feeling of exhaustion") with a reduced ability to perform physical activities that would have previously been easily accomplished. It may be accompanied by mental fatigue with poor concentration and memory, but it is not generally associated with inappropriate episodes of sleep during the day. It is observed in a number of disorders including infections, chronic inflammatory diseases, cancer and neurodegeneration. It is suggested that a dysregulation of the orexin system could contribute to fatigue. In rodents, fatigue (or sickness behavior in animals) induced by lipopolysaccharide was associated with reduced activity of orexin neurons and a reduction of OX-A in the CSF (Grossberg AJ et al.; Inflammation-induced lethargy is mediated by suppression of orexin neuron activity; J Neurosci. 2011 , 31 (31):11376-86). Intracerebroventricular administration of OX-A in lipopolysaccharide-treated rats restored normal home-cage exploratory behavior. Similar findings were retrieved in tumor-bearing rats indicating that the reduction of orexin signaling could play a role in chronic disease.

[0016] In human, Bardsen et al., (Bardsen K et al.; lnterleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjogren's syndrome; J Neuroinflammation. 2019, 16(1): 102) showed that OX-A level was decreased in CSF of patients suffering from primary Sjogren's syndrome, a chronic autoimmune disease clinically characterized by inflammation of the exocrine glands where fatigue is an important symptom (Segal B et al.; Prevalence, severity, and predictors of fatigue in subjects with primary Sjogren's syndrome; Arthritis Rheum. 2008, 59(12): 1780-7).

[0017] It generally suggests that a dysfunction of the orexin system could contribute to fatigue and that an orexin receptor agonist could be helpful in chronically ill patients with fatigue, it could improve their quality of life.

[0018] Traumatic brain injury (TBI) can induce disorders of consciousness (DOC) such as syndromes of coma, vegetative state, and minimally conscious state (O'Donnell JO et al.; Challenges and demand for modeling disorders of consciousness following traumatic brain injury; Neurosci Biobehav Rev. 2019, 98:336-346). Consciousness is a complex state including arousal and awareness and the ascending reticular activating system (ARAS) is known to play an essential role in maintaining consciousness (Edlow BL et al.; Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders; J Neuropathol Exp Neurol. 2012, 71 (6):531- 46). The ARAS is a complex and diffuse network of neuronal fibers that connects the brainstem reticular formation (such as the nuclei containing serotoninergic, noradrenergic, dopaminergic, cholinergic and glutamatergic neurons) with nonspecific thalamic nuclei, the basal forebrain, hypothalamus, and the cerebral cortex. Impairment of the ARAS can cause loss of consciousness following TBI (Jang SH et al.; The Relation Between Loss of Consciousness, Severity of Traumatic Brain Injury, and Injury of Ascending Reticular Activating System in Patients With Traumatic Brain Injury; Am J Phys Med Rehabil. 2019, 98(12): 1067-1071). Monoaminergic drugs acting by increasing for instance dopaminergic levels, norepinephrine levels and acetylcholine levels could have some beneficial impacts on DOC. Given its projections to the wake-promoting system and its contribution to the stabilization of wakefulness / arousal, the orexin system is well placed to support and regulate consciousness. Interestingly, in patients with acute moderate and severe TBI, abnormally low level of OX-A in the CSF was reported (Baumann CR et al.; Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury; Neurology. 2005, 65(1 ): 147- 9). Preclinically, in a mouse model of TBI, it was shown that electromagnetic controlled cortical impact depressed orexin levels in both the hypothalamus and hippocampus, and that the diurnal fluctuation amplitudes of orexins were blunted (Willie JT et al.; Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice; J Neurotrauma. 2012, 29(10): 1908-21). Those data indicate that the orexin system is dysregulated following TBI and an orexin receptor agonist could be a useful therapeutic approach.

[0019] In addition, in a model of unconscious rats induced by acute alcohol intoxication, i.c.v. administration of OX-A or OX-B reduced the duration of right reflex loss, shortened the coma time, and decreased the delta signal of EEG (Jia X et al.; Arousal effects of orexin A on acute alcohol intoxication-induced coma in rats; Neuropharmacology. 2012, 62(2)775-83). It suggests that orexin receptor agonists could have an arousal-promoting effect in coma induced by acute alcohol intoxication. Furthermore, intranasal or i.c.v. administration of OX-A facilitated the recovery of arousal in a cardiac arrest- induced coma rat model (Koenig MA et al.; Intraventricular orexin-A improves arousal and early EEG entropy in rats after cardiac arrest; Brain Res. 2009, 1255:153-61; Modi HR et al.; Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation; PLoS One. 2017, 12(9):e0182707). Orexin agonists could then provide beneficial effects following cardiac failure.

[0020] Additionally, in this model of cardiac arrest, OX-A did not only accelerate arousal and behavior recovery, but it also had some anti-inflammatory effects. Other studies raised the potential role of the orexin system in the regulation of inflammation. For instance, Ogawa et al. (Ogawa Y et al.; Peripherally administered orexin improves survival of mice with endotoxin shock; Elife. 2016, 5) showed that, in a model of septic shock in mice, administration of OX-A helped for survival and recovery and that excessive cytokine production was inhibited. In a mouse model of intracerebral hemorrhage, OX-A improved the neurofunctional outcomes and mitigated brain edema (Li T et al.; Orexin A alleviates neuroinflammation via OXR2 / CaMKKbeta / AMPK signaling pathway after ICH in mice; J Neuroinflammation. 2020, 17(1):187). It is suggested that OX-A was beneficial because of its anti-inflammatory effects.

[0021] Moreover, it is also suggested that orexins facilitate the emergence from anesthetic-induced unconsciousness with anesthesia being either intraperitoneal or gas anesthesia and that inhibiting the orexin signaling delays the emergence (Zhang LN et al.; Orexin-A facilitates emergence from propofol anesthesia in the rat; Anesth Analg. 2012, 115(4)789-96; Kelz MB et al.; An essential role for orexins in emergence from general anesthesia; Proc Natl Acad Sci U S A. 2008, 105(4): 1309-14; Zhang LN et al.; Orexin-A facilitates emergence of the rat from isoflurane anesthesia via mediation of the basal forebrain; Neuropeptides. 2016, 58:7-14; Kushikata T et al.; Orexinergic neurons and barbiturate anesthesia; Neuroscience. 2003, 121 (4): 855-63).

[0022] Besides stabilizing wakefulness, the orexins system seems to play a role in the regulation of many other functions such as energy homeostasis, learning and memory, stress / emotion, reward, and pain. The orexin system is involved in the regulation of feeding behaviors and energy homeostasis. Orexin neurons are sensitive to glucose, leptin and ghrelin with high concentrations of glucose and leptin inhibiting orexinergic neurons, while low concentrations of glucose and ghrelin exciting them (Diano S et al.; Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets; Endocrinology. 2003, 144(9):3774-8; Yamanaka A et al.; Hypothalamic orexin neurons regulate arousal according to energy balance in mice; Neuron. 2003, 38(5):701 - 13). The orexin system is suggested to coordinate the behavioral / wakefulness response to the energy needs (Latifi B et al.; Sleep-Wake Cycling and Energy Conservation: Role of Hypocretin and the Lateral Hypothalamus in Dynamic State-Dependent Resource Optimization; Front Neurol. 2018, 9:790; Chieffi S et al.; Orexin System: The Key for a Healthy Life; Front Physiol. 2017, 8:357). Interestingly, narcoleptic mice show a dysregulation of energy homeostasis. Those mice exhibit obesity despite a significant lower calorie consumption which can be explained, to some extent, by a lower energy expenditure (Zhang S et al.; Sleep / wake fragmentation disrupts metabolism in a mouse model of narcolepsy; J Physiol. 2007, 581 (Pt 2):649-63). In addition, the prevalence of obesity is also increased in narcoleptic patients (Mohammad! S et al.; Metabolic profile in patients with narcolepsy: a systematic review and meta-analysis; Sleep Med. 2021 , 81 :268-284). Studies in rodent models of diet-induced obesity showed that central administration of OX-A protects against obesity (Perez-Leighton CE et al.; Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity; Am J Physiol Endocrinol Metab. 2012, 303(7):E865-74).

[0023] Altogether it suggests that an orexin receptor agonist could be an interesting therapeutic option for the treatment of disease associated with a dysregulation of feeding behaviors or energy homeostasis.

[0024] The orexin system seems to play a role in learning and memory processes. On one hand, given its recognized role for the stability of wakefulness and the regulation of vigilance in accordance with various physiological processes (de Lecea L; Hypocretins and the neurobiology of sleep-wake mechanisms; Prog Brain Res. 2012, 198:15-24; Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci. 2007, 8(3): 171 -81 ; Scammell TE et al.; Neural Circuitry of Wakefulness and Sleep; Neuron. 2017, 93(4)747-765), it will contribute to the sustained arousal level necessary to learn. On the other hand, the orexin neurons also project to areas involved in learning and memory processing such as the hippocampus (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23):9996-10015) which suggest a potential direct effect. Preclinical data have shown that activation of the orexin system can be beneficial for learning and memory. For example, mice data showed that OX-A could contribute to the increase hippocampal plasticity associated with the consolidation of social recognition memory (Yang L et al.; Hypocretin / orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice; J Neurosci. 2013, 33(12):5275-84). Intranasal administration of OX-A improved the performance altered by sleep loss on a short-term memory task in sleep-deprived rhesus monkeys without altering task performance in alert non-sleep-deprived animals (Deadwyler SA et al.; Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates; J Neurosci. 2007, 27(52): 14239-47). In addition, i.c.v. injection of OX-A in wild type mice improved memory processing in 2 different avoidance tasks but also improved memory performance in the senescence-accelerated mouse (SAMP8) strain showing age-related deficits in learning and memory (Jaeger LB et al.; Effects of orexin-A on memory processing; Peptides. 2002, 23(9): 1683-8).

[0025] Cognitive impairment is a common feature of several neuropsychiatric / neurological disorders and of age / age- related dementias. Age is also affecting the orexin system. Indeed in both human and animals, loss of orexin neurons is reported (for review (Nixon JP et al.; Sleep disorders, obesity, and aging: the role of orexin; Ageing Res Rev. 2015, 20:63-73)). Interestingly, age-related impairments in attentional performance could be improved in rats via intranasal administration of OX-A (Galva CB et al.; Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction; Brain Res. 2020, 1731 : 145921 ; Galva CB et al.; Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats; Front Aging Neurosci. 2019, 11 :362) suggesting a therapeutic benefit of orexin receptor agonist for age-related cognitive disorders.

[0026] Furthermore, local intracerebral infusion of OX-A was able to reduced distractor-induced decreases in attention performance in rats (Zajo KN et al.; Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons; Psychopharmacology (Berl). 2016, 233(4):639-47) suggesting that an orexin-receptor agonist could be useful for the treatment of disorders with attentional deficits.

[0027] The orexin system plays a role in behaviours needing motivation (Mahler SV et al.; Motivational activation: a unifying hypothesis of orexin / hypocretin function; Nat Neurosci. 2014, 17(10): 1298-303). And motivation (the psychological drive underlying goal-directed behaviour) is important to organize psychological and physiological processes leading to adaptive behaviours. Motivated behaviours support, for example, food seeking, coordinated stress response and the development of coping strategy. Dysregulation of those processes can lead to neuropsychiatric disorders in which orexin receptor agonists could provide beneficial effects.

[0028] As an example, stimulation of OX2R promoted coping responses in a decision-making test during social stress in mice (in this test: promotion of escape behaviour) (Staton CD et al.; Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression; Neuropharmacology. 2018, 143:79-94). Stimulation of OX2R also increased resilience to social stress (i.e. social novelty seeking) (Staton CD et al.; Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression; Neuropharmacology. 2018, 143:79-94).

[0029] Anhedonia, one of the key symptoms of depression, can be described as the failure to experience pleasure or pursue gratification and encompasses reward-associated disorders such as perturbation in decision-making and motivational drive. Anhedonia symptoms evoke a dysregulation of brain reward processing in which an alteration of the orexin system function could play a role (Coccurello R; Anhedonia in depression symptomatology: Appetite dysregulation and defective brain reward processing; Behav Brain Res. 2019, 372: 112041). Several preclinical and clinical studies have shown a link between dysregulation of the orexin system and depression (Khairuddin S et al.; Dysregulation of the orexinergic system: A potential neuropeptide target in depression; Neurosci Biobehav Rev. 2020, 118:384-396). In Wistar-Kyoto rats, which demonstrate depressive-like behaviours, OX-A immunoreactivity and prepro-orexin mRNA levels were reduced in the hypothalamus compared to Wistar rats (Taheri S et al.; Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats; Neuroreport. 2001 , 12(3):459- 64). In animal models of depression induced by chronic, inescapable stressors such as the social defeat model of chronic stress, downregulation of orexin neurotransmission was observed (Lutter M et al.; Orexin signaling mediates the antidepressant-like effect of calorie restriction; J Neurosci. 2008, 28(12):3071 -5; Nocjar C et al.; The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus; Neuroscience. 2012, 218:138-53). In patients with major depressive disorder (MDD), lower levels of OX-A in the CSF were reported (Brundin L et al.; Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder; Eur Neuropsychopharmacol. 2007, 17(9):573-9) and depressed patients show blunted diurnal variation in CSF orexin levels (Salomon RM et al.; Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects; Biol Psychiatry. 2003, 54(2):96-104).

[0030] In addition, in suicidal attempters, low levels of OX-A in the CSF were correlated with psychiatric symptoms of depression such as lassitude, slowness of movement and higher rating of the overall illness (Brundin L et al.; Orexin and psychiatric symptoms in suicide attempters; J Affect Disord. 2007, 100(1 -3): 259-63).

[0031] Orexin neurons project to many brain regions involved in the regulation of pain, including the spinal dorsal horn, the ventrolateral periaqueductal gray, the rostral ventromedial medulla or the trigeminal caudate nucleus (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23):9996-10015). Administration of orexin into the spinal cord or centrally in brain areas associated with the descending pain regulatory circuits reduces nociceptive responses in animal models of inflammatory pain and in chronic neuropathic pain models. Accordingly, intrathecal injections or local injections in pain-regulating brain areas of orexin receptor antagonists modulate pain responses (for review see: (Kang X et al.; Research progress on the mechanism of orexin in pain regulation in different brain regions; Open Life Sci. 2021 , 16(1):46-52)). In addition, pain threshold is lower in orexin knockout mice following peripheral local inflammation (Watanabe S et al.; Persistent pain and stress activate pain-inhibitory orexin pathways; Neuroreport. 2005, 16(1):5-8). Interestingly, lower CSF orexin levels were reported in patients suffering from cluster headache (Barloese M et al.; Reduced CSF hypocretin-1 levels are associated with cluster headache; Cephalalgia. 2015, 35(10):869-76) and the prevalence of migraine is increased in narcoleptic patients (Dahmen N et al.; Increased frequency of migraine in narcoleptic patients: a confirmatory study; Cephalalgia. 2003, 23(1):14-9).

[0032] Overall, it suggests that orexin receptor agonists could have beneficial effect in the therapeutic approach against pain. US 2014 / 0051700 discloses cyclic guanidinyl OX2R agonists useful for enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag. WO 2014 / 198880 discloses 2-(2-aminophenoxy)-3-chloronaphthalene-1, 4-dione compounds having orexin 2 receptor agonist activities, and their use therapeutic active substances for the treatment of conditions mediated by agonizing the orexin 2 receptor. WO 2017 / 135306 discloses substituted piperidine compounds having an orexin type 2 receptor agonist activity, and their use as prophylactic or therapeutic agents for narcolepsy. WO 2018 / 164191 (English-language family member US 2021 / 0385345) discloses substituted pyrrolidine compounds having an orexin type 2 receptor agonist activity. WO 2019 / 117148 (English-language family member US 2021 / 0078955) discloses sulfonamide derivatives showing an orexin receptor agonist activity. WO 2019 / 027003, WO 2019 / 027058, WO 2020 / 004537 / US 2021 / 198240, WO 2020 / 122092 and WO 2020 / 122093 disclose heterocyclic compounds having orexin type 2 receptor agonist activity. WO 2020 / 167706 discloses 5-alkyl pyrrolidine orexin receptor agonists. Orexin receptor agonists are further reported in WO 2018 / 164192, WO 2021 / 106975, WO 2020 / 158958, US 2021 / 0155636, WO 2020 / 167701 , WO 2021 / 026047, WO 2021 / 107023, WO 2016 / 133160, WO 2021 / 065893, and WO 2019 / 191327.

[0033] Selected indolyl and pyrrolyl aryl sulfones are disclosed as anti-HIV agents (Silvestri R et al., Novel Indolyl Aryl Sulfones Active against HIV-1 Carrying NNRTI Resistance Mutations: Synthesis and SAR Studies, J. Med. Chem. 2003, 46:2482-2493; Ragno R et al., Docking and 3-D QSAR Studies on Indolyl Aryl Sulfones. Binding Mode Exploration at the HIV-1 Reverse Transcriptase Non-Nucleoside Binding Site and Design of Highly Active N-(2- Hydroxyethyl)carboxamide and N-(2-Hydroxyethyl)carbohydrazide Derivatives, J. Med. Chem. 2005, 48:213-223; Ragno R et al., Design, Molecular Modeling, Synthesis, and Anti-HIV-1 Activity of New Indolyl Aryl Sulfones. Novel Derivatives of the lndole-2-carboxamide, J. Med. Chem. 2006, 49:3172-3184; Chamjangali A, Modelling of cytotoxicity data (CC50) of anti-HIV 1-[5-chlorophenyl)sulfonyl]-1 H-pyrrole derivatives using calculated molecular descriptors and levenberg-marquardt artificial neural network, Chemical Biology and Drug Design, 2009, 73(4):456- 465; Xu H et al., Development of indoles an anti-HIV-1 inhibitors, Current Pharmaceutical Design, 2009, 15(18):2120-2148). Selected benzene sulfonamide derivatives are disclosed as Smac analogs for cancer (Baravkar S et al. Synthesis and anticancer activity of conformationally constrained Smac mimetics containing pseudo |3 turns. Tetrahedron Letters, 2018, 59 (38): 3473-3476). Selected benzene sulfonamide derivatives are further disclosed in Vijayadas K et al., Reversal of H-bonding direction by N-sulfonation in a synthetic reverse-turn peptide motif (Organic and Biomolecular Chemistry, 2015, 13(10):3064-3069) and in Vijayadas K et al., An unusual conformational similarity of two peptide folds featuring sulfonamide and carboxamide on the backbone. (Chemical Communications, 2012, 48(78):9747-9749). Certain benzene sulfonamide derivatives are disclosed as selective potassium channel activators (Mattmann M et al., Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective Kv7.1 (KCNQ1) potassium channel activator, 2012, 22(18):5936-5941). WO 2005 / 097162 describes selected aryl sulfonyl derivatives as steroid sparing agents. WO 00 / 04892, WO 2010 / 007027, US 2003 / 0130506 and US 5,753,653 each disclose certain hydroxamic acid-comprising benzene sulfonyl derivatives as MMP inhibitors. US 2001 / 0056184 describes pipecolinic acid derivatives as MMP inhibitors. WO 97 / 18194 and US6225311 discloses certain hydroxamic acidcomprising benzene sulfonamide derivatives as MMP and TACE inhibitors, respectively. WO 2005 / 030728 describes selected aryl sulfonamide derivatives as MMP inhibitors. WO 2013 / 020440 discloses certain aryl sulfonamide derivatives as 11-p hydroxy steroid dehydrogenase type I inhibitors. EP0469984 refers to N-sulfonyl- indoline derivatives as binding to vasopressin and oxytocin receptors. WO 2014 / 098098 describes selected aryl sulfonamide antagonists of TRPA1. JP 2006124387, referring to MCH receptor antagonists, discloses certain sulfone-comprising pyridine derivatives.

[0034] WO 2012 / 025877 discloses certain proline sulfonamide derivatives as orexin receptor antagonists. WO 2008 / 038251 describes selected non-peptide antagonists of orexin receptors. Further orexin receptor antagonists are described in: WO 2002 / 051838, WO 2004 / 004733, WO 2004 / 085403, WO 2005 / 118548, WO 2008 / 020405, WO 2008 / 026149, WO 2008 / 065626, WO 2008 / 078291, WO 2008 / 081399, WO 2008 / 087611, WO 2008 / 117241,

[0035] WO 2008 / 139416, WO 2009 / 004584, WO 2009 / 016560, WO 2009 / 016564, WO 2009 / 022311, WO 2009 / 040730,

[0036] WO 2009 / 104155, WO 2009 / 133522, WO 2009 / 150614, WO 2009 / 156951, WO 2010 / 004507, WO 2010 / 038200,

[0037] WO 2010 / 131191, WO 2010 / 131192, WO 2012 / 063207, and WO 2012 / 110986.

[0038] The following compounds are known as chemical library compounds: 1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-piperidinecarboxamide (CAS no. 2174271-82-8); 1 -([1,1'-biphenyl]-2-ylsulfonyl)-N-methyl-2-piperidinecarboxamide (CAS no. 2421462-12-4); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-pyrrolidinecarboxamide (CAS no. 1956132-61-8); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 1951549-56-6); 1 -([1,1'-biphenyl]-2-ylsulfonyl)-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 2180339-78-8); N-cyclopropyl-1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-2-pyrrolidinecarboxamide (CAS no. 1957026-44-6); 1-([1,T-biphenyl]-2-ylsulfonyl)-N-propyl-2-pyrrolidinecarboxamide (CAS no. 1101182-03-9); 1-[(4-ethoxy-3-pyridinyl)sulfonyl]-2-(methoxymethyl)-N-methyl-2-pyrrolidinecarboxamide (CAS no. 2223951-41-3); N, N-diethyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 1444098-57-0); N-(1, 1-dimethylethyl)-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 2175321- 07-8); N-cyclopropyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-4-thiazolidinecarboxamide (CAS no. 1953618- 16-0); 3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-N-(1-methylethyl)-4-thiazolidinecarboxamide (CAS no. 2174321-10-7); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-cyclopropyl-N-methyl-4-thiazolidinecarboxamide (CAS no. 1315694-49- 5); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(2-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1315666-22-8); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(cyclopropylmethyl)-4-thiazolidinecarboxamide (CAS no. 1316038-32-0); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(1-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1316017-19-2); [3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 1948116-54-8); [1-([1,1'-biphenyl]-2-ylsulfonyl)-2-piperidinyl]-1 -pyrrolidinylmethanone (CAS no. 1277333-36-4); [3-([1,T-biphenyl]-2-ylsulfonyl)-4-thiazolidinyl]-4-thiomorpholinylmethanone (CAS no. 1259167-90-2); [(2S,4R)-1-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-fluoro-2-pyrrolidinyl]-4-morpholinylmethanone (CAS no. 1941933-69-2); [3-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 2174528-45-9); and [1 -[(4-ethoxy-3-pyridinyl)sulfonyl]-2-pyrrolidinyl]-4-thiomorpholinylmethanone (CAS no. 1945338-12-4).

[0039] 1) A first aspect of the invention relates to compounds of the Formula (I) wherein

[0040] Ring B is a 6-membered aromatic ring, wherein independently:

[0041] • in said Ring B X1represents N or CRB2, wherein RB2represents hydrogen, halogen (especially fluoro), or (Ci-3)alkyl (especially methyl), and X2represents CH; [notably such X1represents CH, C-CH3, or N]; or X1represents CH and X2represents N; and

[0042] • RB1represents hydrogen, (Ci-3)alkyl (especially methyl, ethyl, or isopropyl), (Ci-3)alkoxy (especially methoxy), halogen (especially fluoro or chloro), (C2-4)al keny I (especially -CH=CH2), monocyclic (C3-e)cycl oalky I (especially cyclopropyl or cyclobutyl), or (Ci-3)fluoroalkyl (especially trifluoromethyl); and

[0043] • RB3represents: OR01, wherein R01represents (C2-s)alkyl (especially ethyl, propyl, isopropyl, sec-butyl, or isobutyl) that is substituted with zero, one or two (Ci)fluoroalkyl (especially difluoromethyl or trifluoromethyl); wherein R01contains a total of at least 3 carbon atoms; [notably OR01represents propoxy, isopropoxy, sec-butoxy, isobutoxy, (1 , 1 -d if I uoropropan-2-y l)-oxy , (3, 3-d ifl uoro-2, 2-d I methy l-propy l)-oxy , (1 ,1 ,1 -trifl uoropropan-2- yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1 ,1 , 1 ,3, 3, 3- hexafluoropropan-2-yl)-oxy; in particular OR01represents sec-butoxy]; NRN1RN2, wherein independently:

[0044] ■ RN1represents:

[0045] • hydrogen; or

[0046] • (Ci-3)alkyl (especially methyl, ethyl, or isopropyl); and ■ RN2represents:

[0047] • (C2-5)alkyl (especially propyl, isopropyl, sec-butyl, or fert-butyl); wherein said (C2-5)alkyl is unsubstituted, or mono- or di-substituted (especially unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (Ci)fluoroalkyl (especially trifluoromethyl), (C^cycloalkyl (especially cyclopropyl), and (Ci-3)alkoxy (especially methoxy); or

[0048] • monocyclic (C3-5)cycloalkyl (especially cyclopropyl), wherein said monocyclic (C3-5)cycloalkyl is unsubstituted or mono-substituted with (Ci-s)alkyl (especially methyl); and especially wherein the total number of carbon atoms in RN1and RN2is at least 3;

[0049] [notably such group NRN1RN2represents isopropyl-amino, sec-butyl-amino, terf-butyl-amino, (l-methyl-cyclopropyl)-amino, (l-cyclopropyl-ethyl)-amino, (1 -methoxy propan-2-yl)-ami no, (1, 1 ,1 -tr if I uoropropan-2-y l)-ami no, (1 , 1 ,1 -trifl uorobu tan-2 -y I )-am I no, (1 -cy clopropy I-2, 2, 2- trifluoroethyl)-amino, (isopropyl)-(methyl)-amino, (ferf-butyl)-(methyl)-amino, (cyclopropyl)- (methyl)-amino, diethyl-amino, (ethyl)-(isopropyl)-amino, (cyclopropyl)-(ethyl)-amino, (sec- butyl)-(ethyl)-amino, diisopropyl-amino, (isopropyl)-(2-methoxyethyl)-amino, or (ethyl)-(1- methoxypropan-2-yl)-amino]; or

[0050] ■ RN1and RN2together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), (Ci. 2)fluoroalkyl (especially trifluoromethyl or 2,2,2-trifluoroethyl), and (Ci^)alkoxy-(Ci-3)alkyl (especially methoxymethyl); [notably such group NRN1RN2represents pyrrolidin-1 -yl, piperidin-1 - yl, 2-methylpyrrolidin-1-yl, 2-(trifluoromethyl)pyrrolidin-1-yl, 2-methylpiperidin-1-yl, 3- fluoropiperidin-1-yl, 4-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2- (methoxymethyl)piperidin-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2,3-dimethylpyrrolidin-1-yl, 2-ethyl-5- methylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1 -yl, azepan-1-yl, 3-methylmorpholin-4-yl, 3-(2,2,2- trifluoroethyl)morpholin-4-yl, or 3,5-dimethylmorpholin-4-yl]; or

[0051] ■ RN1and RN2together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom; [notably such group NRN1RN2represents 2-azabicyclo[2.2.1]heptan-2-yl, 7- azabicyclo[2.2.1 heptan-7-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, or 3-oxa-8- azabicyclo[3.2.1]octan-8-yl)]; or a saturated or mono-unsaturated monocyclic (C5-z)cycloalkyl (notably cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1 -yl, cycloheptyl, or cyclohept-1-en-1-yl); wherein said (C4-6)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-s)al ky I (especially methyl) or halogen (especially fluoro); [notably such RB3represents cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1-yl, cycloheptyl, cyclohept-1-en-1-yl, 2-methylcyclohexyl, 2-methylcyclohex-1- en-1 -yl, 6-methylcyclohex-1-en-1-yl, 4,4-dimethylcyclohex-1-en-1-yl, or 4,4-difluorocyclohex-1-en-1-yl]; or 5,6-dihydro-2H-pyran-3-yl; or a saturated or mono-unsaturated bridged bicyclic (C6-8)cycloalkyl; [notably such RB3represents bicyclo[2.2.1 ]heptanyl or bicyclo[2.2.1 ]hept-2-en-2-yl]; or phenyl or 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from N, 0, and S (notably isothiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl); wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or mono-, or di- or tri-substituted (especially mono-, di- or tri-substituted, wherein especially at least one substituent is in para position with regard to the point of attachment of the rest of the molecule); wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro or chloro), (Ci-s)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), (Ci-3)alkoxy (especially methoxy), (Ci^)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), and cyano; [notably such RB3represents phenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-cy anophenyl, 2-methoxyphenyl, 2- (trifluoromethoxy)phenyl, 4-fluorophenyl, 2-fluoro-3-methylphenyl, 2,3-difluorophenyl, 2-chloro-3- fluorophenyl, 3-chloro-2-fluorophenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-6-methylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 2-fluoro-6- methoxyphenyl, isothiazol-3-yl, 4-methylisothiazol-3-yl, oxazol-2-yl, 5-methyloxazol-2-yl, 5-methyl-1 H- pyrazol-1-yl, 5-ethyl-1 H-pyrazol-1-yl, 5-cyclopropyl-1 H-pyrazol-1-yl, 2 / 7-1,2,3-triazol-2-yl, 2-methylpyridin- 3-yl, 2-fluoropyridin-3-yl, 2-chloropyridin-3-yl, 2-cyanopyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoropyridin-3- yl, 4-chloropyridin-3-yl, 4-cyanopyridin-3-yl, 3-methylpyridin-2-yl, 3-fluoropyridin-2-yl, 3-chloropyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 3-methoxypyridin-2-yl, 2-chloro-4-methylpyridin-3-yl, 2,4-difluoropyridin-3- yl, 3-methylpyrazin-2-yl, 3-fluoropyrazin-2-yl, or 3-methoxypyrazin-2-yl]; and

[0052] X3represents 0 or NRN3, wherein RN3represents hydrogen, (Ci-s)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom (especially oxetanyl or tetrahydrofuranyl), a 5-membered saturated bridged bicyclic cycloalkyl (especially bicyclo[1.1.1]pentanyl), phenyl, or pyridinyl; [notably X3represents 0, N-methyl, NH, or N-cyclopropyl]; and

[0053] X4represents CH or N such that: when X4represents CH, Ring A represents a monocyclic (C5-6)cycloalkan-diyl; or when X4represents N, Ring A represents: • a 4- to 7-membered (notably 5- to 7-membered) saturated monocyclic heterocycloalkan-diyl comprising X4, and zero or one further ring heteroatom selected from 0 or S (especially azetidin-diyl, pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl; in particular pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl); wherein said saturated heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl), halogen (especially fluoro), (Ci^alkoxy (especially methoxy), (Ci-3)alkylidene (especially H2C=), and oxo; [notably such Ring A represents azetidin-1 ,2- diyl, 4-methylazetidin-1 ,2-diyl, 3,3-difluoroazetidin-1 ,2-diyl, pyrrolidin-1 ,2-diyl, 5-methylpyrrolidin-1,2- diyl, 4-methylpyrrolidin-1,2-diyl, 4-fluoropyrrolidin-1 ,2-diyl, 3-fluoropyrrolidin-1 ,2-diyl, 4- methoxypyrrolidin-1,2-diyl, 4-methylenepyrrolidin-1 ,2-diyl, 4-oxopyrrolidin-1 ,2-diyl, 4,4- dimethy I pyrrol idi n- 1 ,2-diyl, 4, 4-d ifluoropy rrol id I n- 1 ,2-diyl, piperidin-1 ,2-diyl, azepan-1 ,2-diyl, thiazolidin-2,3-diyl, thiazolidin-3,4-diyl, oxazolidin-3,4-diyl, oxazolidin-2,3-diyl, 1 ,3-oxazinan-2,3-diyl, or morpholin-3,4-diyl]; or

[0054] • a 4- to 6-membered (notably 5-membered) mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom (especially dihydro-1 / 7-pyrrol-diyl, dihydropyridin- 1 (2 / - / )-diyl, or dihydro-1 / 7-pyrazol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4; wherein said mono-unsaturated heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci-s)alkyl (especially methyl); [notably such Ring A represents 2, 5-d i hydro- 1 / 7-py rrol- 1 ,2-diyl, 2, 3-d i hydro- 1 / 7-py rrol- 1 ,5-diyl, 3, 6-d I hydropy ri di n-1 (2 / 7)- 1 ,2-diyl, 4,5-dihydro-1 H-pyrazol-1 ,5-diyl, or 3-methyl-4,5-dihydro-1 / 7-pyrazol-1,5-diyl]; or

[0055] • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom (notably hexahydrocyclopenta[b]pyrrol-1 (2 / 7),2-diy I, hexahydro-4 / - / - furo[3,2-b]pyrrol-4,5-diyl, azabicyclo[2.1.1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, or azaspiro[2.4]heptan-diyl; in particular azabi cyclo [2.1 .1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, azaspiro[2.4]heptan-diyl, or 6- azaspiro[2.5]octan-diyl); wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or monosubstituted with (Ci-s)alkyl (especially methyl) or di-substituted with fluoro; [notably such Ring A represents hexahydrocyclopenta[b]pyrrol-1 (2 / 7),2-diyl, hexahydro-4H-furo[3,2-b]pyrrol-4,5-diyl, 4- methyl-2-azabicyclo[2.1 ,1]hexan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3- azabicyclo[3.1 .0] hexan-2, 3-diy 1 , 2-azabicyclo[2.2.1 ]heptan- 1 ,2-diyl, 5-azaspi ro[2.4]heptan-4, 5-diy 1, 5- azaspiro[2.4]heptan-5,6-diyl, 1, 1-difluoro-5-azaspiro[2.4]heptan-5,6-diyl, or 6-azaspiro[2.5]octan-5,6- diyl]; and

[0056] R1represents: hydrogen; or (Ci-3)alkyl (especially methyl or ethyl); wherein said (Ci-3)alkyl is unsubstituted, or mono-substituted with (Ci-3)alkoxy (especially methoxy); and

[0057] R2represents: (Ci-6)alkyl (especially linear (C2-e)alkyl or branched (C3-e)alkyl); wherein said (Ci-e)alkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently halogen (especially fluoro or chloro) or (Ci-3)alkoxy (especially methoxy); or -(CH2)q-Cy1; wherein q is 0 or 1 (especially 0) and Cy1represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl or isopropyl), (Ci-3)alkoxy (especially methoxy), cyano, and hydroxy; [notably such R2represents (cyclopropyl)methyl, 2- isopropylcyclopropyl, (2-trifluoromethyl)-cyclopropyl, (difluorocyclopropyl)methyl, cyclobutyl, (cyclobutyl)methyl, 3-(trifluoromethyl)cyclobutyl, 3-(difluoromethyl)cyclobutyl, 3-methoxycyclobutyl, 3,3- dimethylcyclobutyl, 3,3-difluorocyclobutyl, (3,3-difluorocyclobutyl)methyl, (cyclopentyl)methyl, 1- cyanocyclopentyl, 1 -fluorocyclopentyl, 2-fluorocyclopentyl, 2-methoxycyclopentyl, 2-cyanocyclopentyl, 3- fluorocyclopentyl, 3-cyanocyclopentyl, 3-hydroxycyclopentyl, 3-methoxycyclopentyl, (1- fluorocyclopentyl)methyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl. 1 -methylcyclohexyl,

[0058] 2-methylcyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl, 3-methylcyclohexyl, 3-hydroxycyclohexyl,

[0059] 3-methoxycyclohexyl, 3-cyanocyclohexyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4, 4-di methylcyclohexyl, 4,4-difluorocyclohexyl, or cycloheptyl]; or -(CH2)n-Cy2; wherein n is 0 or 1 (especially 0) and Cy2represents a 4- to 7-membered saturated or monounsaturated (especially saturated) monocyclic heterocycle comprising one ring heteroatomic group selected from -O-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- (notably said heterocycle is oxetanyl, tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, 3,6-dihydro-2 / 7-pyranyl, tetrahydro-2H-thiopyran-1,1 -dioxide, 1- imino-1-oxidohexahydro-1-A6-thiopyranyl, or 1 -methylimino-1-oxidohexahydro-1-A6-thiopyranyl); in particular said heterocycle is tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, or tetrahydro-2 / 7-thiopyran-1,1- dioxide); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci^)fluoroalkyl (especially difluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl), and (Ci-3)alkoxy (especially methoxy); [notably such R2represents [3-(difluoromethyl)oxetan-3-yl]methyl, tetrahydrofuran-3-yl, 3-methyltetrahydrofuran-3-yl, (3- methyltetrahydrofuran-3-yl)methyl, tetrahydro-2 / 7-pyran-4-yl, (tetrahydro-2H-pyran-3-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, 4-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2 / 7-pyran-4-yl, 3- methoxytetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2 / 7-pyran-4-yl, 5,5-difluorotetrahydro-2H-pyran-2-yl, 6,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6-dimethyltetrahydro-2 / - / - pyran-4-yl, 2J2-dimethyltetrahydro-2 / 7-pyran-4-yl, 5-fluoro-3,6-dihydro-2 / - / -pyran-2-yl, 1 ,1- dioxidotetrahydro-2 / 7-thiopyran-4-yl, 1-imino-1-oxidohexahydro-1-A6-thiopyran-4-yl, or 1-methylimino-1- oxidohexahydro-1-A6-thiopyran-4-yl]; or -(CH2)m-Cy3; wherein m is 0 or 1 (especially 0) and Cy3represents a saturated spiro, fused, or bridged bicyclic (C^cycloalkyl (notably bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said bicyclic (Cs-sjcycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from halogen (especially fluoro) or (Ci^alkyl (especially methyl); [notably such R2represents bicyclo[1 .1 .1]pentan-1-yl, 3-methylbicyclo[1 .1 .1]pentan-1-yl, bicyclo[3.1.0]hexan-2-yl, spiro[2.3]hexan-5-yl, 1 ,1-difluorospiro[2.3]hexan-5-yl, spiro[3.3]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-1-yl, (bicyclo[2.1.1]hept-2-yl)methyl, spiro[2.4]heptan-5-yl, 1 , 1-difluorospiro[2.4]heptan-5-yl, spiro[2.4]heptan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-6-yl, or 1 ,1- difluorospiro[2.5]octan-6-yl]; or a 7-membered saturated spiro or bridged bicyclic heterocycle comprising one ring oxygen atom (notably 2- oxaspiro[3.3]heptanyl or 7-oxabicyclo[2.2.1]heptanyl); [notably such R2represents 2-oxaspiro[3.3]heptan- 6-yl or 7-oxabicyclo[2.2.1]heptan-2-yl]; or

[0060] R1and R2together with the nitrogen to which they are attached form:

[0061] • a 5- or 6-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S (notably said 5- or 6-membered heterocycle is pyrrolidine, piperidine, thiazolidine, thiomorpholine, or morpholine); wherein said 5- or 6-membered heterocycle is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: hydroxy, (Ci-3)fluoroalkyl (especially trifluoromethyl), halogen (especially fluoro), (Ci^alkyl (especially methyl), (Ci-3)alkyl-(Ci-3)alkoxy (especially methoxymethyl or ethoxymethyl), ethynyl, and (Ci-3)alkoxy (especially methoxy or ethoxy); [notably such heterocycle represents 2-(methoxymethyl)pyrrolidin-1 -yl, 2-(ethoxymethyl)pyrrolidin-1 - yl, 3-methylpyrrolidin-1 -yl, 2,3-dimethylpyrrolidin-1 -yl, 2,5-dimethylpyrrolidin-1-yl, 3,3- dimethylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4,4-difluoro-2-methylpyrrolidin-1-yl, 2- methylpiperidin-1 -yl, 2-(methoxymethyl)piperidin-1-yl, 3-methylpiperidin-1-yl, 3-fluoropiperidin-1-yl, 3- hydroxypiperidin-1-yl, 4-methylpiperidin-1-yl, 4-fluoropiperidin-1 -yl, 4-(trifluoromethyl)piperidin-1 -yl, 4- ethynylpiperidin-1-yl, 3,3-difluoropiperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4-methoxy-3,3-dimethylpiperidin-1 -yl, thiazolidin-3-yl, thiomorpholin-4-yl, 2- (methoxymethyl)morpholin-4-yl, 2-(trifluoromethyl)morpholin-4-yl, or 3,5-dimethylmorpholin-4-yl]; or

[0062] • a 7- to 11-membered (especially 8-membered) saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms (notably said heterocycle is 2- azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan-

[0063] 6-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan- 2-yl, 1-oxa-6-azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[5.5]undecan-8-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 1 ,4-dioxa-8-azaspiro[4.6]undecan-8- yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, or 8-azaspiro[4.5]decan-8-yl; in particular said heterocycle is 6- azaspiro[2.5]octan-6-yl); wherein said heterocycle is unsubstituted or mono-substituted with hydroxy; or

[0064] • an 8- to 10-membered saturated or mono-unsaturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom (notably said heterocycle is hexahydrocyclopenta[c]pyrrol-2(1 / - / )-yl, octahy d roq ui nol I n-1 (2 / 7)-y I , hexahy d rofu ro[3, 2-c] py rid I n- 5(4 / - / )-yl, or 1 ,3,3a, 4,7, 7a-hexahydro-2 / - / -isoindol-2-yl); or

[0065] • a 7- to 9-membered (especially 7- to 8-membered) saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom (notably said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; in particular said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl or 8-azabicyclo[3.2.1]octan-8-yl); wherein said 7- to 9-membered bridged heterocycle is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: hydroxy, halogen (especially fluoro), (Ci^)alkyl (especially methyl), and (Ci -3)alkoxy (especially methoxy or ethoxy); [notably such 7- to 9-membered bridged heterocycle represents 7-azabicyclo[2.2.1]heptan-7-yl, 2-hydroxy-7-azabicyclo[2.2.1]heptan-

[0066] 7-yl, 2-methoxy-7-azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-methyl-8- azabicyclo[3.2.1]octan-8-yl, 3-methoxy-8-azabicyclo[3.2.1]octan-8-yl, 3-ethoxy-8- azabicyclo[3.2.1]octan-8-yl, 3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl, 1 ,3,3-trimethyl-8- azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 9-aza-bicyclo[3.3.1]non-9-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl]; or

[0067] • a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms (notably 2-azaadamantan-2-yl or 2-oxa-6-azaadamantan-6-yl); with the exception of the following compounds: 1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-piperidinecarboxamide (CAS no. 2174271-82-8); 1 -([1 ,1 '-biphenyl]-2-ylsulfonyl)-N-methyl-2-piperidinecarboxamide (CAS no. 2421462-12-4); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-pyrrolidinecarboxamide (CAS no. 1956132-61-8); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 1951549-56-6); 1 -([1 ,T-biphenyl]-2-ylsulfonyl)-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 2180339-78-8); N-cyclopropyl-1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-2-pyrrolidinecarboxamide (CAS no. 1957026-44-6); 1-([1JT-biphenyl]-2-ylsulfonyl)-N-propyl-2-pyrrolidinecarboxamide (CAS no. 1101182-03-9); 1-[(4-ethoxy-3-pyridinyl)sulfonyl]-2-(methoxymethyl)-N-methyl-2-pyrrolidinecarboxamide (CAS no. 2223951-41-3); N,N-diethyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 1444098-57-0); N-(1 , 1-dimethylethyl)-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 2175321- 07-8); N-cyclopropyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-4-thiazolidinecarboxamide (CAS no. 1953618- 16-0); 3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-N-(1-methylethyl)-4-thiazolidinecarboxamide (CAS no. 2174321-10-7); 3-([1 ,T-biphenyl]-2-ylsulfonyl)-N-cyclopropyl-N-methyl-4-thiazolidinecarboxamide (CAS no. 1315694-49- 5); 3-([1JT-biphenyl]-2-ylsulfonyl)-N-(2-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1315666-22-8); 3-([1JT-biphenyl]-2-ylsulfonyl)-N-(cyclopropylmethyl)-4-thiazolidinecarboxamide (CAS no. 1316038-32-0); 3-([1 ,T-biphenyl]-2-ylsulfonyl)-N-(1-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1316017-19-2); [3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 1948116-54-8); [1-([1,1'-biphenyl]-2-ylsulfonyl)-2-piperidinyl]-1 -pyrrolidinylmethanone (CAS no. 1277333-36-4); [3-([1,T-biphenyl]-2-ylsulfonyl)-4-thiazolidinyl]-4-thiomorpholinylmethanone (CAS no. 1259167-90-2); [(2S,4R)-1-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-fluoro-2-pyrrolidinyl]-4-morpholinylmethanone (CAS no. 1941933-69-2); [3-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 2174528-45-9); and [1 -[(4-ethoxy-3-pyridinyl)sulfonyl]-2-pyrrolidinyl]-4-thiomorpholinylmethanone (CAS no. 1945338-12-4).

[0068] The compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration. The compounds of Formula (I) may further encompass compounds with one or more double bonds which may be present in Z- or E-configuration and / or compounds with substituents at a ring system which may be present, relative to each other, in cis- or transconfiguration. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

[0069] In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched, especially essentially pure, form. In case a particular compound (or generic structure) contains one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration, but where one (or more) of said stereogenic or asymmetric centers is not explicitly designated as (R)- or (S)-, it is understood that said stereogenic or asymmetric center may be in (R)- or (S)-configuration. Such compound name or generic structure is understood to encompass the compound I generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center. Likewise, in case such stereogenic or asymmetric center is designated as being in (RS)-configuration, this means that such stereogenic or asymmetric center in such compound may be present in (R)-configuration, in (S)-configuration, or in any mixture of epimers with regard to such center. In case two or more such stereogenic or asymmetric centers (in undesignated or designated (RS)-configuration) are present in one molecule, it is understood that the order of absolute configuration does not indicate any defined relative configuration with regard to the two or more centers.

[0070] In case any defined relative configuration with regard to the two or more centers is present, such centers are denominated with (R*,R*) or (R*,S*) nomenclature indicating in the first instance that the respective centers are either (R,R) or (S,S), and in the second instance that the respective centers are either (R,S) or (S,R), in each case encompassing any mixture of these stereoisomers including the racemate. It is understood that explicitly designated (R)- or (S)-configuration, undesignated or designated (RS)-configuration, and relative (R*,R*)- or (R*,S*)- configuration can co-exist in one and the same molecule and are to be interpreted accordingly. For example, the compound (2R*,4R*)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide encompasses enantiomerically enriched (2R,4R)-1-[2-(Ethyl- isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide, (2S,4S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide, or any mixture of these stereoisomers of said compound.

[0071] In case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond).

[0072] In case a particular compound (or generic structure) is designated as Sa- or Ra-stereoisomer (i.e., designating an conformational isomer, or atropisomer, arising from a hindered rotation around a single bond), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form.

[0073] The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90: 10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer I the entirety of the respective other stereoisomers.

[0074] The term "essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer I the entirety of the respective other stereoisomers.

[0075] The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of Formula (I) according to embodiments 1) to 27), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

[0076] In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below is the 4,4-difluorocyclohexyl group.

[0077] In some instances, the compounds of Formula (I) may contain tautomeric forms. Such tautomeric forms are encompassed in the scope of the present invention. In case tautomeric forms exist of a certain residue, and only one form of such residue is disclosed or defined, the other tautomeric form(s) are understood to be encompassed in such disclosed residue.

[0078] Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

[0079] Any reference to compounds of Formula (I) according to embodiments 1) to 27) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

[0080] The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts depending on the presence of basic and / or acidic groups in the subject compound. For reference see for example "Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystal s”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

[0081] Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1) to 27), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

[0082] Whenever a substituent is denoted as optional, it is understood that such substituent may be absent, in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and I or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.

[0083] The term "halogen” means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.

[0084] The term "alkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (Ci-e)alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fert-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, and 3,3-dimethyl-butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. Examples of RB1representing (Ci-3)alkyl are methyl, ethyl, and isopropyl. An example of RB2representing (Ci-3)alkyl is methyl. Examples of R01representing (C2-5)alkyl are ethyl, propyl, isopropyl, sec-butyl, and isobutyl; such R01representing (C^alkyl may be unsubstituted or substituted as explicitly defined. Examples of RN1representing (Ci-s)alkyl are methyl, ethyl, and isopropyl. Examples of RN2representing (C^alkyl are propyl, isopropyl, sec-butyl, and fert-butyl; such RN2representing (C2-5)alkyl may be unsubstituted or substituted as explicitly defined. Examples of (Ci-s)alkyl as substituent of a group RB3are methyl and ethyl, and especially methyl. Examples of RN3representing (Ci-s)alkyl are methyl and ethyl. An example of (Ci-s)alkyl as substituent of Ring A is methyl. Examples of R1representing (Ci-3)alkyl are methyl and ethyl; such R1representing (Ci-3)alkyl may be unsubstituted or substituted as explicitly defined. Examples of R2representing (Ci-e)alkyl are methyl, ethyl, propyl, isopropyl, 2,2-dimethyl-propyl, n-butyl, 3- methyl-butyl, 3,3-dimethyl-butyl, and fert-butyl; such R2representing (Ci^alkyl may be unsubstituted or substituted as explicitly defined. Examples of (Ci-s)alkyl as substituent of a group Cy1are methyl and isopropyl. An example of (Ci-3)alkyl as substituent of a group Cy2or Cy3is methyl. An example of (Ci^)alkyl as substituent of a 5- or 6- membered saturated monocyclic heterocycle formed by R1and R2, together with the nitrogen to which they are attached, is methyl. An example of (Ci-3)alkyl as substituent of a 7- to 9-membered saturated bridged bicyclic heterocycle formed by R1and R2, together with the nitrogen to which they are attached, is methyl.

[0085] The term "alkoxy”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term "(Cx-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Ci-4)alkoxy group means a group of the formula (Ci-4)alkyl-O- in which the term “(Ci-4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, and tert-butoxy. Preferred is methoxy. An example of RB1representing (Ci -3)alkoxy is methoxy. An example of (Ci-3)alkoxy as substituent of RB3is methoxy. An example of (Ci-3)alkoxy as substituent of Ring A is methoxy. An example of (Ci-3)alkoxy as substituent of a group R1is methoxy. An example of (Ci-3)alkoxy as substituent of a group R2is methoxy. Examples of (Ci-3)alkoxy as substituent of a 5- to 6-membered saturated monocyclic heterocycle formed by R1and R2, together with the nitrogen to which they are attached, are methoxy and ethoxy. Examples of (Ci-3)al koxy as substituent of a 7- to 9-membered saturated bridged bicyclic heterocycle formed by R1and R2, together with the nitrogen to which they are attached, are methoxy and ethoxy.

[0086] An example of a "(Ci-4)alkoxy-(C2-4)alkyl" group is methoxy methyl. Examples of (Ci^)alkyl-(Ci-3)alkoxy as substituent of a 5- or 6-membered saturated monocyclic heterocycle formed by R1and R2, together with the nitrogen to which they are attached, are methoxymethyl and ethoxymethyl.

[0087] The term "fluoroalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx.yfluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a (Ci-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2- trifluoroethyl; especially trifluoromethyl. Preferred are (Ci-3)fluoroalkyl groups such as trifluoromethyl. An example of RB1representing (Ci-3)fluoroalkyl is trifluoromethyl. Examples of (Ci)fluoroalkyl as substituent of R01are difluoromethyl and trifluoromethyl. An example of (Ci)fluoroalkyl as substituent of RN2representing a (C^alkyl is trifluoromethyl. Examples of (Ci-2)fl uoroalky I as substituent of a 5- to 7-membered saturated monocyclic heterocycle formed by RN1and RN2, together with the nitrogen to which they are attached, are trifluoromethyl and 2,2,2- trifluoroethyl. An example of (Ci-3)fluoroalkyl as substituent of RB3representing phenyl or a 5- or 6-membered heteroaryl is trifluoromethyl. Examples of (Ci-3)fluoroalkyl as substituent of Cy1are difluoromethyl and trifluoromethyl. An example of (Ci ^fluoroalkyl as substituent of Cy2is difluoromethyl. An example of (Ci-3)fluoroalkyl as substituent of R1and R2together with the nitrogen to which they are attached forming a 5- or 6- membered saturated monocyclic heterocycle (comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S) is trifluoromethyl. The term "fluoroalkoxy”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx-y)fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example, a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2 -fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Preferred are (Ci)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy, as well as 2,2,2-trifluoroethoxy. Examples of RB3representing OR01, wherein R01represents (C2- s)alkyl substituted with one or two (Ci)fluoroalkyl, and wherein R01contains a total of at least 3 carbon atoms; are (1, 1-difluoropropan-2-yl)oxy, 3,3-difluoro-2,2-dimethyl-propoxy, (1 ,1, 1-trifluoropropan-2-yl)oxy, (4,4,4- trifluorobutan-2-yl)oxy, (1 ,1 , 1 ,3, 3, 3- hexafluoropropan-2-yl)oxy. An example of (Ci-3)fluoroalkyl as substituent of RB3representing phenyl or 5- or 6-membered heteroaryl is trifluoromethoxy.

[0088] The term "hydroxy" refers to a group -OH.

[0089] The term "cyano" refers to a group -ON.

[0090] The term "oxo" refers to a group =0 which is preferably attached to a chain or ring carbon or sulfur atom as for example in a carbonyl group -(CO)-, or a sulfonyl group -(SO2)-.

[0091] The term "(Cx-Y)alkylidene” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl group as defined before, containing x to y carbon atoms, wherein said alkyl group is linked to the rest of the molecule via a double bond. An example of (Ci^alkylidene is the methylidene group =CH2.

[0092] The term "(Cx-Y)alkenyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl group as defined before, containing x to y carbon atoms, wherein said alkyl group contains a double bond and wherein said alkyl group is linked to the rest of the molecule via a single bond. An example of a (C2-4)alkenyl is vinyl group -CHOH2.

[0093] The term "ethynyl" refers to a group -C CH.

[0094] The term "cycloalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms. The term " (Cx-y)cycloalky I" (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms. For example, a (Cs ejcycloalky I group contains from three to six carbon atoms.

[0095] The term "(Cx.y)cycloalkyl", "monocyclic (Cx.y)cycloalkyl" or "saturated monocyclic (Cx.y)cycloalkyl”, refers to a saturated monocyclic cycloalkyl group as defined before, containing x to y carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of RB1representing a monocyclic (C3-4)cycloalkyl are cyclopropyl and cyclobutyl. An example of RN2representing a monocyclic (C^cycloalkyl is cyclopropyl; such RN2representing a monocyclic (C^cycloalkyl may be unsubstituted or substituted as explicitly defined. An example of (C^cycloalkyl as substituent of RN2representing (C^alkyl is cyclopropyl. Examples of RB3representing a saturated monocyclic (C4-6)cycloalkyl are cyclopentyl, cyclohexyl, and cycloheptyl; such RB3representing a saturated monocyclic (C4-6)cycloalkyl may be unsubstituted or substituted as explicitly defined. An example of (C3-6)cycloalkyl as substituent of RB3representing phenyl or a 5- or 6-membered heteroaryl is cyclopropyl. Examples of RN3representing a monocyclic (C3-6)cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl.

[0096] The term "mono-unsaturated monocyclic (Cx-y)cycloalkyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a mono-unsaturated monocyclic hydrocarbon ring containing x to y carbon atoms (i.e., said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds). Examples of RB3representing a mono-unsaturated monocyclic (C5-

[0097] 7)cycloalkyl are cyclopent-1 -en-1-yl, cyclohex-1 -en-1-yl, and cyclohept-1-en-1-yl; such RB3representing a monounsaturated monocyclic (Cs-zjcycloalkyl may be unsubstituted or substituted as explicitly defined.

[0098] The term “(Cx-y)cycloalkan-diyl” or "monocyclic (Cx-y)cycloalkan-diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to bivalently bound cycloalkyl group, as defined before, containing x to y carbon atoms. When X4represents CH and Ring A represents a monocyclic (Cs-ejcycloalkan-diyl, the points of attachment of said (C5-6)cycloalkan-diy I in Formula (I) are on X4and on a carbon atom neighboring X4; examples are cyclopentane-1 ,2-diyl and cyclohexane-1 ,2-diyl; such monocyclic (C5-6)cycloalkan-diyl may be unsubstituted or substituted as explicitly defined.

[0099] The term "saturated bicyclic (Cx-y)spirocycloalkyl" or "saturated spiro bicyclic (Cx.y) cycloalkyl" (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated spiro-bicyclic hydrocarbon ring containing x to y carbon atoms. Examples of R1representing a saturated bicyclic (C6-8)spirocycloalkyl are spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, and spiro[2.5]octanyl (especially spiro[2.3]hexanyl and spiro[2.5]octanyl); such saturated bicyclic (Ce-sjspirocycloalkyl may be unsubstituted or substituted as explicitly defined. Examples of Cy3representing a saturated spiro bicyclic (C5-

[0100] 8)cycloalkyl are spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, and spiro[2.5]octanyl; such Cy3may be unsubstituted or substituted as explicitly defined.

[0101] The term "saturated fused or bridged bicyclic (Cx-y)cycloalkyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated fused or bridged bicyclic hydrocarbon ring containing x to y carbon atoms. An example of RN3representing a 5-membered saturated bridged bicyclic cycloalkyl is bicyclo[1.1.1]pentanyl. An example of RB3representing a saturated bridged bicyclic (C6-8)cycloalkyl is bicyclo[2.2.1]heptanyl. Examples of Cy3representing a saturated fused or bridged bicyclic (C5- 8)cycloalkyl are bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, and bicyclo[2.2.1]heptanyl; such Cy3may be unsubstituted or substituted as explicitly defined. The term "mono-unsaturated bridged bicyclic (Cx-y)cycloalkyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a mono-unsaturated bridged bicyclic hydrocarbon ring containing x to y carbon atoms (i.e., said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds). An example of RB3representing a mono-unsaturated bridged bicyclic (C6-8)cycloalkyl is bicyclo[2.2.1 ]hept-2-en-2-yl.

[0102] The term "heterocycle” or "saturated monocyclic heterocycle”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term "x- to y-membered heterocycle or "x- to y-membered saturated monocyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. Such heterocycles are unsubstituted or substituted as explicitly defined. Examples of NRN1RN2wherein RN1and RN2together with the nitrogen to which they are attached form a 5- to 7- membered saturated monocyclic heterocycle are pyrrolidinyl, piperidinyl, azepanyl, and morpholinyl; such 5- to 7- membered saturated monocyclic heterocycle may be unsubstituted or substituted as explicitly defined. Examples of RN3representing a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom are oxetanyl and tetrahydrofuranyl. Examples of Cy2representing a 4- to 7-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from -0-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- are oxetanyl, tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, tetrahydro-2 / 7-thiopyran-1,1 -dioxide, 1-imino-1- oxidohexahydro-1 -A6-thiopyranyl, and 1 -methylimino-1-oxidohexahydro-1 -A6-thiopyranyl; such Cy2are substituted or unsubstituted as explicitly defined. Examples of R1and R2, together with the nitrogen to which they are attached, forming a 5- or 6-membered saturated monocyclic heterocycle (comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S) are pyrrolidine, piperidine, thiazolidine, thiomorpholine, and morpholine; such 5- or 6-membered saturated monocyclic heterocycle may be unsubstituted or substituted as explicitly defined.

[0103] The term "mono-unsaturated monocyclic heterocycle”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a mono-unsaturated monocyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups), said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds. The term "x- to y-membered heterocycle or "x- to y-membered saturated monocyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. Such heterocycles are unsubstituted or substituted as explicitly defined. An example of Cy2representing a 4- to 7-membered mono-unsaturated monocyclic heterocycle comprising one ring heteroatomic group selected from -O-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- is 3,6-dihydro-2 / - / -pyranyl.

[0104] The term "saturated spiro bicyclic heterocycle", used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated spiro bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e. , such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term "x- to y-membered saturated spiro bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. An example of R2representing a 7-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom is 2-oxaspiro[3.3]heptanyl. Examples of R1and R2, together with the nitrogen to which they are attached, forming a 7- to 11 -membered saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms, are 2-azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan-6-yl, 2- oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan-2-yl, 1-oxa-6- azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8-azaspiro[5.5]undecan-8-yl, 3-oxa-9- azaspiro[5.5]undecan-9-yl, 1 ,4-dioxa-8-azaspiro[4.6]undecan-8-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, and 8- azaspiro[4.5]decan-8-yl; such 7- to 11-membered saturated spiro bicyclic heterocycle may be unsubstituted or substituted as explicitly defined.

[0105] The term "saturated fused bicyclic heterocycle", used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated fused bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term "x- to y-membered saturated fused bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. Examples of R1and R2, together with the nitrogen to which they are attached, forming an 8- to 10-membered saturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom, are hexahydrocyclopenta[c]pyrrol-2(1 H)-yl, octahydroqui nol in- 1 (2H)-yl, and hexahydrofuro[3,2-c]py ridi n-5(4H)-yl .

[0106] The term "mono-unsaturated fused bicyclic heterocycle", used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a fused bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups), and wherein said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds. The term "x- to y-membered mono-unsaturated fused bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. An example of R1and R2, together with the nitrogen to which they are attached, forming an 8- to 10-membered mono-unsaturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom, is 1 , 3, 3a, 4, 7,7a- hexahydro-2H-isoindol-2-yl.

[0107] The term "saturated bridged bicyclic heterocycle", used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated bridged bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term "x- to y-membered saturated bridged bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. An example of R2representing a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom is 7-oxabicyclo[2.2.1]heptanyl. Examples of NRN1RN2wherein RN1and RN2together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom (and zero or one additional ring oxygen atom) are 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1 heptan-7-yl, 2-oxa- 5-azabicyclo[2.2.2]octan-5-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl. Examples of 7- to 9-membered saturated bridged bicyclic heterocycles formed by R1and R2together with the nitrogen to which they are attached (comprising said nitrogen atom and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom) are 7-azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, and 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; such 7- to 9-membered saturated bridged bicyclic heterocycle may be unsubstituted or substituted as explicitly defined.

[0108] The term "saturated bridged tricyclic heterocycle", used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated bridged tricyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term "x- to y-membered saturated bridged tricyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. Examples of R1and R2, together with the nitrogen to which they are attached, forming a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms, are 2- azaadamantan-2-yl and 2-oxa-6-azaadamantan-6-yl. The term "x- to y-membered heterocycloalkan-diyl” or "x- to y-membered saturated monocyclic heterocycloalkan- diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a bivalently bound heterocycloalkyl as defined before; wherein in each instance, the number and nature of ring heteroatoms or heteroatomic groups are explicitly defined. When X4represents N and Ring A represents a 4- to 7-membered saturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring heteroatoms selected from 0 or S, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X4and on the carbon atom attached to the group -CO-N(R1)(R2); examples of such Ring A are azetidin-diyl, pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, and oxazolidin-diyl; such Ring A is unsubstituted, or substituted as explicitly defined. In a particular embodiment, the carbon atom of Ring A attached to the group -CO-N(R1)(R2) is not further substituted.

[0109] The term "x- to y-membered mono-unsaturated monocyclic heterocycloalkan-diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a bivalently bound monocyclic hydrocarbon ring containing x to y ring atoms of which one or two (especially one) ring atoms are heteroatoms independently selected from N, 0, or S, and wherein said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds. When X4represents N and Ring A represents a 4- to 6- membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom, and no further ring heteroatoms, the points of attachment of said mono-unsaturated heterocycloalkan-diyl in Formula (I) are on X4and on the carbon atom attached to the group -CO-N(R1)(R2); the unsaturated (double) bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4. Examples of such Ring A are 2, 5-dihy d ro- 1 H- pyrrol-1 ,2-diyl, 2,3-dihydro-1 H-pyrrol-1 ,5-diyl, 3,6-dihydropyridin-1 (2H)-1 ,2-diyl, and 4,5-dihydro-1 H-pyrazol-1,5- diyl); such Ring A may be unsubstituted or substituted as explicitly defined. In a particular embodiment, the carbon atom of Ring A attached to the group -CO-N(R1)(R2) is not further substituted.

[0110] The term "x- to y-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a bivalently bound saturated spiro, fused or bridged bicyclic hydrocarbon ring containing x to y ring atoms of which one or two (especially one) ring atoms are heteroatoms independently selected from N, 0, or S. When X4represents N and Ring A represents a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom, the points of attachment of said bicyclic heterocycloalkan-diyl in Formula (I) are on X4and on the carbon atom attached to the group -C0-N(R1)(R2). Examples of such Ring A are hexahydrocyclopenta[b]pyrrol-1 (2 / - / ),2-diyl, hexahydro-4H-furo[3,2-b]pyrrol-4,5-diyl, 2-azabicyclo[2.1.1]hexan-1 ,2- diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3-azabicyclo[3.1.0]hexan-2,3-diyl, 2-azabicyclo[2.2.1]heptan-1 ,2-diyl, 5- azaspiro[2.4]heptan-4,5-diyl, 5-azaspiro[2.4]heptan-5,6-diyl, and 6-azaspiro[2.5]octan-5,6-diyl); such Ring A is unsubstituted, or substituted as explicitly defined. The term "aryl", used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.

[0111] When RB3represents phenyl, such phenyl may be unsubstituted or substituted as explicitly defined. When RB3represents a mono-, di- or tri-substituted (especially mono- or di-substituted) phenyl, especially at least one of the substituent(s) is attached in para position with regard to the point of attachment of the rest of the molecule. Especially such substituent(s) in para position is / are (Ci-3)alkyl (notably methyl), halogen (notably fluoro), or (Ci-3)alkoxy (especially methoxy).

[0112] The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (especially one to a maximum three), each independently selected from N, 0, or S. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, furopyridinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above- mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined. When RB3represents a 5- or 6- membered heteroaryl, such heteroaryl comprises one to three ring heteroatoms independently selected from N, 0, or S, wherein said heteroaryl is especially linked to the rest of the molecule via a ring carbon atom. Such RB3is notably isothiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl; such 5- or 6-membered heteroaryl may be unsubstituted or substituted as explicitly defined.

[0113] Whenever the word "between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4.

[0114] Unless used regarding temperatures, the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus (10% of X) to X plus (10% of X), and preferably to an interval extending from X minus (5% of X) to X plus (5% of X). Likewise, the term "about” placed before a numerical range "X to Y” refers in the current application to an interval extending from X minus (10% of X) to Y plus (10% of Y), and preferably to an interval extending from X minus (5% of X) to Y plus (5% of Y). In the particular case of temperatures, the term "about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. Besides, the term "room temperature” as used herein refers to a temperature of about 25°C. Further embodiments of the invention are presented hereinafter:

[0115] 2) Another embodiment relates to compounds according to embodiment 1), wherein X1represents N or CRB2, wherein RB2represents hydrogen, halogen (especially fluoro), or (Ci-3)alkyl (especially methyl), and X2represents CH [in particular X1represents CH, C-CH3, or N, and X2represents CH],

[0116] 3) Another embodiment relates to compounds according to embodiment 1), wherein X1represents CH and X2represents N.

[0117] 4) Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein RB1represents (Ci-3)alkyl (especially methyl, ethyl, or isopropyl) or (Ci)fluoroalkyl (especially trifluoromethyl) [in particular RB1represents methyl or trifluoromethyl].

[0118] 5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein RB3represents: OR01, wherein R01represents (C^alkyl (especially propyl, isopropyl, sec-butyl, or isobutyl) that is substituted with zero, one or two (Ci)fluoroal ky I (especially difluoromethyl or trifluoromethyl); [notably OR01represents propoxy, isopropoxy, sec-butoxy, isobutoxy, (1,1-difluoropropan-2-yl)-oxy, (3,3-difluoro-2,2- dimethyl-propyl)-oxy, (1,1 , 1-trifluoropropan-2-yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1, 1 ,1 , 3,3,3— hexafl uoropropan-2-yl)-oxy; in particular OR01represents sec-butoxy]; or NRN1RN2, wherein independently:

[0119] ■ RN1represents:

[0120] • hydrogen; or

[0121] • (Ci-3)alkyl (especially methyl, ethyl, or isopropyl); and

[0122] ■ RN2represents:

[0123] • (C2-5)alkyl (especially propyl, isopropyl, sec-butyl, or fert-butyl); wherein said (C2-5)alkyl is unsubstituted, or mono- or di-substituted (especially unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (Ci)fluoroalkyl (especially trifluoromethyl), (C^cycloalkyl (especially cyclopropyl), and (Ci-3)alkoxy (especially methoxy); or

[0124] • monocyclic (C3-5)cycloalkyl (especially cyclopropyl), wherein said monocyclic (C3-5)cycloalkyl is unsubstituted or mono-substituted with (Ci-3)alkyl (especially methyl); and especially wherein the total number of carbon atoms in RN1and RN2is at least 3;

[0125] [notably such group NRN1RN2represents isopropyl-amino, sec-butyl-amino, terf-butyl-amino, (l-methyl-cyclopropyl)-amino, (l-cyclopropyl-ethyl)-amino, (1 -methoxy propan-2-yl)-ami no, (1, 1 ,1 -tr if I uoropropan-2-y l)-ami no, (1 , 1 ,1 -trifl uorobu tan-2 -y I )-am i no, (1 -cy clopropy I-2, 2, 2- trifluoroethyl)-amino, (isopropyl)-(methyl)-amino, (ferf-butyl)-(methyl)-amino, (cyclopropyl)- (methyl)-amino, diethyl-amino, (ethyl)-(isopropyl)-amino, (cyclopropyl)-(ethyl)-amino, (sec- butyl)-(ethyl)-amino, diisopropyl-amino, (isopropyl)-(2-methoxyethyl)-amino, or (ethyl)-(1- methoxypropan-2-yl)-amino]; or

[0126] ■ RN1and RN2together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), (Ci. 2)fluoroalkyl (especially trifluoromethyl or 2,2,2-trifluoroethyl), and (Ci-3)alkoxy-(Ci-3)alkyl (especially methoxymethyl); [notably such group NRN1RN2represents pyrrolidin-1 -yl, piperidin-1 - yl, 2-methylpyrrolidin-1-yl, 2-(trifluoromethyl)pyrrolidin-1-yl, 2-methylpiperidin-1-yl, 3- fluoropiperidin-1-yl, 4-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2- (methoxymethyl)piperidin-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2,3-dimethylpyrrolidin-1-yl, 2-ethyl-5- methylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1 -yl, azepan-1-yl, 3-methylmorpholin-4-yl, 3-(2,2,2- trifluoroethyl)morpholin-4-yl, or 3,5-dimethylmorpholin-4-yl]; or

[0127] ■ RN1and RN2together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom; [notably such group NRN1RN2represents 2-azabicyclo[2.2.1]heptan-2-yl, 7- azabicyclo[2.2.1 heptan-7-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, or 3-oxa-8- azabicyclo[3.2.1]octan-8-yl)]; or a saturated or mono-unsaturated monocyclic (Cs-zjcycloalkyl (notably cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1 -yl, cycloheptyl, or cyclohept-1-en-1-yl); wherein said (C4-6)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-3)al ky I (especially methyl) or halogen (especially fluoro); [notably such RB3represents cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1-yl, cycloheptyl, cyclohept-1-en-1-yl, 2-methylcyclohexyl, 2-methylcyclohex-1- en-1 -yl, 6-methylcyclohex-1-en-1-yl, 4,4-dimethylcyclohex-1-en-1-yl, or 4,4-difluorocyclohex-1-en-1-yl]; or 5,6-dihydro-2H-pyran-3-yl; or a saturated or mono-unsaturated bridged bicyclic (Ce-sjcycloalkyl; [notably such RB3represents bicyclo[2.2.1 ]heptanyl or bicyclo[2.2.1 ]hept-2-en-2-yl]; or phenyl; wherein said phenyl is mono-, di- or tri-substituted (notably mono- or di-substituted; in particular wherein at least one substituent is in para position with regard to the point of attachment of the rest of the molecule); wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro or chloro), (Ci^)alkyl (especially methyl), (Ci-3)alkoxy (especially methoxy), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), and cyano; [notably such RB3represents 2-methyl phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-cy anophenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 4- fluorophenyl, 2-fluoro-3-methylphenyl, 2,3-difluorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2- fluorophenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-dimethylphenyl, 2- fluoro-6-methyl phenyl, 2-chloro-6-methylpheny 1, 2,6-difluorophenyl, or 2-fluoro-6-methoxyphenyl]; or 5- or 6-membered heteroaryl selected from isothiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl (in particular from isothiazolyl, pyrazolyl, pyridinyl, or pyrazinyl); wherein said 5- or 6-membered heteroaryl is independently unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro or chloro), (Ci-3)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), (Ci-3)alkoxy (especially methoxy), (Ci^)fluoroalkyl (especially trifluoromethyl), and cyano; [notably such RB3represents isothiazol-3-yl, 4-methylisothiazol-3- yl, oxazol-2-yl, 5-methyloxazol-2-yl, 5-methyl-1 H-pyrazol-1-yl, 5-ethyl-1 H-pyrazol-1-yl, 5-cyclopropyl-1 H- pyrazol-1-yl, 2 / 7-1 ,2,3-triazol-2-yl, 2-methylpyridin-3-yl, 2-fluoropyridin-3-yl, 2-chloropyridin-3-yl, 2- cyanopyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoropyridin-3-yl, 4-chloropyridin-3-yl, 4-cyanopyridin-3-yl, 3- methylpyridin-2-yl, 3-fluoropyridin-2-yl, 3-chloropyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 3- methoxypyridin-2-yl, 2-chloro-4-methylpyridin-3-yl, 2,4-difluoropyridin-3-yl, 3-methylpyrazin-2-yl, 3- fluoropyrazin-2-yl, or 3-methoxypyrazin-2-yl; in particular such RB3represents 4-methylisothiazol-3-yl, 5- ethyl-1 / 7-pyrazol-1-yl, 2-methylpyridin-3-yl, 2-chloro-4-methylpyridin-3-yl, 2,4-difluoropyridin-3-yl, 3- methylpyrazin-2-yl, or 3-fluoropyrazin-2-yl],

[0128] 6) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein RB3represents: propoxy, isopropoxy, sec-butoxy, isobutoxy, (1 ,1-difluoropropan-2-yl)-oxy, (3,3-difluoro-2,2-dimethyl- propyl)-oxy, (1 ,1 ,1-trifluoropropan-2-yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1 , 1 ,1 , 3,3,3- hexafluoropropan-2-yl)-oxy [in particular RB3represents sec-butoxy]; or NRN1RN2, wherein independently:

[0129] ■ RN1represents:

[0130] • hydrogen; or

[0131] • (Ci-3)alkyl (especially methyl, ethyl, or isopropyl); and

[0132] ■ RN2represents:

[0133] • unsubstituted (C^alkyl (especially propyl, isopropyl, sec-butyl, or fert-butyl); especially wherein the total number of carbon atoms in RN1and RN2is at least 3; [in particular such group NRN1RN2represents (ethyl)-(isopropyl)-amino, diisopropyl-amino, (isopropyl)- (methyl)-amino, isopropyl-amino, or fert-butyl-amino]; or

[0134] ■ RN1and RN2together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and (Ci. 2)fluoroalkyl (especially trifluoromethyl or 2,2,2-trifluoroethyl); [in particular such group NRN1RN2represents piperidin-1-yl, 2-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2,5- dimethylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1-yl, azepan-1-yl, or 3,5-dimethylmorpholin-4-yl]; or a saturated monocyclic (C4-e)cycloalkyl (notably cyclohexyl); wherein said saturated (C4-6)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-s)al ky I (especially methyl); or a mono-unsaturated monocyclic (Ce-zjcycloalkyl (notably cyclohex-1 -en-1-yl, or cyclohept-1-en-1-yl); wherein said mono-unsaturated (Ce-zjcycloalkyl is unsubstituted, or mono-substituted with (Ci-s)alkyl (especially methyl); [in particular such RB3represents cyclohex-1 -en-1-yl, cyclohept-1-en-1-yl, or 2- methylcyclohex-1-en-1-yl]; or a mono-unsaturated bridged bicyclic (Cz)cycloalkyl [in particular such RB3represents bicyclo[2.2.1 ]hept-2- en-2-yl]; or phenyl; wherein said phenyl is mono- or di-substituted (in particular wherein at least one substituent is in para position with regard to the point of attachment of the rest of the molecule); wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro or chloro), (Ci-3)alkyl (especially methyl), and (Ci^alkoxy (especially methoxy); [notably such RB3represents 2-methyl phenyl,

[0135] 2-fluorophenyl, 2-methoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-6- methylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, or 2-fluoro-6-methoxyphenyl]; or 5- or 6-membered heteroaryl selected from isothiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl (in particular from isothiazolyl, pyrazolyl, pyridinyl, or pyrazinyl); wherein said 5- or 6-membered heteroaryl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro or chloro) and (Ci-s)alkyl (especially methyl or ethyl); [notably such RB3represents 4-methylisothiazol-3-yl, 5-ethyl-1 H-pyrazol-1 -yl, 2-methylpyridin-3-yl, 2-chloro-4-methylpyridin-

[0136] 3-yl, 2,4-difluoropyridin-3-yl, 3-methylpyrazin-2-yl, or 3-fluoropyrazin-2-yl],

[0137] 7) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein RB3represents: NRN1RN2, wherein independently:

[0138] ■ RN1represents (Ci-3)alkyl (especially methyl, ethyl, or isopropyl); and

[0139] ■ RN2represents (C^alkyl (especially isopropyl);

[0140] [in particular such group NRN1RN2represents (ethyl)-(isopropyl)-amino, diisopropyl-amino, or (isopropyl)-(methyl)-amino]; or

[0141] ■ RN1and RN2together with the nitrogen to which they are attached form a heterocycle selected from pyrrolidinyl, piperidinyl, or morpholinyl; wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and (Ci-2)fluoroalkyl (especially trifluoromethyl or 2,2,2- trifluoroethyl); [in particular such group NRN1RN2represents piperidin-1-yl, 2-methylpiperidin-1 -yl, 2-(trifluoromethyl)piperidin-1 -yl, 2,5-dimethylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1-yl, or 3,5- dimethylmorpholin-4-yl]; or a mono-unsaturated monocyclic (C6-z)cycloalkyl (notably cyclohex- 1-en-1 -yl, or cyclohept-1 -en-1 -yl); or a mono-unsaturated bridged bicyclic (Cz)cycloalkyl [in particular such RB3represents bicyclo[2.2.1 ]hept-2- en-2-yl]; or phenyl; wherein said phenyl is mono- or di-substituted (in particular wherein at least one substituent is in para position with regard to the point of attachment of the rest of the molecule); wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro), (Ci-3)alkyl (especially methyl), and (Ci^alkoxy (especially methoxy); [notably such RB3represents 2-fluorophenyl, 2-fluoro-6- methylphenyl, 2,6-difluorophenyl, or 2-fluoro-6-methoxyphenyl]; or 5- or 6-membered heteroaryl selected from isothiazolyl or pyridinyl; wherein said 5- or 6-membered heteroaryl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro) and (Ci-3)alkyl (especially methyl); [notably such RB3represents 4-methylisothiazol-3-yl, 2,4-difluoropyridin-3-yl].

[0142] 8) Another embodiment relates to compounds according to embodiment 1), wherein Ring B represents 2- isopropoxy-6-methylpyridin-3-yl, 6-methyl-2-propoxypyridin-3-yl, 2-(sec-butoxy)-6-methylpiridin-3-yl, 2-isobutoxy- 6-methylpyridin-3-yl, 2-((1,1-difluoropropan-2-yl)oxy)-4-methylphenyl, 2-(3,3-difluoro-2,2-dimethyl-propoxy)-4- methy I phenyl , 4-methy l-2-((1 , 1 ,1 -trifl uoropropan-2-yl)oxy) phenyl , 6-methy l-2-(1 ,1 , 1 -trifl uoropropan-2- yl)oxy)pyridin-3-yl, 4-methyl-2-((4,4,4-trifluorobutan-2-yl)oxy)phenyl, 2-((1 ,1,1 ,3,3,3— hexafluoropropan-2-yl)oxy)-4- methylphenyl, 2-(isopropylamino)-4-methylphenyl, 2-(isopropylamino)-6-methylpyridin-3-yl, 2-(sec-butylamino)-6- methylpyridin-3-yl, 2-(ferf-butylamino)-6-methylpyridin-3-yl, 6-methyl-2-((1-methylcyclopropyl)amino)pyridin-3-yl, 2- ((1-cyclopropylethyl)amino)-6-methylpyridin-3-yl, 2-((1-methoxypropan-2-yl)amino)-6-methylpyridin-3-yl, 6-methyl- 2-((1 , 1 , 1 -trifl uoropropan-2-y l)amino) py ridin-3-y I, 6-methy I -2-((1 , 1 ,1 -trif luorobutan-2-y I) ami no)py rid I n-3-y 1 , 2-((1 - cyclopropyl-2,2,2-trifluoroethyl)amino)-6-methylpyridin-3-yl, 2-(isopropyl(methyl)amino)-6-methylpyridin-3-yl, 2- (ferf-butyl(methyl)amino)-6-methylpyridin-3-yl, 2-(cyclopropyl(methyl)amino)-6-methylpyridin-3-yl, 2- (diethylamino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6- (trifluoromethyl)pyridin-3-yl, 2-(ethyl(isopropyl)amino)-4-methylphenyl, 2-(cyclopropyl(ethyl)amino)-6- methylpyridin-3-yl, 2-((sec-butyl)-(ethyl)-amino)-6-methylpyridin-3-yl, 2-(diisopropylamino)-6-methylpyridin-3-yl, 2- (isopropyl(2-methoxyethyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(1-methoxypropan-2-yl)amino)-6-methylpyridin-3- yl, 6-methyl-2-(pyrrolidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 6-methyl-2-(piperidin-1-yl)pyridin-3-yl, 6- methyl-2-(2-methylpyrrolidin-1-yl)pyridin-3-yl, 6-methyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl, 4-methyl-2- (2-methylpiperidin-1-yl)phenyl, 6-methyl-2-(2-methylpiperidin-1 -yl)pyridin-3-yl, 6-methyl-4-(2-methylpiperidin-1- yl)pyridin-3-yl, 2-(3-fluoropiperidin-1-yl)-4-methylphenyl, 6-methyl-2-(4-methylpiperidin-1-yl)pyridin-3-yl, 6-methyl- 2-(2-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl, 2-(2-methoxymethyl)piperidin-1-yl)-6-methylpyridin-3-yl, 2-(2,5- dimethylpyrrolidin-1-yl)-6-methylpyrridin-3-yl, 2-(2,3-dimethylpyrrolidin-1-yl)-6-methylpyrridin-3-yl, 2-(2-ethyl-5- methylpyrrolidin-1-yl)-6-methylpyrridin-3-yl, 2-(2,6-dimethylpiperidin-1-yl)-6-methylpyridin-3-yl, 2-(azepan-1-yl)-4- methylphenyl, 2-(azepan-1-yl)-6-methylpyridin-3-yl, 2-(3-methylmorpholino)-6-(trifluoromethyl)pyridin-3-yl, 6- methyl-2-(3-(2,2,2-trifluoroethyl)morpholino)pyridin-3-yl, 2-(3,5-dimethylmorpholino)-6-methylpyridin-3-yl, 2-(3,5- dimethylmorpholino)-6-(trifluoromethyl)pyridin-3-yl, 2-(3,5-dimethylmorpholino)-4-methylphenyl, 2-(2- azabicyclo[2.2.1]heptan-2-yl)-6-methylpyridin-3-yl, 2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-3-yl, 2-(3- oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-methylpyridin-3-yl, 2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-6-methylpyridin-3- yl, 2-cyclopentyl-4-methylphenyl, 2-(cyclopent-1-en-1-yl)-4-methylphenyl, 2-cyclohexyl-4-methylphenyl, 2- cyclohexyl-6-methylpyridin-3-yl, 2-(cyclohexen-1-en-1-yl)-4-methylphenyl, 2-(cyclohexen-1-en-1-yl)-6- methylpyridin-3-yl, 2-cycloheptyl-4-methylphenyl, 2-(cyclohept-1-en-1-yl)-4-methylphenyl, 6-methyl-2-(2- methylcyclohexyl)pyridin-3-yl, 6-methyl-2-(2-methylcyclohex-1-en-1-yl)pyridin-3-yl, 6-methyl-2-(6-methylcyclohex- 1-en-1-yl)pyridin-3-yl, 2-(4,4,-dimethylcyclohex-1-en-1-yl)-4-methylphenyl, 2-(4, 4, -difluorocyclohex-1 -en-1-yl)-4- methylphenyl, 2-(5J6-dihydro-2 / 7-pyran-3-yl)-4-methylphenyl, 2-(bicyclo[2.2.1]heptan-2-yl)-4-methylphenyl, 2- (bi cycl o [2.2.1 ] hept-2-en-2-y l)-4-methy Ipheny 1 , 6-methy I -[1 , 1 ' -bi pheny l]-2-y 1 , 5-methy I -[1 , 1 ' -bi pheny l]-2-y 1 , 2'- methyl-[1 ,1’-biphenyl]-2-yl, 2’,5-dimethyl-[1 ,1’-biphenyl]-2-yl, 5-fluoro-2’-methyl-[1 , 1’-biphenyl]-2-yl, 2’,6-difluoro- [1 , 1 '-biphenyl]-2-yl, 2’-fluoro-5-methyl-[1 , T-bi pheny l]-2-yl , 5-ethy l-2’-fluoro-[1 , T-bi pheny l]-2-y 1 , 2’-fluoro-5- isopropyl-[1 ,1'-biphenyl]-2-yl, 5-cyclopropyl-2'-fluoro-[1 , 1'-biphenyl]-2-yl, 5-cyclobutyl-2'-fluoro-[1 , 1'-biphenyl]-2-yl, 2’,5-difluoro-[1, 1’-biphenyl]-2-yl, 5-chloro-2’-fluoro-[1 , 1’-biphenyl]-2-yl, 2’-fluoro-5-methoxy-[1 ,1’-biphenyl]-2-yl, 2’- fluoro-5-vinyl-[1 , 1'-biphenyl]-2-yl, 2'-fluoro-5,6-dimethyl-[1 , 1'-biphenyl]-2-yl, 2',6-difluoro-5-methyl-[1 ,1'-biphenyl]-2- yl, 2-(2-fluorophenyl)-6-methylpyridin-3-yl, 2-(2-chlorophenyl)-6-methylpyridin-3-yl, 2'-chloro-5-fluoro-[1 ,1'- bi pheny l]-2-y 1 , 2'-chloro-5-methoxy-[1 , 1 ’ -bi pheny l]-2-y 1 , 2'-cyano-5-methyl-[1 , 1 ’ -bi pheny l]-2-y 1 , 2'-methoxy-5- methy l-[1 , 1 ’ -bi pheny l]-2-yl , 5-methy I-2’- (trifl uoromethoxy)-[ 1 , 1 ’-bi phenyl]-2-y I, 4’ -fl uoro-5-methy l-[1 , 1 ’-bi pheny -2- yl, 2-(2-fluoro-3-methylphenyl)-6-methylpyridin-3-yl, 2',3'-difluoro-5-methyl-[1 ,1'-biphenyl]-2-yl, 2-(2-chloro-3- fluorophenyl)-6-methylpyridin-3-yl, 2-(3-chloro-2-fluorophenyl)-6-methylpyridin-3-yl, 4'-fluoro-2'-methoxy-5-methyl- [1 , 1’-biphenyl]-2-yl, 2’,4’-fluoro-5-methyl-[1 ,1’-biphenyl]-2-yl, 2-(2,5-difluorophenyl)-6-methylpyridin-3-yl, 2-(2’,5’- difluoro-5-methyl-[1 ,1'-biphenyl]-2-yl, 2',5,6'-trimethyl-[1 ,1'-biphenyl]-2-yl, 2-(2-fluoro-6-methylphenyl)-6- methylpyridin-3-yl, 2’-chloro-5,6’-dimethyl-[1 ,1'-biphenyl]-2-yl, 2-(2,6-difluorophenyl)-6-methylpyridin-3-yl, 2-(2,6- difluorophenyl)-6-methoxypyridin-3-yl, 2',6'-difluoro-5-methyl-[1 , 1'-biphenyl]-2-yl, 2'-fluoro-6'-methoxy-5-methyl- [1 , 1 ' -bi pheny l]-2-y 1 , 2-(i soth i azol -3-yl)-4-methy Ipheny 1 , 4-methy l-2-(4-methy I i soth i azol-3-y I )pheny 1 , 4-methyl-2- (oxazol-2-yl)phenyl, 4-methyl-2-(5-methyloxazol-2-yl)phenyl, 4-methyl-2-(5-methyl-1 H-pyrazol-1 -yl)phenyl, 4- methyl-2-(5-ethyl-1 H-pyrazol-1-yl)phenyl, 4-methyl-2-(5-cyclopropyl-1 H-pyrazol-1 -yl)phenyl, 4-methyl-2-(2H-1 ,2,3- triazol-2-yl)phenyl, 4-methyl-2-(2-methylpyridin-3-yl)phenyl, 2-(4-fluoropyridin-3-yl)-4-methylphenyl, 2-(4- chloropyridin-3-yl)-4-methylphenyl, 2-(4-cyanopyridin-3-yl)-4-methylphenyl, 4-methyl-2-(3-methylpyridin-2- yl)phenyl, 2-(3-fluoropyridin-2-yl)-4-methylphenyl, 2-(3-chloropyridin-2-yl)-4-methylphenyl, 4-methyl-2-(3- (trifluoromethyl)pyridin-2-yl)phenyl, 2-(3-methoxypyridin-2-yl)-4-methylphenyl, 2-(2-chloro-4-methylpyridin-3-yl)-4- methylphenyl, 2-(2,4-difluoropyridin-3-yl)-4-methylphenyl, 4-methyl-2-(3-methylpyrazin-2-yl)phenyl, 2-(3- fluoropyrazin-2-yl)-4-methylphenyl, or 2-(3-methoxypyrazin-2-yl)-4-methylphenyl.

[0143] 9) Another embodiment relates to compounds according to embodiment 1), wherein Ring B represents 2-(sec- butoxy)-6-methylpiridin-3-yl, 2-(isopropylamino)-6-methylpyridin-3-yl, 2-(fert-butylamino)-6-methylpyridin-3-yl, 2- (isopropyl(methyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl, 2- (ethyl(isopropyl)amino)-6-(trifluoromethyl)pyridin-3-yl, 2-(ethyl(isopropyl)amino)-4-methylphenyl, 2- (diisopropylamino)-6-methylpyridin-3-yl, 4-methyl-2-(piperidin-1-yl)phenyl, 6-methyl-2-(piperidin-1-yl)pyridin-3-yl, 4-methyl-2-(2-methylpiperidin-1-yl)phenyl, 6-methyl-2-(2-methylpiperidin-1-yl)pyridin-3-yl, 6-methyl-4-(2- methylpiperidin-1-yl)pyridin-3-yl, 6-methyl-2-(2-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl, 2-(2,5-dimethylpyrrolidin-

[0144] 1-yl)-6-methylpyrridin-3-yl, 2-(2,6-dimethylpiperidin-1-yl)-6-methylpyridin-3-yl, 2-(azepan-1-yl)-4-methylphenyl, 2-

[0145] (3,5-dimethylmorpholino)-6-methylpyridin-3-yl, 2-(3,5-dimethylmorpholino)-6-(trifluoromethyl)pyridin-3-yl, 2-(3,5- dimethylmorpholino)-4-methylphenyl, 2-cyclohexyl-4-methylphenyl, 2-cyclohexyl-6-methylpyridin-3-yl, 2- (cyclohexen-1 -en-1-yl)-4-methylphenyl, 2-(cyclohexen-1-en-1-yl)-6-methylpyridin-3-yl, 2-(cyclohept-1-en-1-yl)-4- methylphenyl, 6-methyl-2-(2-methylcyclohex-1-en-1-yl)pyridin-3-yl, 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4- methylphenyl, 2',5-dimethyl-[1 ,1'-biphenyl]-2-yl, 2'-fluoro-5-methyl-[1, 1'-biphenyl]-2-yl, 2’-fluoro-5,6-dimethyl-[1 , 1'- biphenyl]-2-yl, 2'-methoxy-5-methyl-[1 ,1'-biphenyl]-2-yl, 2',3'-difluoro-5-methyl-[1, 1'-biphenyl]-2-yl, 2',4'-fluoro-5- methyl-[1 ,1'-biphenyl]-2-yl, 2-(2’,5’-difluoro-5-methyl-[1 ,1'-biphenyl]-2-yl, 2-(2-fluoro-6-methylphenyl)-6- methylpyridin-3-yl, 2’-chloro-5,6’-dimethyl-[1 ,1'-biphenyl]-2-yl, 2-(2,6-difluorophenyl)-6-methylpyridin-3-yl, 2',6'- difluoro-5-methyl-[1 ,1'-biphenyl]-2-yl, 2'-fluoro-6'-methoxy-5-methyl-[1 , 1'-biphenyl]-2-yl, 4-methyl-2-(4- methylisothiazol-3-yl)phenyl, 4-methyl-2-(5-ethyl-1 H-pyrazol-1 -yl)phenyl, 4-methyl-2-(2-methylpyridin-3-yl)phenyl,

[0146] 2-(2-chloro-4-methylpyridin-3-yl)-4-methylphenyl, 2-(2,4-difluoropyridin-3-yl)-4-methylphenyl, 4-methyl-2-(3- methylpyrazin-2-yl)phenyl, or 2-(3-fluoropyrazin-2-yl)-4-methylphenyl [in particular, Ring B represents 2- (isopropyl(methyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl, 2- (ethyl(isopropyl)amino)-6-(trifluoromethyl)pyridin-3-yl, 2-(ethyl(isopropyl)amino)-4-methylphenyl, 2- (diisopropylamino)-6-methylpyridin-3-yl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(2-methylpiperidin-1- yl)phenyl, 6-methyl-2-(2-methylpiperidin-1-yl)pyridin-3-yl, 6-methyl-2-(2-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl,

[0147] 2-(2,5-dimethylpyrrolidin-1-yl)-6-methylpyrridin-3-yl, 2-(2,6-dimethylpiperidin-1-yl)-6-methylpyridin-3-yl, 2-(3,5- dimethylmorpholino)-6-methylpyridin-3-yl, 2-(3,5-dimethylmorpholino)-4-methylphenyl, 2-(cyclohexen-1-en-1-yl)-4- methylphenyl, 2-(cyclohept-1-en-1 -yl)-4-methylphenyl, 2-(bicyclo[2.2.1]hept-2-en-2-yl)-4-methylphenyl, 2'-fluoro-5- methyl-[1 ,1'-biphenyl]-2-yl, 2'-fluoro-5,6-dimethyl-[1 , 1'-biphenyl]-2-yl, 2-(2-fluoro-6-methylphenyl)-6-methylpyridin-

[0148] 3-yl, 2',6'-difluoro-5-methyl-[1 ,1'-biphenyl]-2-yl, 2'-fluoro-6'-methoxy-5-methyl-[1 ,1'-biphenyl]-2-yl, 4-methyl-2-(4- methylisothiazol-3-yl)phenyl, 2-(2,4-difluoropyridin-3-yl)-4-methylphenyl].

[0149] 10) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein X3represents 0.

[0150] 11) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein X3represents NRN3, wherein RN3represents hydrogen, (Ci-3)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom (especially oxetanyl or tetrahydrofuranyl), a 5-membered saturated bridged bicyclic cycloalkyl (especially bicyclo[1.1.1]pentanyl), phenyl, or pyridinyl.

[0151] 12) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein X3represents NRN3, wherein RN3represents hydrogen, (Ci-3)alkyl (especially methyl), or (C3-6)cycloalkyl (especially cyclopropyl).

[0152] 13) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X4represents N and Ring A represents:

[0153] • a 4- to 7-membered (notably 5- to 7-membered) saturated monocyclic heterocycloalkan-diyl comprising X4, and zero or one further ring heteroatom selected from 0 or S (especially azetidin-diyl, pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl; in particular pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl); wherein said heterocycloalkan-diyl is unsubstituted, or mono- or disubstituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), halogen (especially fluoro), (Ci-3)alkoxy (especially methoxy), (Ci-3)alkylidene (especially H2C=), and oxo; [notably such Ring A represents azetidin-1 ,2-diyl, 4- methylazetidin-1 , 2-diyl, 3, 3-difluoroazetidin-1 ,2-diyl, pyrrolidin-1 ,2-diyl, 5-methylpyrrolidin-1 ,2-diyl, 4- methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1 , 2-diyl, 3-fluoropyrrolidin-1, 2-diyl, 4-methoxypyrrolidin- 1 ,2-diyl, 4-methylenepyrrolidin-1 , 2-diyl, 4-oxopyrrolidin-1 ,2-diyl, 4, 4-dimethylpyrrolidin-1 , 2-diyl, 4,4- difluoropyrrolidin-1 , 2-diyl, piperidin-1 , 2-diyl, azepan-1, 2-diyl, thiazolidin-2,3-diyl, thiazolidin-3,4-diyl, oxazolidin-3,4-diyl, oxazolidin-2,3-diyl, 1 ,3-oxazinan-2,3-diyl, or morpholin-3,4-diyl; in particular such Ring A represents pyrrolidin-1 , 2-diyl, 5-methylpyrrolidin-1 ,2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4- fluoropyrrolidin-1 , 2-diyl, 3-fluoropyrrolidin-1 , 2-diyl, 4-methoxypyrrolidin-1 , 2-diyl, 3- methylenepyrrol id i n- 1 ,2-diyl, 4, 4-d I methy Ipy rrolidin- 1 ,2-diyl, azepan-1 ,2-diyl, thiazolidi n-2, 3-d iy I, thiazolidin-3,4-diyl, or oxazolidin-2,3-diyl];

[0154] • a 4- to 6-membered (notably 5-membered) mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom (especially dihydro-1 H-pyrrol-diyl, dihydropyridin- 1 (2 / 7)-diyl, or dihydro-1 / 7-pyrazol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4; wherein said mono-unsaturated heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci-3)alkyl (especially methyl); [notably such Ring A represents 2, 5-d i hydro- 1 / 7-pyrrol- 1 ,2-diyl, 2, 3-d i hydro- 1 / 7-py rrol-1 ,5-diyl, 3, 6-d I hydropy ri di n-1 (2 / 7)-

[0155] 1 ,2-diyl, 4,5-dihydro-1 H-pyrazol-1 ,5-diyl, or 3-methyl-4,5-dihydro-1 H-pyrazol-1 ,5-diyl; in particular such Ring A represents 2,5-dihydro-1 H-pyrrol-1 ,2-diyl or 3-methyl-4,5-dihydro-1 H-pyrazol-1 ,5-diyl];

[0156] • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom (notably hexahydrocyclopenta[b]pyrrol-1 (2 / 7),2-diy I, hexahydro-4 / - / - furo[3,2-b]pyrrol-4,5-diyl, azabicyclo[2.1.1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, or azaspiro[2.4]heptan-diyl; in particular azabi cyclo [2.1 .1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, azaspiro[2.4]heptan-diyl, or 6- azaspiro[2.5]octan-diyl); wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or monosubstituted with (Ci-3)alkyl (especially methyl) or di-substituted with fluoro.

[0157] 14) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X4represents N and Ring A represents:

[0158] • a 5- to 7-membered saturated monocyclic heterocycloalkan-diyl comprising X4, and zero or one further ring heteroatom selected from 0 or S (especially pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl); wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), halogen (especially fluoro), (Ci-3)alkoxy (especially methoxy), and (Ci-3)alkylidene (especially H2C=); [notably such Ring A represents pyrrolidin-1 ,2-diyl, 5-methylpyrrolidin-1 ,2-diyl, 4- methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1 , 2-diyl, 3-fluoropyrrolidin-1, 2-diyl, 4-methoxypyrrolidin-

[0159] 1.2-diyl, 3-methylenepyrrolidin-1 ,2-diyl, 4, 4-dimethylpyrrolidin-1 , 2-diyl, azepan-1 , 2-diyl, thiazolidin-

[0160] 2.3-diyl, thiazolidin-3,4-diyl, or oxazolidin-2,3-diyl]; or

[0161] • a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom (especially dihydro-1 / 7-pyrrol-diyl or dihydro-1 / 7-pyrazol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4; wherein said monounsaturated heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci^)alkyl (especially methyl); [notably such Ring A represents 2, 5-dihydro-1 / 7-pyrrol-1 , 2-diyl or 3-methyl-4,5-dihydro-1 H- pyrazol-1 ,5-diyl]; or • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom (notably azabicyclo[2.1.1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, or azaspiro[2.4]heptan-diyl); wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci-s)alkyl (especially methyl).

[0162] 15) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X4represents N and Ring A represents hexahydrocyclopenta[b]pyrrol-1 (2 / - / ),2-diyl, hexahydro-4 / - / -furo[3,2-b]pyrrol- 4,5-diyl, 4-methyl-2-azabicyclo[2.1 ,1]hexan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3-azabicyclo[3.1.0]hexan- 2,3-diyl, 2-azabicyclo[2.2.1]heptan-1,2-diyl, 5-azaspiro[2.4]heptan-4,5-diyl, 5-azaspiro[2.4]heptan-5,6-diyl, 1,1- difluoro-5-azaspiro[2.4]heptan-5,6-diyl, or 6-azaspiro[2.5]octan-5,6-diyl.

[0163] 16) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X4represents N and Ring A represents 4-methyl-2-azabicyclo[2.1 .1]hexan-1 ,2-diyl, 2-azabicyclo[3.1 .0] hexan-2, 3-diy I , 3-azabicyclo[3.1.0]hexan-2,3-diyl, 2-azabicyclo[2.2.1]heptan-1 ,2-diyl, or 5-azaspiro[2.4]heptane-4,5-diyl, 5- azaspiro[2.4]heptan-5,6-diyl [notably 4-methyl-2-azabicyclo[2.1.1]hexan-1,2-diyl, 3-azabicyclo[3.1.0]hexan-2,3- diyl, or 2-azabicyclo[2.2.1]heptan-1 ,2-diyl],

[0164] 17) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X4represents CH and Ring A represents a monocyclic (Cs-ejcycloalkan-diyl .

[0165] 18) Another embodiment relates to compounds according to embodiment 17), wherein the substituents -S(=O)(=X3)-(Ring B) and -C(=O)N(R1)(R2) of Ring A are in relative trans configuration.

[0166] Thus, according to this embodiment, a compound of Formula (I) represents either a compound of Formula (II), or a compound of Formula (III), or any mixture thereof (especially enantiomerically-enriched compound of Formula (II)):

[0167] Formula (II) Formula (III).

[0168] 19) Another embodiment relates to compounds according to any one of embodiments 1) to 18), wherein R1represents hydrogen; methyl or ethyl. 20) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R2represents: -(CH2)q-Cy1; wherein q is 0 or 1 (especially 0) and Cy1represents a saturated monocyclic (CsjJcycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl or isopropyl), (Ci-3)alkoxy (especially methoxy), cyano, and hydroxy; [notably such R2represents (cyclopropyl)methyl, 2- isopropylcyclopropyl, (2-trifluoromethyl)-cyclopropyl, (difluorocyclopropyl)methyl, cyclobutyl, (cyclobutyl)methyl, 3-(trifluoromethyl)cyclobutyl, 3-(difluoromethyl)cyclobutyl, 3-methoxycyclobutyl, 3,3- dimethylcyclobutyl, 3,3-difluorocyclobutyl, (3,3-difluorocyclobutyl)methyl, (cyclopentyl)methyl, 1- cyanocyclopentyl, 1 -fluorocyclopentyl, 2-fluorocyclopentyl, 2-methoxycyclopentyl, 2-cyanocyclopentyl, 3- fluorocyclopentyl, 3-cyanocyclopentyl, 3-hydroxycyclopentyl, 3-methoxycyclopentyl, (1- fluorocyclopentyl)methyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl. 1 -methylcyclohexyl,

[0169] 2-methylcyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl, 3-methylcyclohexyl, 3-hydroxycyclohexyl,

[0170] 3-methoxycyclohexyl, 3-cyanocyclohexyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4, 4-di methylcyclohexyl, 4,4-difluorocyclohexyl, or cycloheptyl; in particular such R2represents 2- isopropylcyclopropyl, 3-(trifluoromethyl)cyclobutyl, 3-(difluoromethyl)cyclobutyl, 3,3-dimethylcyclobutyl, 3,3-difluorocyclobutyl, (3,3-difluorocyclobutyl)methyl, (cyclopentyl)methyl, 2-methoxycyclopentyl, 2- cyanocyclopentyl, 3-fluorocyclopentyl, 3-cyanocyclopentyl, 3,3-dimethylcyclopentyl, 3,3- difluorocyclopentyl, cyclohexyl. 2-methylcyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl, 3- methylcyclohexyl, 3-hydroxycyclohexyl, 3-methoxycyclohexyl, 3-cyanocyclohexyl, 4-methylcyclohexyl, 4- methoxycyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, or cycloheptyl]; or -(CH2)n-Cy2; wherein n is 0 or 1 (especially 0) and Cy2represents a 4- to 7-membered saturated or monounsaturated (especially saturated) monocyclic heterocycle comprising one ring heteroatomic group selected from -O-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- (notably said heterocycle is oxetanyl, tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, 3,6-dihydro-2 / 7-pyranyl, tetrahydro-2H-thiopyran-1,1 -dioxide, 1- imino-1-oxidohexahydro-1-A6-thiopyranyl, or 1 -methylimino-1-oxidohexahydro-1-A6-thiopyranyl); in particular said heterocycle is tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, or tetrahydro-2 / 7-thiopyran-1,1- dioxide); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci^)fluoroalkyl (especially difluoromethyl), halogen (especially fluoro), (Ci-s)alkyl (especially methyl), and (Ci-3)alkoxy (especially methoxy); [notably such R2represents [3-(difluoromethyl)oxetan-3-yl]methyl, tetrahydrofuran-3-yl, 3-methyltetrahydrofuran-3-yl, (3- methyltetrahydrofuran-3-yl)methyl, tetrahydro-2 / 7-pyran-4-yl, (tetrahydro-2H-pyran-3-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, 4-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2 / 7-pyran-4-yl, 3- methoxytetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2 / 7-pyran-4-yl, 5,5-difluorotetrahydro-2H-pyran-2-yl, 6,6-dimethyltetrahydro-2 / - / -pyran-3-yl, 2J6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6-dimethyltetrahydro-2 / - / - pyran-4-yl, 2J2-dimethyltetrahydro-2 / 7-pyran-4-yl, 5-fluoro-3,6-dihydro-2H-pyran-2-yl, 1 ,1- dioxidotetrahydro-2 / 7-thiopyran-4-yl, 1-imino-1-oxidohexahydro-1-A6-thiopyran-4-yl, or 1-methylimino-1- oxidohexahydro-1-A6-thiopyran-4-yl; in particular such R2represents 3-methyltetrahydrofuran-3-yl, (3- methyltetrahydrofuran-3-yl)methyl, tetrahydro-2 / 7-pyran-4-ylJ3-methoxytetrahydro-2 / - / -pyran-4-yl, 2- methyltetrahydro-2 / - / -pyran-4-yl, 6,6-dimethyltetrahydro-2 / - / -pyran-3-yl, 2,6-dimethyltetrahydro-2 / 7-pyran-4- yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, or 1, 1-dioxidotetrahydro-2 / 7-thiopyran-4-yl; or -(CH2)m-Cy3; wherein m is 0 or 1 (especially 0) and Cy3represents a saturated spiro, fused, or bridged bicyclic (C^cycloalkyl (notably bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said bicyclic (Cs-sjcycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from halogen (especially fluoro) or (Ci^alkyl (especially methyl); [notably such R2represents bicyclo[1 .1 .1]pentan-1-yl, 3-methylbicyclo[1 .1 .1]pentan-1-yl, bicyclo[3.1.0]hexan-2-yl, spiro[2.3]hexan-5-yl, 1 ,1-difluorospiro[2.3]hexan-5-yl, spiro[3.3]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-1-yl, (bicyclo[2.1.1]hept-2-yl)methyl, spiro[2.4]heptan-5-yl, 1 , 1-difluorospiro[2.4]heptan-5-yl, spiro[2.4]heptan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-6-yl, or 1 ,1- difluorospiro[2.5]octan-6-yl; in particular such R2represents bicyclo[1.1.1]pentan-1-yl, bicyclo[3.1.0]hexan- 2-yl, 1 ,1-difluorospiro[2.3]hexan-5-yl, spiro[3.3]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[2.2.1]heptan-

[0171] 2-yl, (bicyclo[2.1.1]hept-2-yl)methyl, spiro[2.4]heptan-5-yl, 1 ,1-difluorospiro[2.4]heptan-5-yl, spiro[2.4]heptan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-6-yl, or 1 ,1-difluorospiro[2.5]octan-6-yl]; or a 7-membered saturated spiro or bridged bicyclic heterocycle comprising one ring oxygen atom [notably such R2represents 2-oxaspiro[3.3]heptan-6-yl or 7-oxabicyclo[2.2.1]heptan-2-yl; in particular such R27- oxabicyclo[2.2.1]heptan-2-yl],

[0172] 21) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R2represents: -(CH2)q-Cy1; wherein q is 0 or 1 (especially 0) and Cy1represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl or isopropyl), (Ci-3)alkoxy (especially methoxy), cyano, and hydroxy; [notably such R2represents 2-isopropylcyclopropyl,

[0173] 3-(trifluoromethyl)cyclobutyl, 3-(difluoromethyl)cyclobutyl, 3,3-dimethylcyclobutyl, 3,3-difluorocyclobutyl, (3,3-difluorocyclobutyl)methyl, (cyclopentyl)methyl, 2-methoxycyclopentyl, 2-cyanocyclopentyl, 3- fluorocyclopentyl, 3-cyanocyclopentyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl. 2- methylcyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl, 3-methylcyclohexyl, 3-hydroxycyclohexyl, 3- methoxycyclohexyl, 3-cyanocyclohexyl, 4-methylcyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, or cycloheptyl]; or -(CH2)n-Cy2; wherein n is 0 or 1 (especially 0) and Cy2represents a 4- to 7-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from -0- or -(SO2)- (notably said heterocycle is tetrahydrofuranyl, tetrahydro-2 / 7-pyranyl, or tetrahydro-2 / 7-thiopyran-1, 1 -dioxide); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro), (Ci-s)alkyl (especially methyl), and (Ci-3)alkoxy (especially methoxy); [notably such R2represents 3-methyltetrahydrofuran-3-yl, (3- methyltetrahydrofuran-3-yl)methyl, tetrahydro-2 / 7-pyran-4-yl, 3-methoxytetrahydro-2H-pyran-4-yl, 2- methyltetrahydro-2 / - / -pyran-4-yl, 6,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6-dimethyltetrahydro-2 / 7-pyran-4- yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, or 1, 1-dioxidotetrahydro-2 / 7-thiopyran-4-yl]; or -(CH2)m-Cy3; wherein m is 0 or 1 (especially 0) and Cy3represents a saturated spiro, fused, or bridged bicyclic (C^cycloalkyl (notably bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said bicyclic (C^cycloalkyl is unsubstituted, mono-substituted with (Ci-s)alkyl (especially methyl), or di-substituted with halogen (especially fluoro); [notably such R2represents bicyclo[1.1.1]pentan-1-yl, bicyclo[3.1.0]hexan-2-yl, 1 ,1-difluorospiro[2.3]hexan-5-yl, spiro[3.3]heptan-2-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, (bicyclo[2.1.1]hept-2-yl)methyl, spiro[2.4]heptan-5-yl, 1 ,1- difluorospiro[2.4]heptan-5-yl, spiro[2.4]heptan-1-yl, spiro[2.5]octan-4-yl, spiro[2.5]octan-6-yl, or 1 ,1- difluorospiro[2.5]octan-6-yl]; or a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom (notably 7- oxabicyclo[2.2.1]heptanyl).

[0174] 22) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R2represents: -(CH2)q-Cy1; wherein q is 0 and Cy1represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (Cs-zjcycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro), (Ci-s)alkyl (especially methyl), (Ci-3)alkoxy (especially methoxy), and cyano; [notably such R2represents 3,3-dimethylcyclobutyl,

[0175] 3-fluorocyclopentyl, 3-cyanocyclopentyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl. 2- methylcyclohexyl, 2-methoxycyclohexyl, 3-methylcyclohexyl, 3-hydroxycyclohexyl, 3-methoxycyclohexyl,

[0176] 4-methylcyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, or cycloheptyl]; or -(CH2)n-Cy2; wherein n is 0 and Cy2represents a 4- to 7-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from -0- or -(SO2)- (notably said heterocycle is tetrahydro- 2 / - / -pyranyl or tetrahydro-2H-thiopyran-1,1 -dioxide); wherein said heterocycle is mono- or di-substituted; wherein the substituents are independently selected from halogen (especially fluoro) or (Ci-3)alkyl (especially methyl); [notably such R2represents 2-methyltetrahydro-2 / - / -pyran-4-yl, 2,6-dimethyltetrahydro- 2 / - / -pyran-4-yl, 2,2-dimethyltetrahydro-2 / - / -pyran-4-yl, or 1 ,1-dioxidotetrahydro-2 / - / -thiopyran-4-yl]; or -(CH2)m-Cy3; wherein m is 0 and Cy3represents a saturated spiro, fused, or bridged bicyclic (C^cycloalkyl (notably bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said bicyclic (C^cycloalkyl is unsubstituted or disubstituted with halogen (especially fluoro); [notably such R2represents bicyclo[3.1.0]hexan-2-yl, 1 , 1- difluorospiro[2.3]hexan-5-yl, bicyclo[4.1.0]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, 1 ,1- difluorospiro[2.4]heptan-5-yl, spiro[2.5]octan-4-yl, or 1 , 1-difluorospiro[2.5]octan-6-yl]; or a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom (notably 7- oxabicyclo[2.2.1]heptanyl).

[0177] 23) Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein R1and R2together with the nitrogen to which they are attached form:

[0178] • a 7- to 11-membered (especially 8-membered) saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms (notably said heterocycle is 2- azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan- 6-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan- 2-yl, 1-oxa-6-azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[5.5]undecan-8-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 1 ,4-dioxa-8-azaspiro[4.6]undecan-8- yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, or 8-azaspiro[4.5]decan-8-yl; in particular said heterocycle is 6- azaspiro[2.5]octan-6-yl); wherein said heterocycle is unsubstituted or mono-substituted with hydroxy; or

[0179] • a 7- to 9-membered (especially 7- to 8-membered) saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom (notably said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; in particular said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl or 8-azabicyclo[3.2.1]octan-8-yl); wherein said 7- to 9-membered bridged heterocycle is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: hydroxy, halogen (especially fluoro), (Ci^)alkyl (especially methyl), and (Ci -3)alkoxy (especially methoxy or ethoxy); [notably such 7- to 9-membered bridged heterocycle represents 7-azabicyclo[2.2.1]heptan-7-yl, 2-hydroxy-7-azabicyclo[2.2.1]heptan- 7-yl, 2-methoxy-7-azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-methyl-8- azabicyclo[3.2.1]octan-8-yl, 3-methoxy-8-azabicyclo[3.2.1]octan-8-yl, 3-ethoxy-8- azabicyclo[3.2.1]octan-8-yl, 3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl, 1 ,3,3-trimethyl-8- azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 9-aza-bicyclo[3.3.1]non-9-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl]; or

[0180] • a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms (notably 2-azaadamantan-2-yl or 2-oxa-6-azaadamantan-6-yl).

[0181] 24) Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein R1and R2together with the nitrogen to which they are attached form:

[0182] • an 8-membered saturated spiro bicyclic heterocycle comprising said nitrogen atom (notably said heterocycle is 6-azaspiro[2.5]octan-6-yl); or

[0183] • a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom (notably said 7- to 8-membered bridged heterocycle is 7-azabicyclo[2.2.1]heptan-7-yl or 8- azabicyclo[3.2.1]octan-8-yl); wherein said 7- to 8-membered bridged heterocycle is unsubstituted, or mono-substituted with (Ci-3)alkoxy (especially methoxy); [notably such 7- to 8-membered bridged heterocycle represents 7-azabicyclo[2.2.1 ]heptan-7-yl or 3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]; or

[0184] • a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms (notably 2-azaadamantan-2-yl or 2-oxa-6-azaadamantan-6-yl).

[0185] 25) Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein R1and R2together with the nitrogen to which they are attached represent: (4,4-difluorocyclohexyl)-(methyl)-amino, (4,4- difluorocyclohexyl)-amino, (3-cyanocyclopentyl)-amino, (1,1-difluorospiro[2.5]octan-6-yl)-(methyl)-amino, (1 ,1- difluorospiro[2.5]octan-6-yl)-amino, (3-fluorocyclopentyl)-amino, (bicyclo[4.1.0]heptan-3-yl)-amino,

[0186] (bicyclo[4.1.0]heptan-3-yl)-(methyl)-amino, (1 , 1-difluorospiro[2.3]hexan-5-yl)-amino, (bicyclo[2.2.1]heptan-2-yl)- amino, (3,3-difluorocyclopentyl)-amino, (2,6-dimethyltetrahydro-2 / 7-pyran-4-yl)-amino, (2-methylcyclohexyl)- amino, (2-methoxycyclohexyl)-amino, (3,3-dimethyl-cyclobutyl)-amino, (2,6-dimethyltetrahydro-2 / - / -pyran-4-yl)- (methyl)-amino, (1 , 1-difluorospiro[2.3]hexan-5-yl)-(methyl)-amino, (3,3-dimethyl-cyclopentyl)-amino, (cyclohexyl)- (methyl)-amino, 2-azaadamantan-2-yl, (4-methoxy-cyclohexyl)-amino, (3-methoxycyclohexyl)-(methyl)-amino, (3- cyanocyclopentyl)-(methyl)-amino, (4,4-dimethylcyclohexyl)-(methyl)-amino, (2,2-dimethyl-tetrahydro-2 / 7-pyran-4- yl)-(methyl)-amino, 3-methoxy-8-azabicyclo[3.2.1]octan-8-yl, (1 , 1-difluorospiro[2.4]heptan-5-yl)-amino, 2-oxa-6- azaadamantan-6-yl, (2-methyl-tetrahydropyran-4-yl)-(methyl)-amino, (7-oxa-bicyclo[2.2.1]heptan-2-yl)-amino, (1, 1- dioxidotetrahydro-2 / - / -thiopyran-4-yl)-(methyl)-amino, (1 , 1-difluorospiro[2.4]heptan-5-yl)-(methyl)-amino, 7- azabicyclo[2.2.1]heptan-7-yl; (4-methylcyclohexyl)-amino, (4-methylcyclohexyl)-(methyl)-amino, (3- methylcyclohexyl)-amino, (cycloheptyl)-amino, (spiro[2.5]octan-4-yl)-amino, (3-hydroxycyclohexyl)-amino, (bicyclo[3.1.0]hexan-2-yl)-amino, (3-trifluoromethyl-cyclobutyl)-amino, ((3,3-difluorocyclobutyl)-methyl)-amino, ((2- isopropyl)-cyclopropyl)-amino, (3-cyanocyclopentyl)-(methyl)-amino, (spiro[2.5]octan-4-yl)-(methyl)-amino, ((3- methyltetrahydrofuran-3-yl)-methyl)-amino, (2-hydroxycyclohexyl)-amino, (3-methoxyltetrahydropyran-4-yl)- (methyl)-amino, 6-azaspiro[2.5]octan-6-yl, (spiro[2.4]heptan-5-yl)-amino, (3-methyltetrahydrofuran-3-yl)-amino, ((bicyclo[2.2.1]heptan-2-yl)-methyl)-amino, (2-methoxycyclopentyl)-(methyl)-amino, (spiro[3.3]heptan-2-yl)-amino, (tetrahydropyran-4-yl)-(methyl)-amino, (spiro[2.4]heptan-1-yl)-amino, (6,6-dimethyltetrahydro-2 / 7-pyran-3-yl)- (methyl)-amino, 3-methoxy-8-azabicyclo[3.2.1]octan-8-yl, (2-cyanocyclopentyl)-amino, (2,2-dimethyltetrahydro- 2 / 7-pyran-4-yl)-amino, (3,3-dimethyl-cyclopentyl)-(methyl)-amino, (bicyclo[1 .1 ,1]pentan-1-yl)-amino, (3- cyanocyclohexyl)-amino, (3-difluoromethyl-cyclobutyl)-amino, ((cyclopentyl)-methyl)-(methyl)-amino, or (4,4- cyclohexyl)-(ethyl)-amino.

[0187] 26) Another aspect of the invention relates to compounds of the Formula (I) according to any one of embodiments 1) to 25) which are also compounds of the Formula (IV) (i.e. , the absolute configuration of the ring carbon atom to which the group -C(=O)N(R1)(R2) is attached, is as depicted in Formula (IV) below):

[0188] Formula (IV).

[0189] 27) Another embodiment relates to compounds according to embodiment 1) which are selected from the following compounds:

[0190] {(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-((1 S,3R,5R)-3-methoxy-8-aza- bicy clo [3.2.1 ]oct-8-yl)-methanone;

[0191] {(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-(2-oxa-6-aza- tricy clo [3.3.1 .13,7]dec-6-yl)-methanone;

[0192] {(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-((1S,3R,5R)-3- methoxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone;

[0193] (2R*,4R*)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide; (2S,4S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0194] (1R,2S)-2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4-difluoro- cyclohexyl)-amide;

[0195] (1S,2R)-2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4-difluoro- cyclohexyl)-amide

[0196] 5-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-aza-spiro[2.4]heptane-6-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0197] 5-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-aza-spiro[2.4]heptane-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0198] 3-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0199] 3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;

[0200] 3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-oxazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;

[0201] 3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-oxazolidine-2-carboxylic acid (1, 1-difluoro-spiro[2.5]oct-6-yl)-N-methyl- amide;

[0202] 2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-5-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;

[0203] 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methyl-2-aza-bicyclo[2.1 ,1]hexane-1-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0204] 1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-azepane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide; 1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0205] (S)-N-(Cyclopentylmethyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0206] (S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-methyl-[1 , T-biphenyl]-2-yl)sulfonyl)-N-(methyl-d3)pyrrolidine-2- carboxamide;

[0207] (S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'-fluoro-6'-methoxy-5-methyl-[1JT-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;

[0208] (S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-6'-methoxy-5-methyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;

[0209] (S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-(methyl-d3)-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0210] (S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'-fluoro-5,6-dimethyl-[1 , T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide; (S)-N-((SR)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((2-(ethyl(isopropyl)amino)-4-methylphenyl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;

[0211] (S)-N-((RS)-3,3-Dimethylcyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;

[0212] (S)-N-((RS)-3,3-Dimethylcyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;

[0213] (S)-N-((RS)-3,3-Difluorocyclopentyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)pyrrolidine-2- carboxamide;

[0214] (S)-N-((RS)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((2-(ethyl(isopropyl)amino)-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;

[0215] (S)-N-((1R*,3S*)-3-Cyanocyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;

[0216] (S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((4-methyl-2-((S)-2-methylpiperidin-1-yl)phenyl)sulfonyl)pyrrolidine-2- carboxamide;

[0217] (S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)pyrrolidine-2- carboxamide;

[0218] (S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;

[0219] (S)-N-((1R*,3S*)-3-Cyanocyclopentyl)-1-((2'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0220] (S)-N-((1R*,3R*)-3-Cyanocyclohexyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;

[0221] (S)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0222] (S)-1-[6-Methyl-2-((1 S,2R)-2-methyl-cyclohexyl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0223] (S)-1-[6-Methyl-2-(2-methyl-cyclohex-1-enyl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0224] (S)-1-[4-Methyl-2-(4-methyl-isothiazol-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0225] (S)-1-[4-Methyl-2-(4-methyl-isothiazol-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 , 1-difluoro- spiro[2.5]oct-6-yl)-N-methyl-amide;

[0226] (S)-1-[4-Methyl-2-(3-methyl-pyrazin-2-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro-spiro[2.5]oct- 6-yl)-N-methyl-amide; (S)-1-[4-Methyl-2-(2-methyl-pyridin-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0227] (S)-1-[2-(Ethyl-isopropyl-amino)-6-trifluoromethyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0228] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid spiro[3.3]hept-2- ylamide;

[0229] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid spiro[2.4]hept-1- ylamide;

[0230] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(tetrahydro- pyran-4-yl)-amide;

[0231] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(4-methyl- cyclohexyl)-amide;

[0232] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(2-methyl- tetrahydro-pyran-4-yl)-amide;

[0233] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cyclohexyl-N-methyl- amide;

[0234] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cycloheptylamide;

[0235] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[4.1.0]hept-3- ylamide;

[0236] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[3.1.0]hex-2- ylamide;

[0237] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[2.2.1]hept-2- ylamide;

[0238] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[1 .1 .1]pent-1- ylamide;

[0239] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (bicyclo[4.1 ,0]hept-3- yl)-N-methyl-amide;

[0240] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (bicyclo[2.2.1]hept-2- ylmethyl)-amide;

[0241] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (7-oxa- bicy clo [2.2.1 ] hept-2-y l)-amide ;

[0242] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-methyl-cyclohexyl)- amide;

[0243] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-methoxy- cyclohexyl)-amide; (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-amide;

[0244] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0245] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-trifluoromethyl- cyclobutyl)-amide;

[0246] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-methyl-cyclohexyl)- amide;

[0247] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-methoxy-tetrahydro- pyran-4-yl)-N-methyl-amide;

[0248] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-difluoromethyl- cyclobutyl)-amide;

[0249] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-dimethyl- cyclopentyl)-amide;

[0250] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-dimethyl- cyclobutyl)-amide;

[0251] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-difluoro- cyclobutylmethyl)-amide;

[0252] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2-cyano-cyclopentyl)- amide;

[0253] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6-dimethyl- tetrahydro-pyran-4-yl)-N-methyl-amide;

[0254] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,2-dimethyl- tetrahydro-pyran-4-yl)-N-methyl-amide;

[0255] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 R,2R,4S)- bicy clo [2.2.1 ] hept-2-y I amide ;

[0256] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.5]oct-6-yl)-amide;

[0257] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.5]oct-6-yl)-N-methyl-amide;

[0258] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.4]hept-5-yl)-amide;

[0259] (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.3]hex-5-yl)-amide; (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.3]hex-5-yl)-N-methyl-amide;

[0260] (S)-1-[2-(Ethyl-isopropyl-amino)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6-dimethyl-tetrahydro- pyran-4-yl)-N-methyl-amide;

[0261] (S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0262] (S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0263] (S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0264] (S)-1-[2-(5-Ethyl-pyrazol-1-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0265] (S)-1-[2-(3-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0266] (S)-1-[2-(3-Fluoro-pyrazin-2-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro-spiro[2.5]oct- 6-yl)-N-methyl-amide;

[0267] (S)-1-[2-(2,6-Difluoro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0268] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl- spiro[2.5]oct-6-yl-amide;

[0269] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl- (2-methyl-tetrahydro-pyran-4-yl)-amide;

[0270] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cyclohexyl-N-methyl-amide;

[0271] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicy clo [4.1 .0]hept-3-ylamide;

[0272] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicy clo [4.1 .0]hept-3-yl-N-methyl-amide;

[0273] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- dimethyl-cyclohexyl)-N-methyl-amide;

[0274] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-amide;

[0275] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide; (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-amide;

[0276] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;

[0277] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,2- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;

[0278] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.5]oct-6-yl)-amide;

[0279] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.5]oct-6-yl)-N-methyl-amide;

[0280] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.4]hept-5-yl)-N-methyl-amide;

[0281] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.3]hex-5-yl)-amide;

[0282] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.3]hex-5-yl)-N-methyl-amide;

[0283] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid

[0284] ((2S,4S,6R)-2,6-dimethyl-tetrahydro-pyran-4-yl)-amide;

[0285] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid ((2R,4R,6S)-2,6-dimethyl-tetrahydro-pyran-4-yl)-amide;

[0286] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0287] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-amide;

[0288] (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;

[0289] (S)-1-[2-((2R,5S)-2,5-Dimethyl-pyrrolidin-1-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0290] (S)-1-(6'-Methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0291] (S)-1-(5,2'-Dimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;

[0292] (S)-1-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0293] (S)-1-(2-tert-Butylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide; (S)-1-(2-lsopropylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0294] (S)-1-(2-Diisopropylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0295] (S)-1-(2-Cyclohexyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0296] (S)-1-(2-Cyclohex-1-enyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0297] (S)-1-(2-Cyclohept-1-enyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;

[0298] (S)-1-(2-Bicyclo[2.2.1]hept-2-en-2-yl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0299] (S)-1-(2-Azepan-1-yl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0300] (S)-1-(2'-Methoxy-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0301] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-ethyl-amide;

[0302] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-amide;

[0303] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0304] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (1,1 -dioxo-hexahydro-1 l6-thiopyran-4- yl)-N-methyl-amide;

[0305] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methylene-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0306] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2,5-dihydro-1 H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0307] (S)-1-(2',6'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0308] (S)-1-(2',5'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0309] (S)-1-(2',4'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0310] (S)-1-(2',3'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide; (S)-1-((S)-2,6'-Dimethyl-3,4,5,6-tetrahydro-2H-[1J4']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0311] (S)-1-((S)-2,6'-Dimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0312] (S)-1-((2S,6S)-2,6,6'-Trimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid

[0313] (4,4-difluoro-cyclohexyl)-N-methyl-amide;

[0314] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-spiro[2.5]octan-4-yl)pyrrolidine-2- carboxamide;

[0315] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-3-methyltetrahydrofuran-3-yl)pyrrolidine-

[0316] 2-carboxamide;

[0317] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S*,3S*)-3-methoxycyclohexyl)-N- methylpyrrolidine-2-carboxamide;

[0318] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S*,2R*)-2-methylcyclohexyl)pyrrolidine-2- carboxamide;

[0319] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,3S*)-3-methoxycyclohexyl)-N- methylpyrrolidine-2-carboxamide;

[0320] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R* 3S*)-3-fluorocyclopentyl)pyrrolidine-2- carboxamide;

[0321] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,3R*)-3-hydroxycyclohexyl)pyrrolidine-2- carboxamide;

[0322] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-isopropylcyclopropyl)pyrrolidine-2- carboxamide;

[0323] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-hydroxycyclohexyl)pyrrolidine-2- carboxamide;

[0324] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2R*)-2-methylcyclohexyl)pyrrolidine-2- carboxamide;

[0325] (S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-(((RS)-3-methyltetrahydrofuran-3- yl)methyl)pyrrolidine-2-carboxamide;

[0326] (S)-1-((2-((RS)-sec-Butoxy)-6-methylpyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;

[0327] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((SR)-2,2-dimethyltetrahydro-2H- pyran-4-yl)pyrrolidine-2-carboxamide;

[0328] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-spiro[2.4]heptan-5- yl)pyrrolidine-2-carboxamide; (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-6,6-dimethyltetrahydro-2H- pyran-3-yl)-N-methylpyrrolidine-2-carboxamide;

[0329] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((2R,4SR,6S)-2,6-dimethyltetrahydro-

[0330] 2H-pyran-4-yl)-N-methylpyrrolidine-2-carboxamide;

[0331] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((2R,4SR,6S)-2,6-dimethyltetrahydro-

[0332] 2H-pyran-4-yl)pyrrolidine-2-carboxamide;

[0333] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R,2S)-2- methoxycyclopentyl)pyrrolidine-2-carboxamide;

[0334] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S,2R)-2- methoxycyclopentyl)pyrrolidine-2-carboxamide;

[0335] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-methoxycyclopentyl)-N- methylpyrrolidine-2-carboxamide;

[0336] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2- methoxycyclohexyl)pyrrolidine-2-carboxamide;

[0337] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2- hydroxycyclohexyl)pyrrolidine-2-carboxamide;

[0338] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-4-methylphenyl)sulfonyl)-N-((RS)-2,2-dimethyltetrahydro-2H-pyran-4- yl)pyrrolidine-2-carboxamide;

[0339] (S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-4-methylphenyl)sulfonyl)-N-((RS)-2,2-dimethyltetrahydro-2H-pyran-4- yl)-N-methylpyrrolidine-2-carboxamide;

[0340] (S)-1-(((Sa)-2'-Chloro-5,6'-dimethyl-[1, 1'-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;

[0341] (S)-1-(((Ra)-2'-Chloro-5,6'-dimethyl-[1, 1'-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;

[0342] (R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0343] (R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;

[0344] (7-Aza-bicyclo[2.2.1]hept-7-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;

[0345] (6-Aza-spiro[2.5]oct-6-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;

[0346] (6-Aza-spiro[2.5]oct-6-yl)-{(S)-1-[2-((3S,5S)-3,5-dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin- 2-yl}-methanone; (2S,5S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0347] (25.45)-4-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2 -carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0348] (25.45)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-fluoro-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0349] (25.45)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0350] (25.45)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methoxy-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0351] (2S,4R)-4-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0352] (2S)-N-(Bicyclo[4.1.0]heptan-3-yl)-1-((2'-fluoro-5-methyl-[1, -biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0353] (2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{N-(methyl)-(2',6'-difluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0354] (2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{(2'-fluoro-5-methyl-[1 , T-biphen-2-yl])-sulfonimidoyl}-pyrrolidine}-2- carboxamide;

[0355] (2S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5,6'-dimethyl-[1, -biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0356] (2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{N-(methyl)-(6-methyl-2-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0357] (2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,4-difluoropyridin-3-yl)-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;

[0358] (2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(methyl)-(2'-fluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0359] (2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(cyclopropyl)-(2'-fluoro-5-methyl-[1 ,1'-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0360] (2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(methyl)-(2',6'-difluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0361] (2S)-N-(1 , 1-Difluorospiro[2.3]hexan-5-yl)-N-(methyl)-{1-{N-(cyclopropyl)-(2'-fluoro-5-methyl-[1 , -biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;

[0362] (2S)-N-((3R,6s)-1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{(R)-N-(methyl)-(2-cyclohexyl-6-methyl-pyridin-3- yl)-sulfonimidoyl}-pyrrolidine}-2-carboxamide; (2S)-1-((2-(2-Chloro-4-methylpyridin-3-yl)-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide;

[0363] (2R,3S)-3-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;

[0364] (2-Aza-tricyclo[3.3.1 .13,7]dec-2-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;

[0365] (2-Aza-tricyclo[3.3.1 .13,7]dec-2-yl)-{(S)-1-[2-((3S,5S)-3,5-dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]- pyrrolidin-2-yl}-methanone;

[0366] (1S,3S,5S)-2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0367] (1S,2S,5R)-3-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-3-aza-bicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;

[0368] (1S,2S,5R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-3-aza-bicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0369] (1S,2R)-2-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4- difluoro-cyclohexyl)-amide;

[0370] (1S,2R)-2-((2S,6S)-2,6,6'-Trimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-cyclohexanecarboxylic acid (4,4-difluoro-cyclohexyl)-amide;

[0371] (1RS,2SR)-N-(4,4-Difluorocyclohexyl)-2-((2-((2S,6S)-2,6-dimethylpiperidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)cyclopentane-1-carboxamide;

[0372] (1R,3S,4S)-2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;

[0373] ((S)-1-[2-(lsopropyl-methyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide; and

[0374] (S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-5J6-dimethyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide.

[0375] The compounds of Formula (I) according to embodiments 1) to 27) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).

[0376] The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. The present invention also relates to a method for the prevention I prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of Formula (I) according to embodiments 1) to 27).

[0377] For avoidance of any doubt, if compounds are described as useful for the prevention I prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention I prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention I prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.

[0378] The compounds of Formula (I) according to any one of embodiments 1 ) to 27) are useful for the prevention I prophylaxis or treatment of diseases or disorders relating to the OX2R receptor, and notably in disease and disorders in which agonism of OX2R plays a role. Disease and disorders in which agonism of OX2R plays a role are particularly disease and disorders associated with difficulties maintaining wakefulness. Subjects presenting disease and disorders associated with difficulties maintaining wakefulness complain of: feelings of excessive sleepiness; episodes of inadvertently falling asleep, including sleep attacks (episodes of falling asleep without prodromal symptoms of drowsiness); a prolonged main sleep episode that is unrefreshing; recurrent naps in the same day; or sleep inertia (prolonged difficulty waking up, with irritability, automatic behavior or confusion).

[0379] Thus, the compounds of Formula (I) according to embodiments 1) to 27) are useful for improving wakefulness in a subject (especially in a subject having hypersomnia or narcolepsy, or presenting excessive daytime sleepiness (EDS)).

[0380] The term "improving wakefulness in a subject” refers to improving symptoms of, or to the prevention I prophylaxis or treatment of: hypersomnia, particularly prevention I prophylaxis or treatment of:

[0381] • narcolepsy; including especially narcolepsy type 1 and narcolepsy type 2;

[0382] • secondary narcolepsy associated with inherited disorders (such as Prader-Willi syndrome, Niemann- Pick C disease, or myotonic dystrophy);

[0383] • secondary narcolepsy associated with tumors, especially symptoms of narcolepsy associated with tumors that involve the hypothalamus area;

[0384] • secondary narcolepsy associated with head trauma, especially symptoms of narcolepsy associated with head trauma affecting the hypothalamic area;

[0385] • idiopathic hypersomnia; or

[0386] • Kleine-Levin syndrome; excessive daytime sleepiness (EDS), particularly: • improving symptoms of EDS in subjects having a circadian rhythm sleep-wake disorder, particularly improving symptoms of EDS in subjects having: delayed sleep-wake phase disorder, shift work disorder, or jet lag disorder;

[0387] • improving symptoms of EDS due to or associated with a medical disorder, wherein said medical disorder is especially an objective sleep disturbance, obesity, diabetes, a neurodegenerative disorder, an auto-immune disorder, a psychiatric disorder, or insufficient sleep syndrome; in particular:

[0388] ■ improving symptoms of EDS associated with objective sleep disturbances (notably sleep apnea);

[0389] ■ improving symptoms of EDS associated with obesity and / or diabetes;

[0390] ■ improving symptoms of EDS associated with a neurodegenerative disorder, notably associated with: Alzheimer's, Parkinson's, Lewy body dementia, Perry syndrome, multiple system atrophy, or Huntington's disease;

[0391] ■ improving symptoms reminiscent of narcolepsy in subjects having an auto-immune disorder (especially neuromyelitis optica, multiple sclerosis, Guillain-Barre syndrome, or anti-Ma2 encephalitis);

[0392] ■ improving symptoms of EDS I treatment of hypersomnia associated with a psychiatric disorder, such as depression; or

[0393] ■ improving symptoms of EDS I treatment of hypersomnia associated with insufficient sleep syndrome; or

[0394] • improving symptoms of EDS I treatment of hypersomnia due to a medication or substance; or fatigue (especially including chronic fatigue), particularly:

[0395] • fatigue accompanied by mental fatigue with poor concentration and memory;

[0396] • fatigue associated with infections (viral or bacterial), chronic inflammatory diseases, cancer, or neurodegeneration; or

[0397] • fatigue associated with autoimmune disease primary Sjogren's syndrome.

[0398] The term "narcolepsy type 1” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions).

[0399] Fatigue is characterized by a lack of energy ("an overwhelming sense of tiredness, a feeling of exhaustion").

[0400] Further disease and disorders in which agonism of OX2R plays a role include:

[0401] • eating disorders;

[0402] • obesity, particularly obesity in narcoleptic subjects;

[0403] • attention deficit disorders;

[0404] • neuropsychiatric disorders, notably mood disorders, particularly depression (such as major depressive disorder (MDD)); • pain, particularly inflammatory pain, or chronic neuropathic pain;

[0405] • inflammation, particularly inflammation following cardiac arrest, intracerebral hemorrhage, or septic shock; and

[0406] • cognitive impairments, particularly age-related deficits in learning and memory or cognitive impairments due to sleep loss.

[0407] Additionally, agonism of OX2R plays a role in:

[0408] • disorders of consciousness, notably coma, vegetative state and minimally conscious state induced by traumatic brain injury

[0409] • recovery of arousal following unconsciousness associated with cardiac arrest or acute alcohol intoxication, or following anesthetic-induced unconsciousness.

[0410] In the context of the present invention, the term "subject” refers to a mammal, especially a human; in the context of a certain diagnosis or disease, the term "subject” and "patient” are to be understood as being interchangeable.

[0411] The compounds of Formula (I) according to any one of embodiments 1) to 27) are in particular useful as therapeutic agents for the prevention I prophylaxis or treatment of a disease and disorders associated with difficulties maintaining wakefulness. They can be used as single therapeutic agents or in combination with one or more additional therapeutic agents. Such therapeutic agents include modafinil, pitolisant, sodium oxybate, solriamfetol, armodafinil, dextroamphetamine, methylphenidate, clarithromycin, venlafaxine, clomipramine and lithium (see for example Mask! K. et al. J Clin Sleep Med. 2021 , 17(9), 1881-1893; Bassett! C. et al. Eur J Neurol. 2021 , 00, 1-16).

[0412] The invention, thus, also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and one or more additional therapeutic agents.

[0413] The invention, thus, further relates to a kit comprising a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).

[0414] Besides, any preferences and (sub-)embodiments indicated for the compounds of Formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, or uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of Formula (II), Formula (III) and Formula (IV). Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog) including metabolic stability potentially affecting (human) bioavailability and / or dosage requirements, or relating to their ability to cross the blood-brain barrier, using for example a human P-glycoprotein 1 (MDR 1) substrate assay, or an in vivo assay to determine drug concentrations in the brain, e.g. in rats after oral dosing; or relating to their functional behavior in different disease related animal models (for example: the general stimulant effect of the compound using Electroencephalography (EEG) and Electromyography (EMG) signal measurements [Yukitake H et al.; TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice; Pharmacol Biochem Behav. 2019, 187:172794], the effect of the compound on narcolepsy-cataplexy symptoms [Irukayama-Tomobe Y et al.; Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models; Proc Natl Acad Sci U S A. 2017, 114(22):5731-5736]); or for their properties with regard to drug safety and / or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

[0415] Preparation of compounds of Formula (I)

[0416] A further aspect of the invention is a process for the preparation of compounds of Formula (I). Compounds according to Formula (I) of the present invention can be prepared from commercially available or well known starting materials according to the methods described in the experimental part, by analogous methods, or according to the general sequence of reactions outlined below, wherein R1, R2, RB1, RB3, X1, X2, X3, X4, Ring A, and Ring B are as defined for Formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances, the generic groups R1, R2, RB1, RB3, X1, X2, X3and X4might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T. W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse.

[0417] General preparation routes:

[0418] Compound 9, belonging to Formula (I) wherein X3=O and X4= N can be prepared by an amide coupling reaction between an appropriate carboxylic acid with structure 2 and an appropriate amine with structure 3 (or the corresponding salt, like HOI or TFA salts) in a solvent such as THF, DMF, DOM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDO or similar and a base such as DIPEA, TEA or N-methylmorpholine (Scheme 1). Amines 3 are either commercially available, prepared following procedures described in the literature, or prepared as described in the experimental part. Compound 4 can be deprotected using standard deprotection methods known in the literature and familiar to the person skilled in the art to give 5 (or the corresponding salt, like HCI or TFA salts). Amine 5 is condensed with a sulfonyl chloride 6 (where Hal is a halogen such as I, Br, Cl, or F) in solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA to give 7. The RB3group can be introduced from intermediate 7, wherein Hal= I, Br, or Cl, by e.g. a Suzuki-Miyaura cross-coupling reaction with an arylboronic acid or an arylboronic ester in a solvent such as THF or DME and in presence of a base as K2CO3, NaHCOa or K3PO4 and a Pd catalyst as Pd(PPh3)4, by e.g. a Negishi cross coupling reaction with an organozinc reagent in a solvent such as THF and in presence of a Pd precatalyst such as SPhos Pd G2, or by a Stille cross-coupling reaction with the appropriate organostannyl reagent in a solvent such a dioxane or toluene and in presence of a Pd catalyst such as Pd(PPhs)4 or Pd(dppf)Cl2, to yield compound with general formula 9. Alternatively, intermediate 7 (wherein Hal= I, Br, or Cl) can be converted into its boronic acid or boronic ester analogue 8 by e.g. reaction with boronic acid pinacol ester in presence of a Pd catalyst such as PdCI2(MeCN)2and a ligand such as SPhos in a solvent such as 1,4-dioxane and in presence of a base such as TEA, followed by a Suzuki-Miyaura cross-coupling in similar conditions as described herein before to yield 9. Final compound 9 wherein RB3is either -N or -0 linked with Ring B can be prepared from 7 (wherein Hal= F or Cl) via a SNAP (nucleophilic aromatic substitution) reaction with the corresponding amine and an inorganic base such as K2CO3 in a solvent such as DMSO or DME or with the corresponding alcohol in presence of a base such as NaH and in a solvent such as THF. Alternatively, amine 5 can also be condensed with a sulfonyl chloride of general formula 10 in solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA to give 9. Sulfonyl chlorides 6 and 10 and amines 3 may be commercially available, prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.

[0419]

[0420] Scheme 1. Synthesis of sulfonamide compound 9 by variation of sulfonamide part in the last step. Step I) Amide coupling, ii) Deprotection, ill) Sulfonamide formation, iv) Arylboronic acid / ester formation, v) Cross-coupling, vi) Cross-coupling / SNAr reaction, vii) Sulfonamide formation. Alternatively, variation in the amide functional group can be introduced at the very last step following the procedures described in Scheme 2. An appropriate aminoester 11 (or the corresponding salt, like HCI or TFA salts) can be reacted with sulfonyl chloride 6 (where Hal is a halogen such as I, Br, Cl, or F) in solvent such as DCM, DMF, MeCN, and in presence of a base such as TEA or DIPEA to yield intermediate 12. Introduction of RB3can take place by a cross-coupling reaction such as e.g. a Suzuki-Miyaura, Negishi, or Stille reaction using similar conditions as described in Scheme 1 starting from intermediate 12 (wherein Hal= Cl, Br, I) to yield 13. Intermediate 13 can also be synthesized starting from aminoester 11 (or the corresponding salt, like HCI or TFA salts) by condensation with a sulfonyl chloride 10 comprising RB3. Ester 13 can then be hydrolysed into the corresponding acid (14) using a base such as LiOH or NaOH in a mixture of solvents such as THF / water. Amide formation between carboxylic acid 14 and amine 3 in a solvent such as THF, DMF, DCM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC or similar and a base such as DIPEA, TEA or N-methylmorpholine yields compound with formula 9. Final compound 9, wherein RB3is either -N or -0 linked with Ring B, can be prepared by subjecting 12 (wherein Hal= F or Cl) to a hydrolysis (using a base such as LiOH or NaOH in a mixture of solvents such as

[0421] THF / Water) to obtain the corresponding acid (15), followed by an SNAP reaction with the corresponding amine and an inorganic base such as K2CO3 in a solvent such as DMSO or DME, or with the corresponding alcohol in presence of a base such as NaH and in a solvent such as THF, to give 14. Finally, carboxylic acid 14 can be subjected to an amide coupling to give 9 as described herein before.

[0422] Scheme 2. Synthesis of sulfonamide 9 by variation of the amide substituent in the last step. Step I) Sulfonamide formation, ii) Cross-coupling, ill) Hydrolysis, iv) Amide formation, v) Hydrolysis vi) SNAP reaction. Sulfonimidamide (SI A) compounds with structure 20, belonging to Formula (I) wherein X3= NRN1(RN1= alkyl) and X4= N, can be prepared as described in Scheme 3. An arylthiol (16) can be oxidized into its corresponding sulfinate ester 17 by reaction with NBS and MeOH in a solvent such as DCM. Sulfinate ester 17 can be converted into sulfinamide with general structure 19 by reaction with primary amine 18 (or the corresponding salt, like HCI or TFA salts) using a base such as n-BuLi in a solvent like THF. Compound 19 can then be condensed with 5 in presence of a chlorinating agent such as fert-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2- dichloroethane to give SIA derivative 20. If not commercially available, arylthiols 16 are prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.

[0423] Scheme 3. Synthesis of SIA derivatives 20. Step I) Oxidation, II) Sulfinamide formation, ill) SIA formation.

[0424] Compound 24, belonging to Formula (I) wherein X3= NRN1(RN1= H) and X4= N can be produced as described in Scheme 4. Sulfinate ester 17 can be converted into sulfinamide 21 by reaction with lithium hexamethyldisilazide (LHMDS) in a solvent like THF and hydrolysis with sat. aq. NH4CI. Intermediate 21 can be protected with an appropriate protecting group (PG) to yield 22 using standard protection methods known in the literature and familiar to the person skilled in the art. Compound 22 can be condensed with 5 in presence of a chlorinating agent such as ferf-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2-dichloroethane to give SIA intermediate 23. Compound 24 can then be produced by subjecting intermediate 23 to standard deprotection methods known in the literature and familiar to the person skilled in the art.

[0425] Scheme 4. Synthesis of SIA derivative 24. Step i) Sulfinamide formation, ii) Protection, iii) SIA formation, iv) Deprotection.

[0426] Alternatively, 20 and 24 can be obtained via a late-stage RB3functionalization as described in Scheme 5. An arylthiol (25) can be oxidised into its corresponding sulfinate ester (26) and converted into sulfinamide 27 in a similar way as described herein before for the preparation of intermediates 17 and 21. Sulfinamide 28 can be protected with an appropriate protecting group (PG) to yield 28 using standard protection methods known in the literature and familiar to the person skilled in the art. SIA 29 can be obtained by reacting intermediate 28 with 5 in presence of a chlorinating agent such as ferf-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2- dichloroethane. The RB3group can be introduced from 29, wherein Hal= I, Br, or Cl, by e.g. a Stille cross-coupling reaction with the appropriate organostannyl reagent in a solvent such a dioxane or toluene and in presence of a Pd catalyst such as Pd(PPha)4 or Pd(dppf)Cl2, to yield compound 30. Intermediate 30, wherein RB3is -N linked with Ring B, can be prepared from 29 (wherein Hal= F or Cl) via an SNAP reaction with the appropriate amine (or the corresponding salt, like HCI or TFA salts) and an inorganic base as K2CO3 in a solvent such as DMSO or DME. The PG can be cleaved using standard deprotection methods known in the literature and familiar to the person skilled in the art to yield 24. SIA 20 can be obtained by subjecting 24 to alkylation using a base such as NaH or KOfBu and an alkylating agent such as an alkyl halide, or an alkyl sulfonates, in a solvent such as DMF. If not commercially available, arylthiols 25 can be prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.

[0427] Scheme 5. Alternative synthesis of 20 by late-stage RB3functionalization. Step i) Oxidation, ii) Sulfinamide formation, iii) Protection, iv) SIA formation, v) Cross-coupling / SNAr reaction, vi) Deprotection, vii) Alkylation.

[0428] Sulfone compounds with structure 36, belonging to Formula (I) wherein X3= 0 and X4= C can be prepared as described in Scheme 6. Michael addition between arylthiol 25 (wherein Hal= I, Br, Cl) and commercially available a,p-unsaturated ester 31 in a solvent such as piperidine yields thioether 32. Intermediate 32 is subjected to a Suzuki-Miyaura cross-coupling reaction with the appropriate arylboronic acid or ester in a solvent such as THF or DME and in presence of a base such as K2CO3, NaHCOa or K3PO4 and a Pd catalyst such as Pd (PPhs)4 to give 33. Thioether 33 can be oxidized in presence of an oxidant such as MCPBA and in a solvent such as DOM to lead to sulfone 34. Derivative 34 can be hydrolysed using standard methods as described herein before into its corresponding carboxylic acid 35 with frans-relative configuration. Subsequent amide coupling between 35 and a secondary amine 3 (or the corresponding salt, like HCI or TFA salts) in a solvent such as THF, DMF, DCM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC, pyClop (or similar), and a base such as DIPEA, TEA or N-methylmorpholine yields 36.

[0429] Scheme 6. Synthesis of sulfone compound 36. Step i) Michael addition, ii) Cross-coupling, ill) Oxidation, iv) Hydrolysis, v) Amide Coupling.

[0430] Alternatively, 36 can be produced by a RB3late-stage functionalization as described in the sequence in Scheme 7. Thioether 32, wherein Hal= I, Cl, or Br is subjected to oxidation into its corresponding sulfone (37) by reaction with an oxidant such as MCPBA and in a solvent such as DCM. Hydrolysis of the ester using a base such as LiOH or NaOH in a mixture of solvents such as THF / Water gives carboxylic acid 38 with frans-relative stereochemistry. Subsequent amide coupling between 38 and a secondary amine 3 (or the corresponding salt, like HCI or TFA salts) in a solvent such as THF, DMF, DCM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC, pyClop (or similar) and a base such as DIPEA, TEA or N-methylmorpholine yields 39. Intermediate 39, wherein Hal= I, Br, or Cl, can be subjected to a Suzuki-Miyaura cross-coupling reaction with the appropriate arylboronic acid or boronic ester in a solvent such as THF or DME and in presence of a base as K2CO3, NaHCOa or KaPO4 and a Pd catalyst such as Pd(PPha)4 to give 36. Intermediate 39, wherein Hal= F, can alternatively be prepared starting from commercially available a,p-unsaturated ester 31 by amide coupling with an amine 3 (or the corresponding salt, like HCI or TFA salts) in a solvent such as THF, DMF, DCM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC, pyClop (or similar) and a base such as DIPEA, TEA or N- methylmorpholine to give 40. Amide 40 can be subjected to hydrosulfonylation in presence of an iridium catalyst as tris(2-phenylpyridine)iridium and a radical reducing agent such as (TMS^SIH in a solvent such as MeCN and under blue LED irradiation (Angew.Chem.lnt.Ed. 2020,59,11620-11626). The formed diastereomers can be separated by flash chromatography on silica gel, HPLC or chiral HPLC or chiral SFC. Intermediate 39, wherein Hal= F, can also be prepared starting from a iodoaryl (41) by cross-coupling with an arylthiol 42 using a catalyst such as Pd(OAc)2 and a ligand such as XantPhos in a solvent like dioxane to yield thioether 43. Intermediate 43 can be oxidised into 44 using an oxidant such as MCPBA and in a solvent such as DCM. Carboxylic acid 44 can be activated using a coupling reagent such as TBTU, HBTU, HATU, EDC, pyCloP (or similar) and be subjected to amide coupling with amine 3 (or the corresponding salt, like HCI or TFA salts) in presence of a base such as DIPEA, TEA, or N-methylmorpholine, in a solvent such as THF, DMF, DCM or MeCN, to give 39. Final compound 36, wherein RB3is N-linked with Ring B, can be obtained by reacting 39, wherein Hal= F or Cl, with the appropriate amine (or the corresponding salt, like HCI or TFA salts) and an inorganic base such as K2CO3, in a solvent such as DMSO or DME, via an SNAP reaction.

[0431] Scheme 7. Synthesis of sulfone compound 36 by late-stage RB3functionalization. Step I) Oxidation, ii) Hydrolysis, ill) Amide coupling, iv) Cross-coupling / SNAr, v) Amide coupling, vi) Hydrosulfonylation, vii) Cross-coupling, viii) Oxidation, ix) Amide coupling.

[0432] Experimental Part Abbrevations (as used herein and in the description above):

[0433] Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)

[0434] AcOH Acetic acid

[0435] AIBN 2,2'-Azobis(2-methylpropionitrile) anh. Anhydrous aq. aqueous atm Atmosphere tBME fert-Butylmethylether

[0436] Bn Benzyl Boc ferf-Butoxycarbonyl

[0437] BOC2O di-ferf-Butyl dicarbonate

[0438] BSA Bovine serum albumine

[0439] Bu Butyl such as in tBu = fert-butyl = tertiary butyl ca circa

[0440] CAS chemical abstract system

[0441] CHO Chinese Hamster Ovary cone. Concentrated

[0442] CPME Cyclopentyl methyl ether d Day(s)

[0443] DavePhos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl dba dibenzylideneacetone

[0444] DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene

[0445] DCE 1 ,2-Dichloroethane

[0446] DCM Dichloromethane

[0447] DEA Diethylamine

[0448] DIPEA Diisopropylethylamine

[0449] DMA Dimethylacetamide

[0450] DMAP 4-(N,N-Dimethylamino)pyridine

[0451] DME Dimethoxyethane

[0452] DMF N,N-Dimethylformamide

[0453] DMPU N,N'-Dimethylpropyleneurea

[0454] DMSO Dimethyl sulfoxide dppf [1 , 1 '-Bis(d i phenyl phosphino)ferrocene]

[0455] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0456] ELSD Evaporative Light-Scattering Detection eq Equivalent(s)

[0457] ES Electron spray

[0458] Et Ethyl

[0459] Et20 Diethyl ether

[0460] EtOAc Ethyl acetate

[0461] EtOH Ethanol

[0462] Ex. Example

[0463] FC Flash Chromatography on silica gel

[0464] FCS Foetal calf serum FLIPR Fluorescent imaging plate reader

[0465] Fmoc Fluorenylmethoxycarbonyl h Hour(s)

[0466] Hal Halogen

[0467] HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium

[0468] 3-oxide hexafluorophosphate

[0469] HBSS Hank's balanced salt solution

[0470] HBTU 2-(1 H-Benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

[0471] HEPES 4-(2-Hydroxyethyl)-piperazine-1 -ethanesulfonic acid

[0472] Hept Heptane

[0473] 1H-NMR Nuclear magnetic resonance of the proton

[0474] HOBt Hydroxybenzotriazole

[0475] HPLC High performance liquid chromatography

[0476] IPAc Isopropyl acetate

[0477] LC-MS Liquid chromatography - Mass Spectroscopy

[0478] LDA Lithium diisopropylamide

[0479] LHMDS Lithium hexamethyldisilazide

[0480] Lit. Literature

[0481] M Exact mass (as used for LC-MS)

[0482] M Molarity [mol L’1]

[0483] MCPBA 3-Chloroperbenzoic acid

[0484] Me Methyl

[0485] MeCN Acetonitrile

[0486] MeOH Methanol

[0487] Mel Methyl iodide

[0488] MHz Megahertz min Minute(s)

[0489] MS Mass spectroscopy

[0490] N Normality

[0491] NBS N-Bromosuccinimide

[0492] NCS N-Chlorosuccinimide

[0493] NMO N-Methylmorpholine N-oxide

[0494] NMP N-Methyl-2-pyrrolidone org. Organic

[0495] Pd(OAc)2 Palladium diacetate Pd(PPha)4 Tetrakis(triphenyiphosphine)palladium(0)

[0496] PL-HCO3 Polymer supported hydrogen carbonate

[0497] Ph Phenyl

[0498] Prep Preparative pyCloP Chlorotripyrrolidinophosphonium hexafluorophosphate

[0499] PTFE Polytetrafluoroethylene

[0500] Rf Retention factor rt Room temperature sat. saturated

[0501] SIA Sulfonimidamide

[0502] SFC Supercritical fluid chromatography soln. Solution

[0503] SPhos Dicyclohexyl(2',6'-dimethoxy[1, 1'-biphenyl]-2-yl)phosphane

[0504] SPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 , 1 '-biphenyl)[2-(2'-amino-1 ,1 ' biphenyl)]palladium(ll), CAS # 1375325-64-6

[0505] TBME ferf-Butyl methyl ether

[0506] TBTU 2-(1 H-Benzotriazole-1-yl)-1, 1,3,3-tetramethylaminium tetrafluoroborate tBu ferf-Butyl

[0507] TEA Triethylamine

[0508] TFA Trifluoroacetic acid

[0509] THF Tetrahydrofuran

[0510] TMP 2,2,6,6-Tetramethylpiperidine

[0511] IR Retention time

[0512] UPLC Ultra performance liquid chromatography

[0513] Wt. Weight

[0514] XantPhos 9,9-Dimethyl-4,5-(diphenylphospino)anthene

[0515] I. Chemistry

[0516] All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen. Synthesized compounds were purified by flash column chromatography (manual or automatized) on silica gel, or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time IR is given in min; molecular weight obtained from the mass spectrum is given in g / mol) using the conditions listed below. Racemates can be separated into their enantiomers by preparative HPLC or SFC. N-methyl amines were prepared from the corresponding primary amines by Boc-protection, N-methylation and Boc- deprotection, as described in S. T. Cheung, N. L. Benoiton, Can. J. Chemistry, 1977, 55, 506. Many commercial and prepared amines were used either as free base or as hydrochloride salt in amide couplings and in SiAr-type reactions; unless stated otherwise, the amount of base necessary for running these reactions was used in excess and not adapted to the form of the reacting amine.

[0517] NMR

[0518] 1H-spectra were recorded at rt with a Brucker NMR 500 spectrometer. Chemical shifts are reported in ppm downfield from tetramethylsilane using residual solvent signals as internal reference. The multiplicity is described as singulet s, doublet d, triplet t, quadruplet q, multiplet m. Broad signals are indicated as br.

[0519] LC-MS conditions

[0520] LC-MS (1)

[0521] LC-MS-conditions: Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD, DAD: Acquity UPLC PDA Detector. Column: Acquity UPLC CSH C18 1.7 .m, 2.1 x 50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A1 : H2O + 0.05 % formic acid; B1 : MeCN + 0.045 % formic acid. Method: Gradient: 2 % B to 98 % B over 2.0 min. Flow: 1.0 mL / min. Detection at 214 nm and MS, retention time IR is given in min.

[0522] LC-MS (2)

[0523] LC-MS- conditions: Analytical UPLC on a Agilent Zorbax RRHD SB-Aq (2.1x50 mm, 1.8 .m); detection at 210 nM and MS; UPLC / MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; Gradient of water / 0.04% TFA (A) and MeCN (B). The eluent flow rate was 0.8 mL / min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

[0524] LC-MS (3)

[0525] LC-MS- conditions: Analytical UPLC on a Waters BEH C18 (2.1x50 mm, 2.5 .m); detection at 210 nM and MS; UPLC / MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; gradient of water / 0.04% NH3 [c(NH3) = 13 mmol / l] (A) and MeCN (B). The eluent flow rate was 0.8 mL / min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

[0526] Preparative LC-MS (Prep. HPLC) methods:

[0527] Preparative HPLC / MS purifications are performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333 / 334 pumps, Finnigan AQA MS detector system, and a Dionex UV detector, using a Waters Xbridge C18 or a Waters Atlantis column, with a linear gradient of water / formic acid 0.02% (A) and MeCN (B) (acidic prep. HPLC ), or water / ammonia 0.02% (A) and MeCN (B) (basic prep. HPLC ).

[0528] Preparative chiral SFC methods:

[0529] Preparative chiral SFC purifications were performed on a Sepiatec Prep SFC 360 system. The following parameters were used:

[0530] Preparative chiral SFC 1 : A Chiralpak AY-H column (30 x 250 mm, 5 m) was used. The modifier was EtOH (10%), run for 10 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C.

[0531] Preparative chiral SFC 2: A ChiralPak IG column (30 x 250 mm, 5 pm) was used. The modifier was MeOH (20%) with EtaNH (0.1 %), run for 3:80 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C

[0532] Preparative chiral SFC 3 A ChiralPak IF column (30 x 250 mm, 5 pm) was used. The modifier was CHaCN / EtOH 1 :1 (30%), run for 3.0 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C.

[0533] Preparative chiral SFC 4: A ChiralPak IB column (30 x 250 mm, 5 pm) was used. The modifier was MeOH (10%), run for 5 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C

[0534] Preparative chiral SFC 5: A ChiralPak IC column (30 x 250 mm, 5 pm) was used. The modifier was CHaCN / EtOH 1 :1 (25%), run for 7 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C. FC

[0535] Flash Chromatographies were performed using an automated system, typically combiflash from Teledyne ISCO.

[0536] Phase-separator

[0537] Phase separator cartriges used were Isolute® purchased from Biotage

[0538] Preparation of Examples:

[0539] Methods for the preparation of sulfonamides compounds (Examples 1.x)

[0540] Example 1.1 (S)-1-(2'-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide: tert-Butyl (4,4-difluorocyclohexyl)(methyl)carbamate: in a round bottom double-neck flask under N2, NaH (55- 65% in mineral oil, 1.52 g, ca 39.7 mmol, ca 1.5 eq) was suspended in DMF (150 mL) and was stirred at 0 °C. Then, tert-butyl (4,4-difluorocyclohexyl)carbamate (6.23 g, 26.5 mmol, 1 eq) in DMF (50 mL) was added dropwise and the reaction mixture was stirred at 0 °C for 1 h. Methyl iodide (3.30 mL, 52.9 mmol, 2 eq) was added and the reaction mixture was stirred at 0 °C for 3 h. Water (400 mL) was slowly added at 0 °C and the reaction mixture was extracted twice with EtOAc. The combined org. layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used as such in the next step without further purification.1H NMR (500 MHz, CDCI3) 6: 2.75 (s, 3 H), 2.10-2.25 (m, 2 H), 1.69-1.97 (m, 6 H), 1.64-1.68 (m, 1 H), 1.48 (s, 9 H).

[0541] 4,4-Difluoro-N-methylcyclohexan-1-amine hydrochloride: HCI (4M in dioxane, 99 mL, 0.40 mol, 15 eq) was added dropwise to a soln, of tert-butyl (4,4-difluorocyclohexyl)(methyl)carbamate (6.60 g, 26.5 mmol, 1 eq) in DCM (250 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with Et20, filtered, washed with Et20 and dried under reduced pressure to give the title compound.1H NMR (500 MHz, CDCI3) 6: 9.68-9.89 (m, 2 H), 3.03-3.14 (m, 1 H), 2.70 (t, J = 5.6 Hz, 3 H), 2.25-2.34 (m, 4 H), 1.96-2.06 (m, 2 H), 1.76-1.91 (m, 2 H).

[0542] ((2-Bromophenyl)sulfonyl)-L-proline: L-proline (1.00 g, 8.64 mmol, 1 eq) was dissolved in aq. NaOH (2M, 17.3 mL, 34.6 mmol, 4 eq). The colorless soln, was cooled to 0 °C and 2-bromobenzenesulfonyl chloride (2.21 g, 8.64 mmol, 1 eq) in THF (13.3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 min, then warmed up to rt and stirred at rt for 1 h. The solvent was removed under reduced pressure, the residue was acidified with aq. 1 M HCI until pH 1-2, and extracted with EtOAc. The org. layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound, which was used as such in the next step without further purification. LC-MS (2): IR = 0.74 min; [M+H]+: 334.10.

[0543] (S)-1-((2-Bromophenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide: ((2- bromophenyl)sulfonyl)-L-proline (540 mg, 1.60 mmol, 1.1 eq) was dissolved in DMF (10 mL), and DIPEA (0.996 mL, 5.82 mmol, 4 eq) followed by HATU (741 mg, 1 .89 mmol, 1 .3 eq) were added. 4,4-difluoro-N-methylcyclohexan- 1-amine hydrochloride (300 mg, 1.45 mmol, 1 eq) in DMF (4 mL) was immediately added and the yellow soln, was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The org. layer was washed with water and brine, dried over MgSC , filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 4:6) followed by acidic prep. HPLC to give the title compound. Rf (Hept / EtOAc 1 :2) = 0.38. LC-MS (2): tR= 0.94 min; [M+H]+: 465.97.

[0544] (S)-1-(2'-Methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide: to a soln, of (S)-1-((2-bromophenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (40 mg, 0.086 mmol, 1 eq) in degassed DME (0.85 mL) was added 2-tolylboronic acid (14.8 mg, 0.103 mmol, 1.2 eq), followed by aq. 2M K2CO3, (0.052 mL, 0.10 mmol, 1.20 eq) and Pd(PPh3)4 (29.8 mg, 0.0258 mmol, 0.3 eq). The resulting mixture was stirred at 88 °C for 4 h. The reaction mixture was filtered through a PTFE 0.45pm filter, rinsed with EtOAc and water. The layers were separated and the org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.257 min; [M+H]+: 477.2.

[0545] Example 1.2 (S)-1-(5-Methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide:

[0546] ((2-Bromo-4-methylphenyl)sulfonyl)-L-proline: L-proline (150 mg, 1.30 mmol, 1 eq) was dissolved in aq. 2M NaOH (2.60 mL, 5.19 mmol, 4 eq). The soln, was cooled to 0 °C and 2-bromo-4-methyl-benzenesulfonyl chloride (349 mg, 1 .30 mmol, 1 eq) in THF (2 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 min then at rt for 3 h. The solvent was removed under reduced pressure, the residue was acidified with aq. 1 M HCI to pH 1-2, and was extracted with EtOAc. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used as such in the next step. LC-MS (2): tR= 0.79 min; [M+H]+: 348.15.

[0547] (S)-1-((2-Bromo-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide: ((2-bromo-4-methylphenyl)sulfonyl)-L-proline (193 mg, 0.533 mmol, 1.1 eq) was dissolved in DMF (3 mL). DIPEA (0.332 mL, 1.94 mmol, 4 eq) followed by HATU (247 mg, 0.63 mmol, 1.3 eq) were added. 4,4-Difluoro-N- methylcyclohexan-1 -amine hydrochloride (100 mg, 0.485 mmol, 1 eq) in DMF (1.8 mL) was immediately added and the soln, was stirred at rt for 2 h. The reaction mixture was filtered through a PTFE 0.45 pm filter and directly purified by basic prep. HPLC to give the title compound. LC-MS (2): tR= 0.99 min; [M+H]+: 479.10.

[0548] (S)-1-(5-Methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide: was synthesized using (S)-1 -((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide and phenylboronic acid in analogy to Example 1.1 to give the title compound. LC- MS (1): tR= 1.266 min; [M+H]+: 477.2. Example 1.3 (S)-1-(5,2'-Dimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and 2-tolylboronic acid in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 1.317 min; [M+H]+: 491.2.

[0549] Example 1.4 to Example 1.5: were synthesized using 4,4-difluoro-N-methylcyclohexan-1-amine hydrochloride, L- proline, the appropriate phenyboronic acid, and following the procedure described in Example 1.1. LC-MS data of Example 1.4 to Example 1.5 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0550] Example 1.6 (S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-(methyl-d3)-[1 ,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide: tert-Butyl (S)-2-((4,4-difluorocyclohexyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate: 4,4-difluoro-N- methylcyclohexan-1 -amine hydrochloride (33.0 g, 0.178 mol, 1 eq), Boc-L-proline (46.4 g, 0.213 mol, 1.2 eq) and HOBt (32.7 g, 0.213 mol, 1.2 eq) were mixed with DMF (250 mL) and TEA (99.1 mL, 0.711 mol, 4 eq). The soln, was stirred for 10 min at rt, then EDC HCI (41.3 g, 0.213 mol, 1.2 eq) was added at rt. The temperature was kept below 30 °C by the use of a cold water bath and the mixture was stirred for 1 .5 h. The water bath was then removed and the reaction mixture was stirred overnight at rt. The mixture was diluted with IPAc and water. The layers were separated. The org. layer was washed with aq. 1 M HCI and water, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil, which was used as such in the next step. Rf (Hept / EtOAc 1 :1)= 0.22. LC-MS (2): tR= 0.88 min; [M+H]+: 347.27.

[0551] (S)-N-(4,4-Difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide: HCI (5M in / -PrOH, 160 mL, 0.808 mol, 5 eq) was added dropwise to tert-butyl (S)-2-((4,4-difluorocyclohexyl)(methyl)carbamoyl)pyrrolidine-1 -carboxylate (56.0 g, 0162 mol, 1 eq) and the reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure. CPME and water were added. The mixture was basified with aq. 1 M NaOH and extracted with DCM. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (2): tR= 0.51 min; [M+H]+: 247.26.

[0552] ((2-Bromo-4-chlorophenyl)sulfonyl)-L-proline: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide and 2-bromo-4-chlorobenzene-1 -sulfonyl chloride in analogy to Example 1.3 to give the title compound. LC-MS (2): tR= 1 .03 min; [M+H]+: 499.07. (S)-1-((5-Chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide: was synthesized using ((2-bromo-4-chloropheny l)sulfony l)-L-proli ne and 2-fluoropheny Iboronic acid in analogy to Example 1.3 to give the title compound. LC-MS (2): tR= 1.09 min; [M+H]+: 515.15.

[0553] (S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-(methyl-d3)-[1,r-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine- 2-carboxamide: to a degassed soln, of (S)-1-((5-chloro-2'-fluoro-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (51.5 mg, 0.100 mmol, 1 eq), methyl-d3-boronic acid (25.2 mg, 0.400 mmol, 4 eq), and CsF (0.0113 mL, 0.300 mmol, 3 eq) in dioxane (1 mL), Pd(OAc)2 (3.44 mg, 0.015 mmol, 0.15 eq) and DavePhos (12.2 mg, 0.030 mmol, 0.3 eq) were added in sequence. The mixture was degassed with N2 for 2 min and stirred at 100 °C for 72 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): tR= 1.238 min; [M+H]+: 498.2.

[0554] Example 1.7 (S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-(methyl- d3)pyrrolidine-2-carboxamide: tert-Butyl (4,4-difluorocyclohexyl)(methyl-d3)carbamate: in a round bottom double-neck flask under N2 atmosphere, to an ice-cooled NaH (55-65%, 244 mg, ca 6.38 mmol, ca 1.5 eq) suspension in DMF (30 mL), was added tert-butyl (4,4-difluorocyclohexyl)carbamate (1000 mg, 4.25 mmol, 1 eq) portionwise. The reaction mixture was stirred at 0 °C for 20 min, then CD3I (0.532 mL, 8.50 mmol, 2 eq) was added. The resulting mixture was stirred at rt for 2 h. The mixture was partitioned between water and EtOAc. The layers were separated and the aq. layer was extracted with EtOAc. The combined org. layers were washed with aq. sat. NaCI, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification in the next step. LC-MS (2): tR= 0.98 min; [M-CH3]+: 238.19.1H NMR (500 MHz, d6-DMSO) 5: 3.77-4.05 (m, 1 H), 1.83-2.10 (m, 4 H), 1.57-1.76 (m, 4 H), 1.41 (s, 9 H).

[0555] 4,4-Difluoro-N-(methyl-d3)cyclohexan-1-amine hydrochloride: to an ice-cooled soln, of tert-butyl (4,4- difluorocyclohexyl)(methyl-d3)carbamate (1.10 g, 4.36 mmol, 1 eq) in DOM (20 mL) was added HOI (4M in dioxane, 4 mL, 16 mmol). The resulting mixture was stirred at 0 °C for 10 min then at rt overnight. The reaction mixture was concentrated under reduced pressure to give the title compound. LC-MS (2): tR= 0.32 min; [M+H]+: 153.18.

[0556] Methyl ((2-bromo-4-methylphenyl)sulfonyl)-L-prolinate: 2-bromo-4-methylbenzene-1 -sulfonyl chloride (9.99 g, 35.2 mmol, 1.1 eq) was added at rt to a stirred soln, of L-proline methyl ester hydrochloride (5.30 g, 32.0 mmol, 1 eq) and TEA (13.4 mL, 96.0 mmol, 3 eq) in DCM. The resulting soln, was stirred at rt for 1 h. The reaction mixture was diluted with DCM and washed once with brine. The org. layer was separated and the aq. layer was extracted again with DCM. The combined org. layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound. LC-MS (2): tR= 0.91 min; [M+H]+: 362.1. Methyl ((2'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-L-prolinate: methyl ((2-bromo-4- methylphenyl)sulfonyl)-L-prolinate (9.97 g, 27.5 mmol, 1 eq), (2-fluorophenyl)boranediol (6.08 g, 41.3 mmol, 1.5 eq), Na2CC>3 (8.79 g, 82.5 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (2.25 g, 2.75 mmol, 0.1 eq) were dissolved in degassed 1,4-dioxane I water 4:1 (1.0 mL) and the resulting mixture was stirred at 70 °C for 2.5 h. The reaction mixture was diluted with brine and extracted with DCM. The layers were separated by a separation cartridge. The solvent was removed under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound. LC-MS (2): tR= 1.00 min; [M+H]+: 378.10.

[0557] ((2'-Fluoro-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-L-proline: to a soln, of methyl ((2'-fluoro-5-methyl-[1,T- biphenyl]-2-yl)sulfonyl)-L-prolinate (8.30 g, 22.0 mmol, 1 eq) in H2O (41.5 mL) and THF (145 mL) was added at rt UOH H2O (1.40 g, 33.0 mmol, 1.5 eq) and the soln, was stirred during 4 h. The soln, was diluted with brine and washed with DCM. The aq. layer was acidified with aq. 1 M HCI and extracted with DCM. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS (2): tR= 0.87 min; [M+H]+: 364.23.

[0558] (S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-(methyl-d3)pyrrolidine- 2-carboxamide: to a soln, of ((2'-fluoro-5-methyl-[1,T-biphenyl]-2-yl)sulfonyl)-L-proline (30.8 mg, 0.0849 mmol, 1 eq) and 4,4-difluoro-N-(methyl-d3)cyclohexan-1-amine hydrochloride (16.0 mg, 0.0849 mmol, 1 eq) in DMF (2 mL), TEA (0.0597 mL, 0.424 mmol, 5 eq) and HATU (34.9 mg, 0.0891 mmol, 1.05 eq) were added in sequence. The resulting mixture was stirred at rt overnight. The mixture was then concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.240 min; [M+H]+: 498.2.

[0559] Example 1.8 to Example 1.10: were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and the appropriate phenylboronic acid in analogy to Example 1.1. LC-MS data of Example 1.8 to Example 1.10 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0560] Example 1.11 (S)-1-(2-Cyclopent-1-enyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: a soln. of (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (30.0 mg, 0.0626 mmol, 1 eq), cyclopent-1 -en-1-ylboronic acid (10.7 mg, 0.0939 mmol, 1.5 eq), Pd(dppf)Cl2CH2Cl2 (10.7 mg, 0.0131 mmol, 0.2 eq), and NaHCOa (15.8 mg, 0.188 mmol, 3 eq) in H2O (0.12 mL) and DME (0.48 mL) was degassed with N2 for 15 min and stirred at 100 °C for 16 h. The reaction mixture was filtered through a PTFE 0.45 m filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 6:4) to give the title compound. LC-MS (1): tR= 1.313 min; [M+H]+: 467.2.

[0561] Example 1.12 to Example 1.16: were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and the appropriate phenylboronic acid in analogy to Example 1.11. LC-MS data of Example 1.12 to Example 1.16 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0562] Example 1.17 (S)-1-(2-Bicyclo[2.2.1]hept-2-yl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: (S)-1-(2-bicyclo[2.2.1]hept-2-en-2-yl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide (24.2 mg, 0.0491 mmol, 1 eq) was dissolved in EtOH (1 mL) and Pd / C (10% Pd, -50% H2O, ca 5.23 mg, ca 0.00491 mmol, 0.1 eq) was added. The reaction mixture was purged with H2 and was then stirred at rt for 24 h under a H2 atmosphere. The suspension was filtered through a pad of Celite®, rinsed with DCM, and the filtrate concentrated under reduced pressure to give the title compound as a 1 : 1 mixture of diastereomers. LC-MS (1): tR= 1.313 min; [M+H]+: 467.2.

[0563] Example 1.18 (S)-1-(2-Cyclohexyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclohex-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound. LC-MS (1): tR= 1.390 min; [M+H]+: 483.2. Example 1.19 (S)-1-[2-(5,6-Dihydro-2H-pyran-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane in analogy to Example 1.11 to give the title compound. LC-MS (1): IR= 1.151 min; [M+H]+: 483.2.

[0564] Example 1.20 (S)-1-(2-Cyclopentyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclopent-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound. LC-MS (1): IR= 1.33 min; [M+H]+: 469.2.

[0565] Example 1.21 (S)-1-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide:

[0566] (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide hydrochloride: HCI (4M in dioxane, 46.0 mL, 184 mmol, 19.15 eq) was added dropwise to the soln, of tert-butyl (S)-2-((4,4- difluorocyclohexyl)(methyl)carbamoyl)pyrrolidine-1 -carboxylate (3.88 g, 9.62 mmol, 1 eq) in DCM (96 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the title compound which was used as such in the next step without further purification. LC-MS (2): IR= 0.52 min; [M+H]+: 247.34.

[0567] (S)-N-(4,4-Difluorocyclohexyl)-1-((2-fluoro-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: to a mixture of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (150 mg, ca 0.509 mmol, 1 eq), and TEA (0.717 mL, 5.09 mmol, 10 eq) in DCM (5 mL) was added 2-fluoro-4-methylbenzenesulfonyl chloride (106 mg, 0.509 mmol, 1 eq) and the mixture was stirred at rt for 1 h. Water (5 mL) was added and the reaction mixture was stirred for 10 min, and filtered through phase separator. The org. layer was concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 1 : 1 ) to give the title compound. LC- MS (2): tR= 0.95 min; [M+H]+: 419.19.

[0568] (S)-1-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide: (S)-N-(4,4-difluorocyclohexyl)-1-((2-fluoro-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2- carboxamide (20.0 mg, 0.0468 mmol, 1 eq) and piperidine (0.0241 mL, 0.234 mmol, 5 eq) were dissolved in DMSO (0.5 mL) and the mixture was stirred at 120 °C for 22 h. The reaction mixture was diluted with water and extracted with EtOAc. The org. layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.225 min; [M+H]+: 484.3.

[0569] Example 1.22 (S)-1-(2-Cycloheptyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclohept-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound. LC-MS (1): tR= 1.444 min; [M+H]+: 497.4.

[0570] Example 1.23 to Example 1.24: were synthesized using (S)-N-(4,4-difluorocyclohexyl)-1-((2-fluoro-4- methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and the appropriate amine or amine salt in analogy to Example 1.21. LC-MS data of Example 1.23 to Example 1.24 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0571] Example 1.25 (S)-1-[2-(2-Fluoro-pyridin-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0572] (S)-N-(4,4-Difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide: (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (1.00 g, 2.09 mmol, 1 eq), PdCl2(MeCN)2 (11 mg, 0.0417 mmol, 0.02 eq) and SPhos (68.5 mg, 0.167 mmol, 0.08 eq) were put in a microwave vial. The vial was sealed and purged with N2. Dioxane (10 mL), TEA (0.877 mL, 6.26 mmol, 3 eq) and boronic acid pinacol ester (422 mg, 3.13 mmol, 1.5 eq) were added and the resulting mixture was stirred at 110 °C for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue purified by FC (Hept to Hept / EtOAc 4:6) to give the title compound. Rf (Hept / EtOAc 1 :1)= 0.25. LC-MS (2): tR= 1.06 min; [M+H]+: 527.30.

[0573] (S)-1-[2-(2-Fluoro-pyridin-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide (20 mg, 0.038 mmol, 1 eq), 2-fluoro-3-iodopyridine (17 mg, 0.076 mmol, 2 eq), NaHCOa (9.6 mg, 0.11 mmol, 3 eq) and Pd(PPha)4 (4.5 mg, 0.0038 mmol, 0.1 eq) were dissolved in degassed DME / water 4: 1 (0.3 mL) and the resulting mixture was stirred at 85 °C for 1 h. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.1 18 min; [M+H]+: 496.2.

[0574] Example 1.26 to Example 1.30: were synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and the appropriate aryl halide in analogy to Example 1.25. LC-MS data of Example 1.26 to Example 1.30 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0575] Example 1.31 (S)-1-(5,2'-Difluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide:

[0576] (S)-1-((2-Bromo-4-fluorophenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide hydrochloride and 2- bromo-4-fluorobenzenesulfonyl chloride in analogy to Example 1.21 to give the title compound. LC-MS (2): tR= 0.96 min; [M+H]+: 483.03.

[0577] (S)-1-(5,2'-Difluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide: (S)-1-((2-bromo-4-fluorophenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0414 mmol, 1 eq), 2-fluorophenylboronic acid (11.8 mg, 0.0828 mmol, 2 eq), Na2CO3 (13.2 mg, 0.124 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (3.38 mg, 0.00414 mmol, 0.1 eq) were dissolved in degassed 1 ,4-dioxane I water 4: 1 (0.6 mL) and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered through a PTFE 0.45 m filter and rinsed with EtOAc. The residue was purified basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.216 min; [M+H]+: 499.2.

[0578] Example 1.32 to Example 1.37: were synthesized according to the procedures described herein before using (S)- N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide hydrochloride, the appropriate sulfonyl chloride and the appropriate boronic acid or boronic ester. LC-MS data of Example 1.32 to Example 1.37 are listed in the table below.

[0579] Example 1.38 (S)-1-(4-Methyl-2-pyrimidin-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2- (4, 4, 5, 5-tetramethy I- 1 ,3, 2-d ioxaborol an -2-y l)pheny I )sulfony l)py rrol id i ne-2-carboxamide and 2-bromopyrimidine in analogy to Example 1.25 to give the title compound. LC-MS (1): IR= 0.957 min; [M+H]+: 479.3.

[0580] Example 1.39 (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-amide: was synthesized using ((2'-fluoro-5-methyl-[1,T-biphenyl]-2-yl)sulfonyl)-L-proline and 4,4- difluorocyclohexan- 1 -amine in analogy to Example 1 .7 to give the title compound. LC-MS (1): IR= 1 .204 min; [M+H]+: 481.2. Example 1.40: (S)-1-(5-Chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide hydrochloride, 2-bromo-4-chlorobenzene-1 -sulfonyl chloride, and 2-fluorophenylboronic acid in analogy to Example 1.31 to give the title compound. LC-MS (1): IR= 1.291 min; [M+H]+: 515.1.

[0581] Example 1.41 to Example 1.49: were synthesized according to the procedures described herein before using ((2- fluoro-5-methyl-[1, -biphenyl]-2-yl)sulfonyl)-L-proline and the appropriate amine or amine salt. LC-MS data of

[0582] Example 1.41 to Example 1.49 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0583] Example 1.51 (S)-1-(5-Cyclobutyl-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-1-(5-chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide (15 mg, 0.0291 mmol, 1 eq) and SPhos Pd G2 (0.84 mg, 0.0012 mmol, 0.04 eq) were dissolved in THF (0.5 mL) under N2 atmosphere. Cyclobutylzinc bromide (0.5 M in THF, 0.175 mL, 0.0874 mmol, 3.0 eq) was added and the reaction mixture was stirred at 55 °C for 5.5 h. The reaction mixture was partitioned between aq. sat. NH4CI and DCM and stirred for 20 min. The org. layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.386 min; [M+H]+: 535.2. Example 1.52 (2S)-1-((2',6-difluoro-[1,r-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide hydrochloride, 2-bromo-3-fluorobenzenesulfonyl chloride, and 2-fluorophenylboronic acid in analogy to Example 1.31 to give the title compound as a mixture of 2 atropisomers. LC-MS (1): IR= 1.173 min; [M+H]+: 499.2. Example 1.53 to Example 1.60: were synthesized according to the procedures described herein before using ((2 - fluoro-5-methyl-[1 ,1 '-biphenyl]-2-yl)sulfonyl)-L-proline and the appropriate amine or amine salt. LC-MS data of Example 1.53 to Example 1.60 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.60 (S)-1-(5-Cyclopropyl-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: (S)-1-(5-chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide (20.0 mg, 0.0388 mmol, 1 eq) and SPhos Pd G2 (1.12 mg, 0.00155 mmol, 0.04 eq) were dissolved in THF (0.5 mL) under N2 atmosphere. Cyclopropylzinc bromide (0.5 M in THF, 0.234 mL, 0.1 17 mmol, 3 eq) was added and the reaction mixture was stirred at 55 °C for 5 h. The reaction mixture was partitioned between aq. sat. NH4CI and DCM and stirred for 20 min. The org. layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.286 min; [M+H]+: 521.4.

[0584] Example 1.61 (S)-1-(2'-Fluoro-5-isopropyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(5-chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide and 2-propylzinc bromide (0.5 M in THF) in analogy to Example 1.60 to give the title compound. LC-MS (1): IR= 1.344 min; [M+H]+: 523.3.

[0585] Example 1.62 (S)-4,4-Difluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: 2-Bromo-2'-fluoro-5-methyl-1 , 1 '-biphenyl : to a degassed soln, of 2-bromo-5-methylphenylboronic acid (443 mg, 2.00 mmol, 1 eq), 2-fluoroiodobenzene (0.233 mL, 2.00 mmol, 1 eq), and CsF (0.133 mL, 3.60 mmol, 1.8 eq) in dioxane (6 mL), PPh3(106 mg, 0.400 mmol, 0.2 eq) and Pd(OAc)2 (22.5 mg, 0.100 mmol, 0.05 eq) were added. The reaction mixture was stirred at 120 °C for 20 h. The mixture was allowed to cool to rt, diluted with H2O and extracted with DCM. The combined org. layers were dried over MgSC , filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound. Rf (Hept / EtOAc 9:1 )= 0.55. LC-MS (2): tR= 1.08 min; [M+H]+: not seen.1H NMR (500 MHz, d6-DMSO) 5 7.62 (d, J = 8.1 Hz, 1 H), 7.46-7.51 (m, 1 H), 7.28-7.35 (m, 3 H), 7.17-7.22 (m, 2 H), 2.32 (s, 3 H).

[0586] 2'-Fluoro-5-methyl-[1,1'-biphenyl]-2-sulfonyl chloride LiCI: to a soln, of 2-bromo-2'-fluoro-5-methyl-1,T- biphenyl (220 mg, 0.83 mmol, 1 eq) in THF (2 mL), cooled to -78 °C, n-BuLi (2.5 M in hexanes, 0.400 mL, 0.996 mmol, 1 .2 eq) was added dropwise. The mixture was stirred at -78 °C for 30 min. SO2 (0.5 M in THF, 3.32 mL, 1 .66 mmol, 2 eq) was added, and the mixture was stirred at -78 °C for 5 h, then allowed to warm to rt and stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in hexane (8 mL) and cooled to -78 °C. A soln, of SO2CI2 (0.0832 mL, 0.996 mmol, 1 .2 eq) in hexane (2 mL) was added. The reaction mixture was stirred at -78 °C for 30 min, allowed to warm to rt and stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification. LC-MS (2): tR= 1 .06 min; [M+H]+: not seen.1H NMR (500 MHz, d6-DMSO) 5 7.80 (d, J = 8.0 Hz, 1 H), 7.42 (td, Ji = 1 .8 Hz, J2= 7.6 Hz, 1 H), 7.26-7.31 (m, 1 H), 7.15 (ddd, Ji = 0.6 Hz, J2= 1.7 Hz, J3= 8.0 Hz, 1 H), 7.06-7.12 (m, 2 H), 6.90 (s, 1 H), 2.30 (s, 3 H).

[0587] (S)-4,4-Difluoro-1-((2'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)pyrrolidine-2-carboxylic acid: to an ice- cooled soln, of (2S)-4,4-difluoropyrrolidine-2-carboxylic acid (62.3 mg, 0.4 mmol, 1 eq) in aq. 2M NaOH (1 mL, 2 mmol, 5 eq), a suspension of 2'-fluoro-5-methyl-[1 , T-biphenyl]-2-sulfonyl chloride LiCI (131 mg, ca 0.40 mmol, 1 eq) in THF (1 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 10 min and then at rt for 1 .5 h. The reaction mixture was diluted with water and acidified with aq. 1 M HCI to pH 1. The mixture was extracted with EtOAc. The combined org. layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (2): tR= 0.94 min; [M+H]+: 400.06.

[0588] (S)-4,4-Difluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: to a soln, of (S)-4,4-difluoro-1-((2'-fluoro-5-methyl-[1 , T-biphenyl]-2- yl)sulfonyl)pyrrolidine-2-carboxylic acid (39.9 mg, 0.100 mmol, 1 eq.) in DMF (1 mL), DIPEA (0.0685 mL, 0.400 mmol, 4 eq) and HATU (49.4 mg, 0.130 mmol, 1.3 eq) were added in sequence. 4,4-Difluoro-N-methylcyclohexan- 1-amine hydrochloride (18.6 mg, 0.100 mmol, 1 eq) was added and the mixture was stirred at rt for 6 h. The mixture was purified by acidic prep. HPLC to give the title compound as a white solid. LC-MS (1): tR= 1.288 min; [M+H]+: 531.2. Example 1.63 (S)-1-(2'-Fluoro-5-vinyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-1-((5-chloro-2'-fluoro-[1 , T-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide (46.0 mg, 0.0893 mmol, 1 eq), K2CO3 (24.7 mg, 0.179 mmol, 2 eq), Pd(PPh3)4 (10.3 mg, 0.00893 mmol, 0.1 eq) and 2,4,6-trivinylcyclotriboroxane pyridine complex (21.5 mg, 0.0893 mmol, 1 eq) were dissolved in DME (0.8 mL) and H2O (0.2 mL), and the reaction mixture was degassed for 3 min, then stirred at 100 °C for 6 h. The reaction mixture was filtered through a PTFE 0.45 m filter and rinsed with EtOAc. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.267 min; [M+H]+: 507.2.

[0589] Example 1.64 to Example 1.65: were synthesized according to the procedures described herein before using (S)- N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)sulfony l)pyrrolidine-2-carboxamide and the appropriate aryl halide (chloride, bromide, or iodide). LC-MS data of Example 1.64 to Example 1.65 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0590] Example 1.66 (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-(2-methoxy-ethyl)-amide:

[0591] 4,4-Difluoro-N-(2-methoxyethyl)cyclohexan-1-amine hydrochloride: 2-methoxy-ethylamine (0.300 mL, 3.38 mmol, 1 eq), 4,4-difluorocyclohexanone (463 mg, 3.38 mmol, 1 eq), sodium triacetoxyborohydride (2.27 g, 10.2 mmol, 3 eq) and AcOH (0.194 mL, 3.38 mmol, 1 eq) were dissolved in DCM (10 mL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was poured into water and acidified to pH 2 with aq. 5M HCI. The layers were separated and the aq. layer was basified by addition of aq. 5M NaOH and extracted with DCM. The org. layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was suspended in Et20 and HCI (4M in dioxane) was added. The white suspension was stirred at rt for 15 min and filtered. The solid was washed with Et20 and dried to give the title compound.1H NMR (500 MHz, CDCI3) 5: 3.52 (m, 2 H), 3.39 (s, 3 H), 2.81 (m, 2 H), 2.61-2.69 (m, 1 H), 2.07-2.18 (m, 2 H), 1.89-1.94 (m, 2 H), 1.70-1.84 (m, 4 H).

[0592] (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2- methoxy-ethyl)-amide: ((2'-fluoro-5-methyl-[1,T-biphenyl]-2-yl)sulfonyl)-L-proline (28.3 mg, ca 0.0779 mmol, ca 1.1 eq) was dissolved in DMF (0.7 mL) then DIPEA (0.0485 mL, 0.283 mmol, 4 eq) and HATU (36.1 mg, 0.0921 mmol, 1.3 eq) were added. 4,4-Difluoro-N-(2-methoxyethyl)cyclohexan-1-amine hydrochloride (16.3 mg, 0.0709 mmol, 1 eq) was immediately added and the yellow soln, was stirred at rt for 2.5 h. The reaction mixture was filtered through a PTFE 0.45 m filter and purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.285 min; [M+H]+: 539.3.

[0593] Example 1.67 (S)-1-[2-(2-Cyano-pyridin-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4- methy l-2-(4, 4, 5,5-tetramethy 1-1 , 3, 2-dioxaborol an-2-y I) phenyl)su Ifony l)py rrol idi ne-2-carboxami de and 3- bromopyridine-2-carbonitrile in analogy to Example 1.25 to give the title compound. LC-MS (1): IR = 1.089 min; [M+H]+: 503.2.

[0594] Example 1.68 to Example 1.83: were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1,1'- biphenyl]-2-sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to example 1.62. LC-MS data of Example 1 .68 to Example 1 .83 are listed in the table below.

[0595] Example 1.84 (S)-1-(5-Ethyl-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-1-(2'-fluoro-5-vinyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide (28.7 mg, 0.0567 mmol, 1 eq) was dissolved in EtOH (1 mL) and Pd / C (10% Pd, -50% H2O, 6.03 mg, ca 0.00567 mmol, ca 0.1 eq) was added. The reaction mixture was purged with H2 and was then stirred at rt for 20 h under an H2 atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 6:4) to give the title compound. Rf (Hept / EtOAc 1 :1)= 0.30. LC-MS (1): tR= 1.267 min; [M+H]+: 507.2.

[0596] Example 1.85 (S)-1-[2-(4-Cyano-pyridin-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4- methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and 3- bromoisonicotinonitrile in analogy to Example 1.25 to give the title compound. LC-MS (1): tR= 1.059 min; [M+H]+: 503.2. Example 1.86 (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl- (tetrahydro-pyran-4-yl)-amide: was synthesized using ((2'-fluoro-5-methyl-[1 , T-biphenyl]-2-yl)sulfonyl)-L-proline and N-methyloxan-4-amine in analogy to Example 1.7 to give the title compound. LC-MS (1): tR= 1.076 min; [M+H]+: 461.2.

[0597] Example 1.87 (2S,5R)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized according to the procedures described herein before using (2S,5R)-1-[(tert-butoxy)carbonyl]-5-methylpyrrolidine-2-carboxylic acid, 2'-fluoro-5-methyl-[1 ,1 '-biphenyl]-2- sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochloride in analogy to Example 1.6 to give the title compound. LC-MS (2): tR= 0.94 min; [M+H]+: 378.12.

[0598] Example 1.88 (S)-1-(4-Methyl-2-oxazol-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide (20.0 mg, 0.0417 mmol, 1 eq), 2-(tri-n-butylstannyl)oxazole (29.9 mg, 0.0834 mmol, 2 eq) and Pd(dppf)Cl2CH2Cl2 (3.41 mg, 0.004 mmol, 0.1 eq) were dissolved in dioxane (0.5 mL) and the resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered through a PTFE 0.45 m filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by basic prep. HPLC conditions to give the title compound. LC-MS (1): tR= 1.027 min; [M+H]+: 468.2.

[0599] Example 1.89 to Example 1.93: were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1 ,T- biphenyl]-2-sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to Example 1.62. LC-MS data of Example 1.89 to Example 1.93 are listed in the table below. The LC-MS conditions used were LC- MS (1). Example 1.94 (S)-1-(4-Methyl-2-[1,2,3]triazol-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0600] 2-(5-Methyl-2-nitrophenyl)-2H-1,2,3-triazole: 1 H-1 ,2,3-triazole (0.839 mL, 14.5 mmol, 1 eq) and 3-fluoro-4- nitrotoluene (2.25 g, 14.5 mmol, 1 eq) and K2CO3 (2.02 g, 14.5 mmol, 1 eq) were dissolved in DMF (25 mL), and the reaction mixture was stirred at 75 °C for 15 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined org. layers were washed with brine, dried over MgSC , filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 4:6) to give 2-(5-methyl-2- nitrophenyl)-2H-1 ,2,3-triazole (first eluting isomer) and 1-(5-methyl-2-nitrophenyl)-1 H-1 ,2,3-triazole. 2-(5-Methyl-2- nitrophenyl)-2H-1 ,2,3-triazole: Rf(Hept / EtOAc 1 : 1) = 0.62, LC-MS (2): tR= 0.83 min; [M+H]+: 205.24. 1-(5-methyl- 2-nitrophenyl)-1 H-1 ,2,3-triazole: Rf(Hept / EtOAc 1 : 1) = 0.28, LC-MS (2): tR= 0.72 min; [M+H]+: 205.24.

[0601] 4-Methyl-2-(2H-1,2,3-triazol-2-yl)aniline: 2-(5-methyl-2-nitrophenyl)-2H-1,2,3-triazole (890 mg, 4.36 mmol, 1 eq) was dissolved in MeOH (50 mL) and Pd / C (10% Pd, -50% H2O, 928 mg, ca 0.436 mmol, ca 0.1 eq) was added. The reaction mixture was purged with H2 and the mixture was then stirred at rt for 1 .5 h under an H2 atmosphere at atmospheric pressure. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification in the next step. LC- MS (2): tR= 0.69 min; [M+H]+: 175.44.

[0602] 2-(2-Bromo-5-methylphenyl)-2H-1 ,2,3-triazole: CuE (0.136 mL, 2.87 mmol, 1 eq) was dissolved in CH3CN (10 mL) and tert-butyl nitrite (0.419 mL, 3.16 mmol, 1 .1 eq) was added. The solution was cooled to 0 °C and a soln, of 4-methyl-2-(2H-1 ,2,3-triazol-2-yl)aniline (500 mg, 2.87 mmol, 1 eq) in CH3CN (5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h and then at rt for 1 h. The reaction mixture was cooled down to 0 °C and quenched with an aq. soln, of sulfamic acid (1mL containing 56.1 mg, 0.574 mmol, 0.2 eq), followed by the addition of aq. 2M HCI (2.16 mL, 4.31 mmol, 1.5 eq). The mixture was then diluted with water and extracted with EtOAc. The combined org. layers were washed with water, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound as a yellow oil. Rf (Hept / EtOAc 8:2)= 0.40. LC-MS (2): tR= 0.89 min; [M+H]+: 238.18.

[0603] 2-(2-(Benzylthio)-5-methylphenyl)-2H-1,2,3-triazole: 2-(2-bromo-5-methylphenyl)-2H-1 ,2,3-triazole (100 mg, 0.42 mmol, 1 eq), benzyl mercaptan (0.0498 mL, 0.42 mmol, 1 eq) and DIPEA (0.147 mL, 0.84 mmol, 2 eq) were dissolved in degassed dioxane (1.6 mL) and the resulting mixture was stirred at 95 °C. Pd2(dba)3 (19.2 mg, 0.021 mmol, 0.05 eq) and XantPhos (24.8 mg, 0.042 mmol, 0.1 eq) were added, and the reaction mixture was stirred at 95 °C for 24 h. Benzyl mercaptan (0.0498 mL, 0.42 mmol, 1 eq), DIPEA (0.147 mL, 0.84 mmol, 2 eq), Pd2(dba)3 (19.2 mg, 0.021 mmol, 0.05 eq) and XantPhos (24.8 mg, 0.042 mmol, 0.1 eq) were added again and the reaction mixture was stirred at 95 °C for 48 supplementary hours. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EA 95:5) to give the title compound. LC-MS (2): tR= 1.04 min; [M+H]+: 282.23. 4-Methyl-2-(2H-1,2,3-triazol-2-yl)benzenesulfonyl chloride: 2-(2-(benzylthio)-5-methylphenyl)-2H-1 ,2,3-triazole (50 mg, 0.102 mmol, 1 eq) was dissolved in DCM (1.5 mL) and stirred at 0 °C. Water (73.2 JLLL, 0.406 mmol, 4 eq), AcOH (23.2 |j.L, 0.406 mmol, 4 eq) and SO2CI2 (33.9 JLLL, 0.406 mmol, 4 eq) were added dropwise and the reaction mixture was stirred at 0 °C for 5 min then at rt for 1 .5 h. The reaction mixture was cooled down to 0 °C and water (1 mL) was added. The phases were separated and the aq. layer was extracted with DCM. The combined org. layers were washed with cold water, dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used as such in the next step without further purification. LC-MS (2): IR= 0.89 min; [M+H]+: 258.04.

[0604] (S)-1-(4-Methyl-2-[1,2,3]triazol-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: to a mixture of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (25.0 mg, 0.102 mmol, 1 eq), and TEA (0.0429 mL, 0.305 mmol, 3 eq) in DCM (1 mL) was added 4-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzenesulfonyl chloride (26.2 mg, 0.102 mmol, 1 eq) and the mixture was stirred at rt for 10 min. H2O (1 mL) was added and the reaction mixture was stirred for 5-10 min and the mixture filtered over a phase separator. The org. phase was concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 3:7) to give the title compound. Rf (Hept / EtOAc 1 : 1)= 0.10. LC-MS (1): IR= 1.031 min; [M+H]+: 468.2.

[0605] Example 1.95 (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-oxo-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized using 4-oxo-L-proline hydrobromide, 2'-fluoro-5-methyl- [1 , 1 '-biphenyl]-2-sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochloride in analogy to Example 1.62 to give the title compound. LC-MS (1): IR= 1.215 min; [M+H]+: 509.1.

[0606] Example 1.96 (S)-1-[4-Methyl-2-(5-methyl-oxazol-2-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide (20 mg, 0.037 mmol, 1 eq), 2- bromo-5-methyl-oxazole (12 mg, 0.075 mmol, 2 eq), Na2CO3 (12 mg, 0.11 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (3 mg, 0.0037 mmol, 0.1 eq) were dissolved in degassed 1 ,4-dioxane / water 4: 1 (0.5 mL) and the resulting mixture was stirred at 70 °C for 1.5 h. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to 100% EtOAc) to give the title compound. Rf (Hept / EtOAc 2:8)= 0.25. LC-MS (1): IR= 1.082 min; [M+H]+: 482.2.

[0607] Example 1.97 (S)-1-(5,2',6'-Trimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide:

[0608] 2-Bromo-2',5,6'-trimethyl-1,1'-biphenyl: in a microwave vial, 4-bromo-3-iodotoluene (97%, 100 mg, 0.327 mmol, 1 eq), 2,6-dimethylphenylboronic acid (49.0 mg, 0.327 mmol, 1 eq), K2CO3 (228 mg, 1.63 mmol, 5 eq) and Pd(PPh3)4 (38.9 mg, 0.0327 mmol, 0.1 eq) were dissolved in degassed dioxane I water 4:3 (3.3 mL) and the resulting mixture was stirred at 165 °C for 20 min under microwave irradiations. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (100% Hept) to give the title compound. Rf (Hept)= 0.38. LC-MS (2): IR= 1.16 min; [M+H]+: not seen.1H NMR (500 MHz, CDCI3) 6: 7.57 (d, J = 8.2 Hz, 1 H), 7.20-7.24 (m, 1 H), 7.12-7.14 (m, 2 H), 7.05 (dd, Ji = 2.0 Hz, J2= 8.3 Hz, 1 H), 6.98-7.00 (m, 1 H), 2.36 (s, 3 H), 2.02 (s, 6 H).

[0609] 2,,5,6'-Trimethyl-[1,1'-biphenyl]-2-sulfonyl chloride LiCI: 2-bromo-2', 5, 6’-trimethyl-1 ,1 '-biphenyl (50 mg, 0.145 mmol, 1 eq) was dissolved in THF (1.5 mL) and stirred at -78 °C. n-BuLi (1.6 M in hexanes, 0.109 mL, 0.174 mmol, 1.2 eq) was added dropwise and the reaction mixture was stirred at -78°C for 2 h. SO2(0.5 M in THF, 0.582 mL, 0.291 mmol, 2 eq) was added and the reaction mixture was stirred at -78 °C for 1 h then at rt for 22 h. The reaction mixture was concentrated under reduce pressure and the residue was suspended in DCM (1 .5 mL) and stirred at - 78 °C. A soln, of SO2CI2 (0.0146 mL, 0.174 mmol, 1.2 eq) in DCM (2 mL) was added. The reaction mixture was stirred at -78 °C for 45 min, allowed to warm to rt and concentrated to give the title compound, which was used as such in the next steps. LC-MS (2): IR= 1.13 min; [M+H]+: not seen.

[0610] (S)-1-(5,2',6'-Trimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide: to a mixture of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (36.0 mg, 0.146 mmol, 1 eq), and TEA (0.0617 mL, 0.438 mmol, 3 eq) in DCM (1.5 mL) was added 2',5,6'-trimethyl-[1 , T-biphenyl]- 2-sulfonyl chloride LiCI (49 mg, ca 0.146 mmol, 1 eq) and the mixture was stirred at rt for 17 h. Water (1 mL) was added and the reaction mixture was stirred for 5-10 min, filtered over phase separator and the solvent removed under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 6:4) followed by basic prep. HPLC to give the title compound. Rf (Hept / EtOAc 1 :1)= 0.30. LC-MS (1): IR= LC-MS (2): IR= 1.271 min; [M+H]+: 505.2.

[0611] Example 1.98 (S)-1-[2-(2-Chloro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0612] (S)-1-((2-Chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide: to a soln, of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (401 mg, 1.63 mmol, 1.2 eq), DIPEA (0.927 mL, 5.42 mmol, 4 eq) and DMAP (16.6 mg, 0.136 mmol, 0.1 eq) in DCM (2 mL) was added 2-chloro-6-methylpyridine-3-sulfonyl chloride (450 mg, 1.36 mmol, 1 eq) at rt. The mixture was stirred for 1 h at rt, and the solvents were removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (2): IR = 0.91 min; [M+H]+: 436.22.

[0613] (S)-1-[2-(2-Chloro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), 2-chlorophenylboronic acid (14.6 mg, 0.0918 mmol, 2 eq) and Na2CO3 (11.6 mg, 0.138 mmol, 3 eq) in a 4:1 mixture of DME and water (0.3 mL) was degassed with N2. The mixture was rapidly heated to 100 °C, and Pd(PPhs)4 (5.5 mg, 0.0046 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 1 h, and allowed to cool to rt. The mixture was filtered and the solvents removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.113 min; [M+H]+: 512.2. Example 1.99 (S)-1-[2-(2-Fluoro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (15.0 mg, 0.0334 mmol, 1 eq), 2-fluorophenylboronic acid (9.9 mg, 0.069 mmol, 2 eq) and Na2COa (8.7 mg, 0.10 mmol, 3 eq) in a 4:1 mixture of DME and water (0.3 mL) was degassed with N2. The mixture was rapidly heated to 100 °C, and Pd(PPh3)4 (4.1 mg, 0.0034 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 1 h, and allowed to cool to rt. The mixture was filtered and the solvents removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC- MS (1): tR= 1.070 min; [M+H]+: 496.2.

[0614] Example 1.100 to example 1.101 : were synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl- 2-(4,4, 5,5-tetramethy 1-1 , 3, 2-dioxaborolan-2-y I) pheny l)su Ifony I) py rrol idine-2-carboxami de and the appropriate bromoaryl in analogy to Example 1.96. LC-MS data of Example 1.100 to Example 1.101 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0615] Example 1.102 (S)-1-[4-(2-Chloro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0616] 5-(Benzylthio)-4-chloro-2-methylpyridine: a mixture of 5-bromo-4-chloro-2-methylpyridine (500 mg, 2.32 mmol, 1 eq), benzyl mercaptan (292 mg, 2.32 mmol, 1 eq) and DIPEA (0.812 mL, 4.65 mmol, 2 eq) in dioxane (10 mL) was degassed with N2. The mixture was rapidly heated to 95 °C, and Pd2(dba)3 (106 mg, 0.116 mmol, 0.05 eq) and XantPhos (137 mg, 0.232 mmol, 0.1 eq) were added. The mixture was heated under microwave irradiation at 95 °C for 15 min, and was allowed to cool to rt. The mixture was filtered and the solvents were removed under reduced pressure. The residue was purified by FC (Hept to EtOAc I Hept 7:3) to give the title compound. LC-MS (2): tR= 0.89 min; [M+H]+: 250.25.

[0617] 4-Chloro-6-methylpyridine-3-sulfonyl chloride: to a soln, of 5-(benzylthio)-4-chloro-2-methylpyridine (495 mg, 1 .98 mmol) in THF (2 mL), AcOH (0.2 mL) and water (0.4 mL) at 0 °C was added 1 , 3-dich loro-5,5-dimethy I hydantoi n (1.21 g, 5.95 mmol, 3 eq) in portions. The mixture was stirred for 1 h at 0 °C. DCM (30 mL) was added, and this mixture was washed with aq. sat. NaHCOs and brine. The org. layer was dried through a phase separator, filtered, and the solvents were removed under reduced pressure to give the title compound, wich was used without further purification. (S)-1-((4-Chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide: to a mixture of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (458 mg, 1.86 mmol, 1.2 eq), DIPEA (1.59 mL, 9.29 mmol, 6 eq) and DMAP (18.9 mg, 0.155 mmol, 0.1 eq) in DCM (2 mL) was added 4-chloro-6-methylpyridine-3-sulfonyl chloride (350 mg, ca 1.55 mmol, ca 1 eq) in DCM (1 mL). The mixture was stirred for 1 h at rt, and the solvents were removed under reduced pressure. The residue was purified by FC (Hept to EtOAc) to give the title compound. LC-MS (2): tR= 0.90 min; [M+H]+: 436.21.

[0618] (S)-1-[4-(2-Chloro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((4-chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (50.0 mg, 0.115 mmol, 1 eq), 2-chlorophenylboronic acid (36.6 mg, 0.229 mmol, 2 eq) and Na2CO3 (29.0 mg, 0.344 mmol, 3 eq) in a 4:1 mixture of DME and water (2 mL) was degassed with N2. The mixture was rapidly heated to 100 °C, and Pd(PPh3)4 (13.7 mg, 0.0115 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 18 h, and allowed to cool to rt. The mixture was filtered and the solvents removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.150 min; [M+H]+: 512.1.

[0619] Example 1.103 (S)-1-[4-(2-Fluoro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((4-chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (50.0 mg, 0.115 mmol, 1 eq), 2-fluorophenylboronic acid (32.8 mg, 0.229 mmol, 2 eq) and Na2CO3 (29.0 mg, 0.344 mmol, 3 eq) in a 4:1 mixture of DME and water (2 mL) was degassed with N2. The mixture was rapidly heated to 100 °C, and Pd(PPh3)4 (13.7 mg, 0.0115 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 18 h, and allowed to cool to rt. The mixture was filtered and the solvents removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.094 min; [M+H]+: 496.2.

[0620] Example 1.104 to Example 1.109: were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1,T- biphenyl]-2-sulfonyl chloride LICI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to Example 1.62. LC-MS data of example 1.104 to Example 1.109 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0621] Example 1.110 (S)-1-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-4,4-difluoro-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide:

[0622] (S)-1-((2-Bromo-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-4,4-difluoro-N-methylpyrrolidine-2- carboxamide: was synthesized using (2S)-4,4-difluoropyrrolidine-2-carboxylic acid and 2-bromo-4- methylbenzene-1 -sulfonyl chloride in analogy to Example 1.1 to give the title compound. LC-MS (2): IR = 1.05 min; [M+H]+: 515.08.

[0623] (S)-N-(4,4-Difluorocyclohexyl)-4,4-difluoro-N-methyl-1-((4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide: was synthesized using (S)-1-((2-bromo-4- methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-4,4-difluoro-N-methylpyrrolidine-2-carboxamide in analogy to Example 1.25 to give the title compound. LC-MS (2): IR= 1.11 min; [M+H]+: 563.23.

[0624] (S)-1-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-4,4-difluoro-N- methyl-1-((4-methyl-2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2 -carboxamide and 2-bromo-3-chloropyridine in analogy to Example 1.25 to give the title compound. LC-MS (1): IR= 1.198 min; [M+H]+: 548.2.

[0625] Example 1.111 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: tert-Butyl -1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-5-carboxylate: to a soln, of tert-butyl-4,5-dihydro-1 H-pyrazole-5-carboxylate (40.0 mg, 0.235 mmol, 1 eq) in MeCN (3 mL), K2CO3 (162 mg, 1.18 mmol, 5 eq) and 2'-fluoro-5-methyl-[1 , 1 '-biphenyl]-2-sulfonyl chloride LICI (66.9 mg, ca 0.235 mmol, 1 eq) were added in sequence and the reaction mixture was heated at 80 °C overnight. The reaction mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (2): IR = 1.04 min; [M+H]+: 419.27.

[0626] 1-((2'-Fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-4,5-dihydro-1 H-pyrazole-5-carboxylic acid: to a soln, of tert-butyl 1-((2'-fluoro-5-methyl-[1 , T-biphenyl]-2-yl)sulfonyl)-4,5-dihydro-1 H-pyrazole-5-carboxylate (39 mg, 0.0932 mmol, 1 eq) in DCM (2 mL), TFA (0.0721 mL, 0.932 mmol, 10 eq) was added dropwise. The resulting mixture was stirred at rt overnight. The volatiles were removed under reduced pressure to give the title compound. LC-MS (2): tR= 0.83 min; [M+H]+: 363.25.

[0627] 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: to a soln, of 1-((2'-fluoro-5-methyl-[1,T-biphenyl]-2-yl)sulfonyl)-4,5-dihydro-1 H- pyrazole-5-carboxylic acid (15.4 mg, 0.0424 mmol, 1 eq) and 4,4-difluoro-N-methylcyclohexan-1-amine hydrochloride (7.87 mg, 0.0424 mmol, 1 eq) in DMF (1 mL), TEA (0.0298 mL, 0.212 mmol, 5 eq) and HATU (17.4 mg, 0.0445 mmol, 1.05 eq) were added in sequence. The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.157 min; [M+H]+: 494.2.

[0628] Example 1.112: (2S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5,6'-dimethyl-[1,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide:

[0629] 2'-Fluoro-5,6'-dimethyl-[1 ,1'-biphenyl]-2-sulfonyl chloride LICI: was synthesized using 4-bromo-3-iodotoluene and 2-fluoro-6-methylphenylboronic acid in analogy to Example 1.97 to give the title compound. LC-MS (2): tR= 1.07 min; [M+H]+: not seen.

[0630] (2S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5,6'-dimethyl-[1 ,1'-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide: was synthesized using 2'-fluoro-5,6'-dimethyl-[1,T-biphenyl]-2-sulfonyl chloride LiCI and (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide in analogy to Example 1.97 to give the title compound. LC-MS (2): tR= 1.270 min; [M+H]+: 509.3.

[0631] Example 1.113 1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4,5-dihydro-1 H-pyrrole-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0632] (2R,3R)-3-Fluoro-1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)pyrrolidine-2-carboxylic acid: to an ice- cooled soln, of (2R,3R)-1-[(tert-butoxy)carbonyl]-3-fluoropyrrolidine-2-carboxylic acid (35 mg, 0.15 mmol, 1 eq) in DCM (3 mL), HCI (4M in dioxane, 0.5 mL) was added. The resulting soln, was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), and TEA (0.105 mL, 0.75 mmol, 5 eq) and 2'-fluoro-5,6'-dimethyl-[1 ,T-biphenyl]-2-sulfonyl chloride LiCI (49 mg, ca 0.15 mmol, 1 eq) were added in sequence. The resulting soln, was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (2): tR= 0.88 min; [M+H]+: 382.28.

[0633] 1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4,5-dihydro-1 H-pyrrole-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: a soln. of (2R,3R)-3-fluoro-1-((2'-fluoro-5-methyl-[1,T-biphenyl]-2- yl)sulfonyl)pyrrolidine-2-carboxylic acid (19 mg, 0.05 mmol, 1 eq) and 4,4-difluoro-N-methylcyclohexan-1-amine hydrochloride (9.3 mg, ca 0.05 mmol, 1 eq) in DCM (2 mL) were treated with TEA (0.028 mL, 0.20 mmol, 4 eq) and HATU (21 mg, 0.055, 1.1 eq). The resulting soln, was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.248 min; [M+H]+: 493.2.

[0634] Example 1.114 to Example 1.119: were synthesized in analogy to Example 1.98 using the appropriate boronic acids. LC-MS data of Example 1.1 14 to Example 1.119 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0635] Example 1.120: 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: l-(tert-Butyl) 5-ethyl 3-methyl-4,5-dihydro-1H-pyrazole-1,5-dicarboxylate: CuCI2(26.9 mg, 0.200 mmol, 0.2 eq) was added to a soln, of tert-butyl (E)-2-(1-chloropropan-2-ylidene)hydrazine-1-carboxylate (207 mg, 1.00 mmol, 1 eq), ethyl diazoacetate (0.363 mL, 3.00 mmol, 3 eq), and Na2CO3 (530 mg, 5.00 mmol, 5 eq) in DCM (8 mL), and the reaction mixture was stirred at rt for 5 h. The mixture was then filtered through a Celite® pad and washed with DCM. After removal of the solvent, the residue was purified by FC (Hept to Hept / EtOAc 1 :1) to give the title compound. Rf(Hept / EtOAc 1 : 1)= 0.25;1H NMR (500 MHz, CDCI3) 6: 4.70 (dd, Ji = 5.8 Hz, J2= 12.2 Hz, 1 H), 4.19- 4.29 (m, 2 H), 3.18 (dd, Ji = 17.9 Hz, J2= 12.6 Hz, 1 H), 2.85 (dd, Ji = 18.0 Hz, J2= 6.0 Hz, 1 H), 2.05 (s, 3 H), 1 .47-1 .56 (m, 9 H), 1 .30 (t, J = 7.1 Hz, 3 H); LC-MS (2): tR= 0.76 min; [M+H]+: not seen.

[0636] Ethyl 1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate: to an ice-cooled soln, of (tert-butyl) 5-ethyl 3-methyl-4,5-dihydro-1 H-pyrazole-1 ,5-dicarboxylate (51.3 mg, 0.200 mmol, 1 eq) in DCM (3 mL), HCI (4M in dioxane, 0.5 mL) was added. The resulting soln, was stirred at rt overnight. The volatiles were removed under reduced pressure. The residue was dissolved in DCM (2 mL), and TEA (0.139 ml, 1.00 mmol, 5 eq) and 2'-fluoro-5,6'-dimethyl-[1,T-biphenyl]-2-sulfonyl chloride LICI (65.4 mg, ca 0.2 mmol,1 eq) were added in sequence. The resulting soln, was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (2): IR = 0.99 min; [M+H]+: 405.29.

[0637] 1-((2'-Fluoro-5-methyl-[1 J'-biphenyl]-2-yl)sulfonyl)-3-methyl-4,5-dihydro-1 H-pyrazole-5-carboxylic acid: to a soln, of ethyl 1-((2'-fluoro-5-methyl-[1 ,1 '-biphenyl]-2-yl)sulfonyl)-3-methyl-4,5-dihydro-1 H-pyrazole-5-carboxylate (19.7 mg, 0.0487 mmol, 1 eq) in THF (2 mL) and EtOH (1 mL) was added aq. 1 M NaOH (1 mL) and the reaction stirred overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (2): IR= 0.86 min; [M+H]+: 377.29.

[0638] 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: to a soln, of 1-((2'-fluoro-5-methyl-[1 ,1 '-biphenyl]-2-yl)sulfonyl)-3-methyl- 4,5-dihydro-1 H-pyrazole-5-carboxylic acid (16 mg, 0.0424 mmol, 1 eq) and 4,4-difluoro-N-methylcyclohexan-1- amine hydrochloride (7.87 mg, ca 0.0424 mmol, 1 eq) in DMF (1 mL), TEA (0.0298 mL, 0.212 mmol, 5 eq) and HATU (17.4 mg, 0.0445 mmol, 1.05 eq) were added in sequence. The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.178 min; [M+H]+: 508.2.

[0639] Example 1.121 (1S,2S,5R)-3-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-3-aza- bicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride, 2-bromo-4-methylbenzene-1 -sulfonyl chloride and 2-bromo-3-chloropyridine in analogy to Example 1.110 to give the title compound. LC-MS (1): IR= 1.176 min; [M+H]+: 524.3.

[0640] Example 1.122 (1S,3S,5S)-2-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-2-aza- bicyclo[3.1.0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid hydrochloride, 2-bromo-4-methylbenzene-1 -sulfonyl chloride and 2-bromo-3-chloropyridine in analogy to Example 1.110 to give the title compound. LC-MS (1): IR= 1.167 min; [M+H]+: 524.2.

[0641] Example 1.123 (S)-1-(6'-Methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), piperidine (0.0114 mL, 0.1 15 mmol, 2.5 eq) and K2CO3 (32.0 mg, 0.229 mmol, 5 eq) in DMSO (1 mL) and DME (0.25 mL) was heated to 100 °C for 24 h. The mixture was allowed to cool to rt and diluted with water (2 mL) and DCM (50 mL). The layers were separated, and the aq. layer was extracted with DCM (2x). The combined org. layers were washed with brine, dried over MgSO4, and the solvents were removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR = 1.275 min; [M+H]+: 485.3. Examples 1.124 to 1.130: were synthesized in analogy to Example 1.123 using the corresponding amines. LC- MS data of Example 1.124 to Example 1.130 are listed in the table below. The LC-MS conditions used were LC- MS (1). Example 1.131 (S)-1-(2',6'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:

[0642] (S)-N-(4,4-Difluorocyclohexyl)-1-((2-iodo-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: to a mixture of (S)-N-(4,4-difl uorocyclohexy l)-N-methy Ipy rrolidi ne-2-carboxamide (739 mg, 3.00 mmol, 1 eq), and TEA (1.27 mL, 9.00 mmol, 3 eq) in DCM (29.6 mL) was added 2-iodo-4-methylbenzene-1 -sulfonyl chloride (1.00 g, 3.00 mmol, 1 eq) and the mixture was stirred at rt for 1 h. Water was added at rt, the reaction mixture was stirred for 5 min then filtered over phase separator. The solvent was evaporated under reduced pressure. The residue was purified by FC (Hept to Hept / EAtOAc 4:6) to give the title compound. LC-MS (2): IR = 1 .05 min; [M+H]+: 527.08.

[0643] (S)-1-(2',6'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide: in an oven dried sealed microwave vial, to a soln, of 2,6-difluoroiodobenzene (0.061 mL, 0.35 mmol, 2.3 eq) in DMPU (0.152 mL, 0.152 mmol, 1 eq) was added Et2Zn (1.0 M in hexanes, 0.228 mL, 0.228 mmol, 1.5 eq) at rt. The soln, was warmed to 77 °C and stirred for 3 h. The soln, was cooled to rt. The seal was removed, (S)- N-(4,4-difluorocyclohexyl)-1-((2-iodo-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide (80 mg, 0.152 mmol, 1 eq), 1 , 10-phenanthroline (5.65 mg, 0.0304 mmol, 0.2 eq) and Cui (2.89 mg, 0.0152 mmol, 0.1 eq) were added, the vial sealed again, purged with N2 and heated to 120 °C and stirred overnight. Aq. 1 M HCI and DCM were added and mixture was stirred for 5 min. The two phases were separated by a separation cartridge. The solvent was removed under reduced pressure and the residue was purified by acidic prep HPLC followed by FC (Hept to Hept / EtOAc 1 : 1) to give the title compound. LC-MS (1): IR = 1.227 min; [M+H]+: 513.2.

[0644] Example 1.132 to Example 1.135: were synthesized using the appropriate amino acid or amino acid salt according to the procedures described in Example 1.21. LC-MS data of Example 1.132 to Example 1.135 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0645] Example 1.136 (S)-1-[4-Methyl-2-(3-methyl-pyrazin-2-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1 -((4- methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and 2-bromo-3- methylpyrazine in analogy to Example 1.96 to give the title compound. LC-MS (1): IR = 1.027 min; [M+H]+: 493.2.

[0646] Example 1.137 (S)-1-[4-Methyl-2-(5-methyl-pyrazol-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-N-(4,4-difluorocyclohexyl)-1-((2-iodo-4- methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide (150 mg, 0.285 mmol, 1 eq), 3-methylpyrazole (24.1 mg, 0.285 mmol, 1 eq), CU2O (1.36 mg, 0.0095 mmol, 0.1 eq), salicylaldoxime (16.0 mg, 0.114 mmol, 0.4 eq) and CS2CO3 (186 mg, 0.57 mmol, 2 eq) in CH3CN (2.85 mL) was degassed with a N2 flux during 10 min and heated to reflux for 18 h. The mixture was filtered, the solvent removed under reduced pressure and the residue was purified by FC (Hept / EtOAc 3:7) followed by basic HPLC to give the title compound. LC-MS (3): IR = 0.97 min; [M+H]+: 481.17. (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(3-methyl-1 H-pyrazol-1- yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide: LC-MS (3): IR = 0.98 min; [M+H]+: 481.85.

[0647] Example 1.138 and Example 1.139 (S)-N-(4,4-difluorocyclohexyl)-1-(((Sa)-2'-fluoro-6'-methoxy-5-methyl- [1,1'-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and (S)-N-(4,4-difluorocyclohexyl)-1- (((Ra)-2'-fluoro-6'-methoxy-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide : 2-Bromo-2'-fluoro-6'-methoxy-5-methyl-1,1'-biphenyl: 4-bromo-3-iodotoluene 97% (150 mg, 0.49 mmol, 1 eq),

[0648] 2-fluoro-6-methoxyphenylboronic acid (83.3 mg, 0.490 mmol, 1 eq), K2CO3 (342 mg, 2.45 mmol, 5 eq) and Pd(PPh3)4 (58.4 mg, 0.049 mmol, 0.1 eq) were dissolved in degassed dioxane / water 4:3 (4.9 mL) and the resulting mixture was stirred at 150 °C for 30 min under microwave irradiations. The reaction mixture was then filtered through a PTFE 0.45 m filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound. Rf (Hept / EtOAc 9:1)= 0.44. LC- MS (2): tR= 1.07 min; [M+H]+: 295.18.

[0649] (2S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-6'-methoxy-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide: 2-bromo-2'-fluoro-6'-methoxy-5-methyl-1,T-biphenyl (65.0 mg, 0.196 mmol, 1 eq) was dissolved in THF (2 mL) and stirred at -78 °C. n-BuLi (1.6 M in hexanes, 0.147 mL, 0.235 mmol, 1.2 eq) was added dropwise and the reaction mixture was stirred at -78 °C for 2 h. SO2 (0.5 M in THF, 0.784 mL, 0.392 mmol, 2 eq) was added and the reaction mixture was stirred at -78 °C for 1 h then at rt overnight. The reaction mixture was concentrated and the pale yellow solid was suspended in DCM (2 mL) and stirred at -78 °C. A soln, of SO2CI2 (0.0197 mL, 0.235 mmol, 1.2 eq) in DCM (2 mL) was added. The reaction mixture was stirred at -78 °C for 45 min then at rt for 1 h. SO2CI2 (0.0082 mL, 0.098 mmol, 0.5 eq) in DCM (1 mL) was added again at -78 °C and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification.

[0650] (2S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-6'-methoxy-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide: (2S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-6'-methoxy-5-methyl-[1, 1'- biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide (61.7 mg, 0.196 mmol, 1 eq) in DCM (1.5 mL) was added to a soln, of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (48.3 mg, 0.196 mmol, 1 eq), and TEA (0.0828 mL, 0.588 mmol, 3 eq) in DCM (0.5 mL) and the mixture was stirred at rt for 2.5 h. Water was added and the reaction mixture was stirred for 10 min, filtered over phase separator and the solvent removed under reduced pressure. The org. phase layer concentrated under reduced pressure and purified by FC (Hept to Hept / EtOAc 5.5:4.5) followed by basic prep. HPLC to give a first eluting atropisomer and a second eluting atropisomer. First eluting atropisomer: LC-MS (1): tR = 1.194 min; [M+H]+: 525.3. Second eluting atropisomer: LC- MS (1): tR= 1.229 min; [M+H]+: 525.2.

[0651] Example 1.140 (2S)-1-((2-(2-Chloro-4-methylpyridin-3-yl)-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide:

[0652] 3-(2-Bromo-5-methylphenyl)-2-chloro-4-methylpyridine: 2-bromo-5-methylphenylboronic acid (0.0212 mL, 0.0903 mmol, 1 eq), 2-chloro-3-iodo-4-methylpy ridine (46.7 mg, 0.181 mmol, 2 eq), NaHCOs (22.8 mg, 0.271 mmol, 3 eq) and Pd(PPh3)4 (10.8 mg, 0.00903 mmol, 0.1 eq) were dissolved in degassed DME / water 4: 1 (1 mL) and the resulting mixture was stirred at 85 °C overnight. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound. Rf (Hept / EtOAc 1 : 1)= 0.69. LC-MS (2): IR = 1.0 min; [M+H]+: 296.08.

[0653] (2S)-1-((2-(2-Chloro-4-methylpyridin-3-yl)-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide: was synthesized using 2-(2-bromo-5-methylphenyl)-6-chloro-3- methylpyridine and (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide in analogy to Example 1.138 to give the title compound. LC-MS (1): IR= 1.145 min; [M+H]+: 526.3.

[0654] Example 1.141 (S)-1-[2-(2,6-Difluoro-phenyl)-6-methoxy-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide:

[0655] (S)-1-((2-Chloro-6-methoxypyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide: to a soln, of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (370 mg, 1.31 mmol, 1.1 eq), DIPEA (0.819 mL, 4.76 mmol, 4 eq) and DMAP (14.5 mg, 0.119 mmol, 0.1 eq) in DCM (2 mL) was added 2-chloro-6-methoxypyridine-3-sulfonyl chloride (300 mg, 1.19 mmol, 1 eq) at rt. The mixture was stirred for 1 h at rt, and the solvents were removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (2): IR = 0.98 min; [M+H]+: 452.19.

[0656] (S)-1-[2-(2,6-Difluoro-phenyl)-6-methoxy-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (99 mg, 0.219 mmol, 1 eq), 2,6-difluorophenylboronic acid (72.2 mg, 0.438 mmol, 2 eq) and Na2CO3 (55.4 mg, 0.657 mmol, 3 eq) in a 4: 1 mixture of DME and water (2 mL) was degassed with N2. The mixture was rapidly heated to 100 °C, and Pd(PPh3)4 (26.1 mg, 0.0219 mmol, 0.1 eq) was added. The mixture was stirred at 100 °C for 18 h, and allowed to cool to rt. The mixture was filtered and the solvents removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR = 1.181 min; [M+H]+: 530.2.

[0657] Example 1.142 (S)-1-[2-((2R,5S)-2,5-Dimethyl-pyrrolidin-1-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3- yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (30 mg, 0.0688 mmol, 1 eq), c / s-2,5- dimethylpyrrolidine hydrochloride (14.6 mg, 0.103 mmol, 1.5 eq) and KF (12 mg, 0.21 mmol, 3 eq) in DMF (1 mL) was heated to 140 °C for 96 h. The mixture was allowed to cool to rt. The mixture was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR = 0.996 min; [M+H]+: 499.4.

[0658] Example 1.143 to Example 1.145: were synthesized using the amine or amine salt in analogy to Example 1.142. LC-MS data of Examples 1.143 to 1.145 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0659] Example 1.146 (S)-1-[2-(2-Ethyl-5-methyl-pyrrolidin-1-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3- yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), 2-ethyl-5- methylpyrrolidine hydrochloride (72.3 mg, 0.459 mmol, 10 eq) and KF (48.0 mg, 0.83 mmol, 18 eq) in DMA (1 mL) was heated to 140 °C for 2 h. The mixture was allowed to cool to rt. The mixture was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR = 1.087 min; [M+H]+: 513.4.

[0660] Example 1.147 (2S)-N-(4,4-difluorocyclohexyl)-1-((2-(3-fluoropiperidin-1-yl)-4-methylphenyl)sulfonyl)-N- methylpyrrolidine-2-carboxamide:

[0661] 1-(2-Bromo-5-methylphenyl)-3-fluoropiperidine: a mixture of 4-bromo-3-iodotoluene (184 mg, 0.60 mmol, 1 eq), 3-fluoropiperidine hydrochloride (104 mg, 0.72 mmol, 1.2 eq), NaOtBu (150 mg, 1.56 mmol, 2.6 eq), XantPhos (53.7 mg, 0.090 mmol, 0.15 eq) and Pd2(dba)3 (22 mg, 0.024 mmol, 0.04 eq) in dioxane (3 mL) was heated to 90 °C for 14 h under an N2 atmosphere. The mixture was diluted with sat. aq. NaHCOa and extracted with EtOAc. The org. layer was dried over MgSC>4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to Hept / EA 9: 1) to give the title compound. LC-MS (2): IR = 1.06 min; [M+H]+: 272.24.

[0662] (2S)-N-(4,4-difluorocyclohexyl)-1-((2-(3-fluoropiperidin-1-yl)-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-

[0663] 2-carboxamide: 1 -(2-bromo-5-methylphenyl)-3-fluoropiperidine (86.0 mg, 0.316 mmol, 1 eq) was dissolved in THF (3.24 mL) and stirred at -78° C. n-BuLi (1 .6 M in hexanes, 0.238 mL, 0.379 mmol, 1 .2 eq) was added dropwise and the reaction mixture was stirred at -78 °C for 2 h. SO2 (0.5 M in THF, 1.27 mL, 0.632 mmol, 2 eq) was added and the reaction mixture was stirred at -78 °C for 1 h then at rt overnight. The reaction mixture was concentrated and the pale yellow solid was suspended in DCM (2 mL) and stirred at -78 °C. A soln, of SO2CI2 (0.0317 mL, 0.379 mmol, 1 .2 eq) in DCM (1.3 mL) was added at rt and the reaction stirred at rt. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DCM (0.5 mL) and (S)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide (22.7 mg, 0.0922 mmol) and TEA (0.0389 mL, 0.277 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by acidic prep. HPLC to give the title compound as a mixture of 2 stereoisomers. LC-MS (1): IR = 1.232 min; [M+H]+: 502.2. Example 1.148 (2S)-N-(4,4-difluorocyclohexyl)-1-((2-(2-(methoxymethyl)piperidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20 mg, 0.0459 mmol, 1 eq), rac-2- (methoxymethyl)piperidine (62 mg, 0.46 mmol, 10 eq) and KF (48 mg, 0.83 mmol, 18 eq) in DMF (1 mL) was heated to 140 °C for 18 h. The mixture was allowed to cool to rt. Thecrude mixture was purified by basic prep. HPLC to give the title compound as a mixture of 2 stereoisomers. LC-MS (1): IR = 1.232 min; [M+H]+: 529.4.

[0664] Example 1.149: (2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,4-difluoropyridin-3-yl)-4-methylphenyl)sulfonyl)-N- methylpyrrolidine-2-carboxamide:

[0665] 3-(2-Bromo-5-methylphenyl)-2,4-difluoropyridine: 2-bromo-5-methylphenylboronic acid (0.106 mL, 0.451 mmol, 1 eq), 2,4-difluoro-3-iodopyridine (229 mg, 0.903 mmol, 2 eq), NaHCOa (114 mg, 1.35 mmol, 3 eq) and Pd(PPh3)4 (53.8 mg, 0.0451 mmol, 0.1 eq) were dissolved in degassed DME I water 4:1 (4.5 mL) and the resulting mixture was stirred at 85 °C for 17 h. Pd(PPha)4 (26.9 mg, 0.0225 mmol, 0.05 eq) was added again and the reaction mixture was stirred at 85 °C overnight. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 95:5) to give the title compound. LC-MS (2): IR = 1.01 min; [M+H]+: 284.13.

[0666] (2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,4-difluoropyridin-3-yl)-4-methylphenyl)sulfonyl)-N- methylpyrrolidine-2-carboxamide: was synthesized using 3-(2-bromo-5-methylphenyl)-2,4-difluoropyridine in analogy to Example 1.147 to give the title compound as a white solid. LC-MS (1): IR = 1.121 min; [M+H]+: 514.3.

[0667] Example 1.150 to Example 1.154: were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methy Ipy rrolidi ne-2-carboxamide and the appropriate boronic acid or boronic ester in analogy to Example 1.1. LC-MS data of Example 1 .150 to Example 1 .154 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.155 (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (12.0 mg, 0.0275 mmol, 1 eq), ethylisopropylamine (0.034 mL, 0.28 mmol, 10 eq) and KF (24 mg, 0.41 mmol, 15 eq) in DMF (1 mL) was heated to 140 °C overnight. The mixture was allowed to cool to rt. The crude mixture was purified by by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.168 min; [M+H]+: 487.2.

[0668] Example 1.156 and Example 1.157: (S)-1-(((Ra)-2'-Chloro-5,6'-dimethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and (S)-1-(((Sa)-2'-Chloro-5,6'-dimethyl-[1,r- biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide : were synthesized using 4-bromo-3-iodotoluene and (2-chloro-6-methylphenyl)boronic acid in analogy to Example 1.138 to give the title compound. First eluting atropisomer: LC-MS (1): tR= 1.316 min; [M+H]+: 525.3. Second eluting atropisomer: LC-MS (1): tR= 1.360 min; [M+H]+: 525.3.

[0669] Example 1.158 (2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,3-dimethylpyrrolidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), 2,3-dimethylpyrrolidine hydrochloride (66 mg, 0.46 mmol, 10 eq) and KF (40 mg, 0.69 mmol, 15 eq) in DMF (2.8 mL) was heated to 140 °C for 1 h. The mixture was allowed to cool to rt. The crude mixture was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.356 min; [M+H]+: 499.4.

[0670] Example 1.159 (S)-1-[6-Methyl-2-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3- yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), (R)-2- (trifluoromethyl)pyrrolidine (64 mg, 0.46 mmol, 10 eq) and KF (40 mg, 0.69 mmol, 15 eq) in DMF (2.8 mL) was heated to 140 °C overnight. The mixture was allowed to cool to rt. The crude mixture was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.331 min; [M+H]+: 539.2.

[0671] Example 1.160 and Example 1.161 : (S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-5,6-dimethyl-[1,1'- biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and (S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'- fluoro-5,6-dimethyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide :

[0672] 2'-Fluoro-2,3-dimethyl-6-nitro-1,r-biphenyl: 2-bromo-3,4-dimethyl-1-nitrobenzene (300 mg, 1.30 mmol, 1 eq), 2-fluorophenylboronic acid (223 mg, 1.56 mmol, 1.2 eq), K3PO4 H2O (802 mg, 3.48 mmol, 2.67 eq) and Pd(PPha)4 (155 mg, 0.130 mmol, 0.1 eq) were dissolved in degassed DME I water 4:1 (13 mL) and the resulting mixture was stirred at 85 °C for 18 h. The reaction mixture was filtered through a PTFE 0.45 pm filter and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 95:5) to give the title compound. Rf (Hept / EtOAc 95:5)= 0.25. LC-MS (3): tR= 1.05 min; [M+H]+: not seen.1H NMR (500 MHz, CDCI3) 5: 7.77 (d, J = 8.3 Hz, 1 H), 7.42 (m, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 7.17-7.24 (m, 2 H), 7.12 (td, Ji = 1.8 Hz, J2= 7.4 Hz, 1 H), 2.43 (s, 3 H), 2.05 (s, 3 H).

[0673] 2'-Fluoro-5,6-dimethyl-[1,r-biphenyl]-2-amine: Fe (powder, 683 mg, 12.2 mmol, 10 eq) and NH4CI (65.8 mg, 1.22 mmol, 1 eq) were dissolved in EtOH / water 8: 1 (5 mL) and the resulting suspension was stirred at 85 °C. A soln, of 2'-fluoro-2,3-dimethyl-6-nitro-1,1 '-biphenyl (300 mg, 1.22 mmol, 1 eq) in EtOH (20 mL) was then added dropwise and the reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was filtered through a PTFE 0.45 m filter and rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound. Rf (Heptane I EtOAc 9: 1)= 0.18. LC-MS (2): IR = 0.72 min; [M+H]*: 216.25.

[0674] 6-Bromo-2'-fluoro-2,3-dimethyl-1,r-biphenyl: CuBr2(325 mg, 1.44 mmol, 1.1 eq) was suspended in CH3CN (9 mL) and tert-butyl nitrite (0.191 mL, 1 .44 mmol, 1 .1 eq) was added. The reaction mixture was stirred at 0 °C before the dropwise addition of a soln, of 2'-fluoro-5,6-dimethyl-[1 ,T-biphenyl]-2-amine (282 mg, 1.31 mmol, 1 eq) in CH3CN (4 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled down to 0 °C and quenched with a soln, of sulfamic acid (25.6 mg, 0.262 mmol, 0.2 eq) in water (7 mL) followed by the addition of aq. 2M HOI (0.985 mL, 1.97 mmol, 1.5 eq). The reaction mixture was extracted with EtOAc (25 mL). The aq. layer was extracted with EtOAc (20 mL). The combined org. layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 95:5) followed by basic prep. HPLC to give the title compound. LC-MS (2): IR = 1.12 min; [M+H]+: not seen.

[0675] (S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-5,6-dimethyl-[1,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide and (S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'-fluoro-5,6-dimethyl-[1,r- biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: 6-bromo-2'-fluoro-2,3-dimethyl-1 , T-biphenyl

[0676] (101 mg, 0.362 mmol, 1 eq) was dissolved in THF (4 mL) and stirred a...

Claims

Claims1 . A compound of the Formula (I)whereinRing B is a 6-membered aromatic ring, wherein independently:• in said Ring B X1represents N or CRB2, wherein RB2represents hydrogen, halogen, or (Ci-3)alkyl, and X2represents CH; or X1represents CH and X2represents N; and• RB1represents hydrogen, (Ci-3)alkyl, (Ci-3)alkoxy, halogen, (C2-4)alkenyl, monocyclic (C3-6)cycloalkyl, or (Ci-3)fluoroalkyl; and• RB3represents: OR01, wherein R01represents (C2-5)alkyl that is substituted with zero, one or two (Ci)fluoroalkyl; wherein R01contains a total of at least 3 carbon atoms; NRN1RN2, wherein independently:■ RN1represents:• hydrogen; or• (Ci-3)alkyl; and■ RN2represents:• (C2-5)alkyl; wherein said (C2-5)alkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci)fluoroalkyl, (C3-5)cycloalkyl, and (Ci-3)alkoxy; or• monocyclic (Cs-sjcycloalkyl, wherein said monocyclic (C^cycloalkyl is unsubstituted or mono-substituted with (Ci-3)alkyl; or■ RN1and RN2together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom; wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl, (Ci-2)fluoroalkyl, and (Ci-3)alkoxy-(Ci-3)alkyl; or■ RN1and RN2together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom; or a saturated or mono-unsaturated monocyclic (Cs-zjcycloalkyl; wherein said (C4-6)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-3)alkyl or halogen; or a saturated or mono-unsaturated bridged bicyclic (C6-8)cycloalkyl;or phenyl or 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from N, 0, and S; wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or mono-, or di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: halogen, (Ci-3)alkyl, (C3-6)cycloalkyl, (Ci-3)alkoxy, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and cyano; andX3represents 0 or NRN3, wherein RN3represents hydrogen, (Ci-3)alkyl, (C3-6)cycloalkyl, a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom, a 5-membered saturated bridged bicyclic cycloalkyl, phenyl, or pyridinyl; andX4represents CH or N such that: when X4represents CH, Ring A represents a monocyclic (Cs-ejcycloalkan-diyl; or when X4represents N, Ring A represents:• a 4- to 7-membered saturated monocyclic heterocycloal kan-diy I comprising X4, and zero or one further ring heteroatom selected from 0 or S; wherein said saturated heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl, halogen, (Ci-3)alkoxy, (Ci-3)alkylidene, and oxo; or• a 4- to 6-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom; wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4; wherein said mono-unsaturated heterocycloalkan-diyl is unsubstituted, or monosubstituted with (Ci-3)alkyl; ora 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom; wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci-3)alkyl or di-substituted with fluoro; andR1represents: hydrogen; or (Ci-3)alkyl; wherein said (Ci-3)alkyl is unsubstituted, or mono-substituted with (Ci-3)alkoxy; andR2represents: (Ci-6)alkyl; wherein said (Ci^alkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from halogen or (Ci-3)alkoxy; or -(CH2)q-Cy1; wherein q is 0 or 1 and Cy1represents a saturated monocyclic (CsjJcycloalkyl; wherein said monocyclic (C3-7)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl, halogen, (Ci-3)alkyl, (Ci^)alkoxy, cyano, and hydroxy; or -(CH2)n-Cy2; wherein n is 0 or 1 and Cy2represents a 4- to 7-membered saturated or mono-unsaturated monocyclic heterocycle comprising one ring heteroatomic group selected from -O-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)-; wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl, halogen, (Ci^)alkyl, and (Ci-3)alkoxy; or -(CH2)m-Cy3; wherein m is 0 or 1 and Cy3represents a saturated spiro, fused, or bridged bicyclic (C5- 8)cycloalkyl; wherein said bicyclic (C^cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from halogen or (Ci-3)alkyl; or a 7-membered saturated spiro or bridged bicyclic heterocycle comprising one ring oxygen atom; orR1and R2together with the nitrogen to which they are attached form:• a 5- or 6-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S; wherein said 5- or 6-membered heterocycle is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: hydroxy, (Ci-3)fluoroalkyl, halogen, (Ci-3)alkyl, (Ci-3)alkyl-(Ci^)alkoxy, ethynyl, and (Ci-3)alkoxy; or• a 7- to 11-membered saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms; wherein said heterocycle is unsubstituted or mono-substituted with hydroxy; or• an 8- to 10-membered saturated or mono-unsaturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom; or• a 7- to 9-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom; wherein said 7- to 9-membered bridged heterocycle is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: hydroxy, halogen, (Ci-3)alkyl, and (Ci-3)alkoxy; or• a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms; with the exception of the following compounds: 1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-piperidinecarboxamide (CAS no. 2174271-82-8); 1 -([1,1'-biphenyl]-2-ylsulfonyl)-N-methyl-2-piperidinecarboxamide (CAS no. 2421462-12-4); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-pyrrolidinecarboxamide (CAS no. 1956132-61-8); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 1951549-56-6); 1 -([1,1'-biphenyl]-2-ylsulfonyl)-N,N-dimethyl-2-pyrrolidinecarboxamide (CAS no. 2180339-78-8); N-cyclopropyl-1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-2-pyrrolidinecarboxamide (CAS no. 1957026-44-6); 1-([1,T-biphenyl]-2-ylsulfonyl)-N-propyl-2-pyrrolidinecarboxamide (CAS no. 1101182-03-9); 1-[(4-ethoxy-3-pyridinyl)sulfonyl]-2-(methoxymethyl)-N-methyl-2-pyrrolidinecarboxamide (CAS no. 2223951-41-3); N, N-diethyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 1444098-57-0); N-(1, 1-dimethylethyl)-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 2175321- 07-8); N-cyclopropyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-4-thiazolidinecarboxamide (CAS no. 1953618- 16-0); 3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-N-(1-methylethyl)-4-thiazolidinecarboxamide (CAS no. 2174321-10-7); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-cyclopropyl-N-methyl-4-thiazolidinecarboxamide (CAS no. 1315694-49- 5); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(2-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1315666-22-8); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(cyclopropylmethyl)-4-thiazolidinecarboxamide (CAS no. 1316038-32-0); 3-([1 ,1'-biphenyl]-2-ylsulfonyl)-N-(1-methylpropyl)-4-thiazolidinecarboxamide (CAS no. 1316017-19-2); [3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 1948116-54-8); [1-([1,1'-biphenyl]-2-ylsulfonyl)-2-piperidinyl]-1 -pyrrolidinylmethanone (CAS no. 1277333-36-4); [3-([1,T-biphenyl]-2-ylsulfonyl)-4-thiazolidinyl]-4-thiomorpholinylmethanone (CAS no. 1259167-90-2); [(2S,4R)-1-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-fluoro-2-pyrrolidinyl]-4-morpholinylmethanone (CAS no. 1941933-69-2); [3-[(4-ethoxy-3-pyridinyl)sulfonyl]-4-thiazolidinyl]-1 -pyrrolidinylmethanone (CAS no. 2174528-45-9); and [1 -[(4-ethoxy-3-pyridinyl)sulfonyl]-2-pyrrolidinyl]-4-thiomorpholinylmethanone (CAS no. 1945338-12-4).

2. A compound of Formula (I) according to claim 1, wherein X1represents N or CRB2, wherein RB2represents hydrogen, halogen, or (Ci-3)alkyl, and X2represents CH;or a pharmaceutically acceptable salt thereof.

3. A compound of Formula (I) according to claim 1 or 2, wherein RB1represents (Ci-3)alkyl or (Ci)fluoroalkyl; or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (I) according to any one of claims 1 to 3, wherein RB3represents: NRN1RN2, wherein independently:■ RN1represents (Ci-3)alkyl; and■ RN2represents (C^alkyl; or■ RN1and RN2together with the nitrogen to which they are attached form a heterocycle selected from pyrrolidinyl, piperidinyl, or morpholinyl; wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from (Ci-3)alkyl or (Ci. 2)fluoroalkyl; or a mono-unsaturated monocyclic (CsjJcycloalkyl; or a mono-unsaturated bridged bicyclic (Cz)cycloalkyl; or phenyl; wherein said phenyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen, (Ci-3)alkyl, and (Ci-3)alkoxy; or 5- or 6-membered heteroaryl selected from isothiazolyl or pyridinyl; wherein said 5- or 6-membered heteroaryl is mono- or di-substituted; wherein the substituents are independently selected from halogen or (Ci-3)alkyl; or a pharmaceutically acceptable salt thereof.

5. A compound of Formula (I) according to any one of claims 1 to 4, wherein X4represents N and Ring A represents:• a 5- to 7-membered saturated monocyclic heterocycloal kan-diy I comprising X4, and zero or one further ring heteroatom selected from 0 or S; wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl, halogen, (Ci-3)alkoxy, and (Ci-3)alkylidene; or• a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X4and zero or one further ring N atom; wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X4; wherein said mono-unsaturated heterocycloalkan-diyl is unsubstituted, or monosubstituted with (Ci-3)alkyl; or• a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, and zero or one ring oxygen atom; wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or mono-substituted with (Ci-3)alkyl;or a pharmaceutically acceptable salt thereof.

6. A compound of Formula (I) according to any one of claims 1 to 5, wherein R1represents hydrogen; methyl or ethyl; or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (I) according to any one of claims 1 to 6, wherein R2represents: -(CH2)q-Cy1; wherein q is 0 and Cy1represents a saturated monocyclic (CsjJcycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen, (Ci^alkyl, (Ci-3)alkoxy, and cyano; or -(CH2)n-Cy2; wherein n is 0 and Cy2represents a 4- to 7-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from -0- or -(SO2)-; wherein said heterocycle is mono- or di-substituted; wherein the substituents are independently selected from halogen or (Ci-3)alkyl; or -(CH2)m-Cy3; wherein m is 0 and Cy3represents a saturated spiro, fused, or bridged bicyclic (Cs-sjcycloalkyl; wherein said bicyclic (Cs-sjcycloalkyl is unsubstituted or di-substituted with halogen; or a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom; or a pharmaceutically acceptable salt thereof.

8. A compound of Formula (I) according to any one of claims 1 to 6, wherein R1and R2together with the nitrogen to which they are attached form:• an 8-membered saturated spiro bicyclic heterocycle comprising said nitrogen atom; or• a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom; wherein said 7- to 8-membered bridged heterocycle is unsubstituted, or mono-substituted with (Ci-3)alkoxy; or• a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms; or a pharmaceutically acceptable salt thereof.

9. A compound of Formula (I) according to any one of claims 1 to 8, selected from the group consisting of: {(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-((1 S,3R,5R)-3-methoxy-8-aza- bicy clo [3.2.1 ]oct-8-yl)-methanone;{(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-(2-oxa-6-aza- tricy clo [3.3.1 .13,7]dec-6-yl)-methanone;{(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}-((1 S,3R,5R)-3- methoxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone;(2R*,4R*)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(2S,4S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(1R,2S)-2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4-difluoro- cyclohexyl)-amide;(1S,2R)-2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4-difluoro- cyclohexyl)-amide5-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-aza-spiro[2.4]heptane-6-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;5-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-aza-spiro[2.4]heptane-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;3-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-oxazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-oxazolidine-2-carboxylic acid (1, 1-difluoro-spiro[2.5]oct-6-yl)-N-methyl- amide;2-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-5-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methyl-2-aza-bicyclo[2.1.1]hexane-1-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-azepane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide; 1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-N-(Cyclopentylmethyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-methyl-[1, T-biphenyl]-2-yl)sulfonyl)-N-(methyl-d3)pyrrolidine-2- carboxamide;(S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'-fluoro-6'-methoxy-5-methyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;(S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-6'-methoxy-5-methyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;(S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5-(methyl-d3)-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'-fluoro-5J6-dimethyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(S)-N-((SR)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((2-(ethyl(isopropyl)amino)-4-methylphenyl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;(S)-N-((RS)-3,3-Dimethylcyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;(S)-N-((RS)-3,3-Dimethylcyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;(S)-N-((RS)-3,3-Difluorocyclopentyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)pyrrolidine-2- carboxamide;(S)-N-((RS)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((2-(ethyl(isopropyl)amino)-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;(S)-N-((1R*,3S*)-3-Cyanocyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;(S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((4-methyl-2-((S)-2-methylpiperidin-1-yl)phenyl)sulfonyl)pyrrolidine-2- carboxamide;(S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)pyrrolidine-2- carboxamide;(S)-N-((1 R*, 3S*)-3-Cyanocyclopentyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide;(S)-N-((1R* 3S*)-3-Cyanocyclopentyl)-1-((2'-fluoro-5-methyl-[1 , -biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(S)-N-((1R*,3R*)-3-Cyanocyclohexyl)-1-((2-((3S,5S)-3,5-dimethylmorpholino)-6-methylpyridin-3- yl)sulfonyl)pyrrolidine-2-carboxamide;(S)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-[6-Methyl-2-((1 S,2R)-2-methyl-cyclohexyl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[6-Methyl-2-(2-methyl-cyclohex-1-enyl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[4-Methyl-2-(4-methyl-isothiazol-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[4-Methyl-2-(4-methyl-isothiazol-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 , 1-difluoro- spiro[2.5]oct-6-yl)-N-methyl-amide;(S)-1-[4-Methyl-2-(3-methyl-pyrazin-2-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro-spiro[2.5]oct- 6-yl)-N-methyl-amide;(S)-1-[4-Methyl-2-(2-methyl-pyridin-3-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-trifluoromethyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid spiro[3.3]hept-2- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid spiro[2.4]hept-1- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(tetrahydro- pyran-4-yl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(4-methyl- cyclohexyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl-(2-methyl- tetrahydro-pyran-4-yl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cyclohexyl-N-methyl- amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cycloheptylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[4.1.0]hept-3- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[3.1.0]hex-2- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[2.2.1]hept-2- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicyclo[1 .1 .1]pent-1- ylamide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (bicyclo[4.1 ,0]hept-3- yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (bicyclo[2.2.1]hept-2- ylmethyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (7-oxa- bicy clo [2.2.1 ] hept-2-y l)-amide ;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-methyl-cyclohexyl)- amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-methoxy- cyclohexyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-trifluoromethyl- cyclobutyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-methyl-cyclohexyl)- amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-methoxy-tetrahydro- pyran-4-yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3-difluoromethyl- cyclobutyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-dimethyl- cyclopentyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-dimethyl- cyclobutyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (3,3-difluoro- cyclobutylmethyl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2-cyano-cyclopentyl)- amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6-dimethyl- tetrahydro-pyran-4-yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,2-dimethyl- tetrahydro-pyran-4-yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 R,2R,4S)- bicy clo [2.2.1 ] hept-2-y I amide ;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.5]oct-6-yl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.5]oct-6-yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.4]hept-5-yl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.3]hex-5-yl)-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro- spiro[2.3]hex-5-yl)-N-methyl-amide;(S)-1-[2-(Ethyl-isopropyl-amino)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6-dimethyl-tetrahydro- pyran-4-yl)-N-methyl-amide;(S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[2-(Cyclopropyl-ethyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-[2-(5-Ethyl-pyrazol-1-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-[2-(3-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(S)-1-[2-(3-Fluoro-pyrazin-2-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 ,1-difluoro-spiro[2.5]oct- 6-yl)-N-methyl-amide;(S)-1-[2-(2,6-Difluoro-phenyl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl- spiro[2.5]oct-6-yl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid methyl- (2-methyl-tetrahydro-pyran-4-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid cyclohexyl-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicy clo [4.1 .0]hept-3-ylamide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid bicy clo [4.1 .0]hept-3-yl-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- dimethyl-cyclohexyl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (2,2- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.5]oct-6-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.5]oct-6-yl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.4]hept-5-yl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.3]hex-5-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1- difluoro-spiro[2.3]hex-5-yl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid((2S,4S,6R)-2,6-dimethyl-tetrahydro-pyran-4-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid((2R,4R,6S)-2,6-dimethyl-tetrahydro-pyran-4-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-amide;(S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (2,6- dimethyl-tetrahydro-pyran-4-yl)-N-methyl-amide;(S)-1-[2-((2R,5S)-2,5-Dimethyl-pyrrolidin-1-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(S)-1-(6'-Methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-(5,2'-Dimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;(S)-1-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2-tert-Butylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-(2-lsopropylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-(2-Diisopropylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-(2-Cyclohexyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2-Cyclohex-1-enyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-(2-Cyclohept-1-enyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide;(S)-1-(2-Bicyclo[2.2.1]hept-2-en-2-yl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(S)-1-(2-Azepan-1-yl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2'-Methoxy-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-ethyl-amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (1,1 -dioxo-hexahydro-1 l6-thiopyran-4- yl)-N-methyl-amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methylene-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2,5-dihydro-1 H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(S)-1-(2',6'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2',5'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2',4'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-(2',3'-Difluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(S)-1-((S)-2,6'-Dimethyl-3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(S)-1-((S)-2,6'-Dimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(S)-1-((2S,6S)-2,6,6'-Trimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-spiro[2.5]octan-4-yl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-3-methyltetrahydrofuran-3-yl)pyrrolidine- 2-carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S*,3S*)-3-methoxycyclohexyl)-N- methylpyrrolidine-2-carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S*,2R*)-2-methylcyclohexyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,3S*)-3-methoxycyclohexyl)-N- methylpyrrolidine-2-carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R* 3S*)-3-fluorocyclopentyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,3R*)-3-hydroxycyclohexyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-isopropylcyclopropyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-hydroxycyclohexyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2R*)-2-methylcyclohexyl)pyrrolidine-2- carboxamide;(S)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-N-(((RS)-3-methyltetrahydrofuran-3- yl)methyl)pyrrolidine-2-carboxamide;(S)-1-((2-((RS)-sec-Butoxy)-6-methylpyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((SR)-2,2-dimethyltetrahydro-2H- pyran-4-yl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-spiro[2.4]heptan-5- yl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((RS)-6,6-dimethyltetrahydro-2H- pyran-3-yl)-N-methylpyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((2R,4SR,6S)-2,6-dimethyltetrahydro- 2H-pyran-4-yl)-N-methylpyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((2R,4SR,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R,2S)-2- methoxycyclopentyl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 S,2R)-2- methoxycyclopentyl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2-methoxycyclopentyl)-N- methylpyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2- methoxycyclohexyl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-6-methylpyridin-3-yl)sulfonyl)-N-((1 R*,2S*)-2- hydroxycyclohexyl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-4-methylphenyl)sulfonyl)-N-((RS)-2,2-dimethyltetrahydro-2H-pyran-4- yl)pyrrolidine-2-carboxamide;(S)-1-((2-((3S,5S)-3,5-Dimethylmorpholino)-4-methylphenyl)sulfonyl)-N-((RS)-2,2-dimethyltetrahydro-2H-pyran-4- yl)-N-methylpyrrolidine-2-carboxamide;(S)-1-(((Sa)-2'-Chloro-5,6'-dimethyl-[1, 1'-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;(S)-1-(((Ra)-2'-Chloro-5,6'-dimethyl-[1, 1'-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide;(R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-4-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-thiazolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl- amide;(7-Aza-bicyclo[2.2.1]hept-7-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;(6-Aza-spiro[2.5]oct-6-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;(6-Aza-spiro[2.5]oct-6-yl)-{(S)-1-[2-((3S,5S)-3,5-dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin- 2-yl}-methanone;(2S,5S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(25.45)-4-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2 -carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(25.45)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-fluoro-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(25.45)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(25.45)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-4-methoxy-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(2S,4R)-4-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(2S)-N-(Bicyclo[4.1.0]heptan-3-yl)-1-((2'-fluoro-5-methyl-[1 , -biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{N-(methyl)-(2',6'-difluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{(2'-fluoro-5-methyl-[1,T-biphen-2-yl])-sulfonimidoyl}-pyrrolidine}-2- carboxamide;(2S)-N-(4,4-Difluorocyclohexyl)-1-((2'-fluoro-5J6'-dimethyl-[1 , -biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(2S)-N-(4,4-Difluorocyclohexyl)-N-(methyl)-{1-{N-(methyl)-(6-methyl-2-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,4-difluoropyridin-3-yl)-4-methylphenyl)sulfonyl)-N-methylpyrrolidine-2- carboxamide;(2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(methyl)-(2'-fluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(cyclopropyl)-(2'-fluoro-5-methyl-[1 , T-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-(1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{N-(methyl)-(2',6'-difluoro-5-methyl-[1 , 1 '-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-(1 , 1-Difluorospiro[2.3]hexan-5-yl)-N-(methyl)-{1-{N-(cyclopropyl)-(2'-fluoro-5-methyl-[1 ,1 '-biphen-2-yl])- sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-N-((3R,6s)-1 , 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)-{1-{(R)-N-(methyl)-(2-cyclohexyl-6-methyl-pyridin-3- yl)-sulfonimidoyl}-pyrrolidine}-2-carboxamide;(2S)-1-((2-(2-Chloro-4-methylpyridin-3-yl)-4-methylphenyl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide;(2R,3S)-3-Fluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)- N-methyl-amide;(2-Aza-tricyclo[3.3.1 .13,7]dec-2-yl)-{(S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl}- methanone;(2-Aza-tricyclo[3.3.1 .13,7]dec-2-yl)-{(S)-1-[2-((3S,5S)-3,5-dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]- pyrrolidin-2-yl}-methanone;(1S,3S,5S)-2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(1S,2S,5R)-3-(4-Methyl-2-piperidin-1-yl-benzenesulfonyl)-3-aza-bicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide;(1S,2S,5R)-3-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-3-aza-bicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;(1S,2R)-2-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-cyclohexanecarboxylic acid (4,4- difluoro-cyclohexyl)-amide;(1S,2R)-2-((2S,6S)-2,6,6'-Trimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-sulfonyl)-cyclohexanecarboxylic acid (4,4-difluoro-cyclohexyl)-amide;(1RS,2SR)-N-(4,4-Difluorocyclohexyl)-2-((2-((2S,6S)-2,6-dimethylpiperidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)cyclopentane-1-carboxamide;(1R,3S,4S)-2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide;((S)-1-[2-(lsopropyl-methyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide; and(S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-5J6-dimethyl-[1 ,T-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2- carboxamide; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.11 . A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in improving wakefulness.

13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof:• for use in the treatment of hypersomnia including narcolepsy, narcolepsy associated with inherited disorders; narcolepsy associated with tumors, narcolepsy associated with head trauma, idiopathic hypersomnia, or Kleine-Levin syndrome;• for use in improving symptoms of excessive daytime sleepiness (EDS) including: improving symptoms of EDS in subjects having a circadian rhythm sleep-wake disorder; improving symptoms of EDS due to or associated with a medical disorder, wherein said medical disorder is especially an objective sleep disturbance, obesity, diabetes, a neurodegenerative disorder, an auto-immune disorder, a psychiatric disorder, or insufficient sleep syndrome; improving symptoms of EDS due to a medication or substance;• for use in the treatment of fatigue; or• for use in the treatment of eating disorders, obesity, neuropsychiatric disorders, pain, inflammation, or cognitive impairments associated with diminished wakefulness.

14. Use of a compound of Formula (I) as defined in any one of claims 1 to 9, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for improving wakefulness.

15. A method for improving wakefulness comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) as defined in any one of claims 1 to 9, or of a pharmaceutically acceptable salt thereof.

Images