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, R3, RB1, X1, X2, X3, 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 404A

[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] Evidence 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.; Interleukin-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 JC 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 (Mohammadi 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 (Calva CB et al.; Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction; Brain Res. 2020, 1731 : 145921; Calva 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 reduce 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 headaches (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.

[0033] Orexin receptor antagonists are well documented, such as, for example, in WO 2010 / 131192. 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. Macrocyclic orexin receptor agonists are reported in WO 2021 / 108628, WO 2022 / 051583, WO 2022 / 094012, WO 2022 / 109117, WO 2022 / 140316, WO 2022 / 232025, WO 2022 / 251302, and WO 2022 / 251304. Orexin receptor agonists are further reported in JP2022012861 , JP2022064180, US8258163, WO 2000 / 047580, WO 2014 / 006402, WO 2015 / 088000, WO 2015 / 152367, WO 2016 / 133160, WO 2016 / 199906,

[0034] WO 2018 / 164192, WO 2019 / 112007, WO 2019 / 191327, WO 2020 / 004536, WO 2020 / 158958, WO 2020 / 167701,

[0035] WO 2020 / 167706, WO 2021 / 026047, WO 2021 / 048821 , WO 2021 / 048822, WO 2021 / 107023, WO 2021 / 065893,

[0036] WO 2021 / 106975, WO 2022 / 014680, WO 2022 / 040058, WO 2022 / 040070, WO 2022 / 051596, WO 2022 / 119888,

[0037] WO 2022 / 132696, WO 2022 / 140317, WO 2022 / 187231 , WO 2022 / 207935, WO 2022 / 233872, WO 2022 / 250108,

[0038] WO 2022 / 269049, W02023017180, WO2023167865, WO2023167925, WO2023199091 , and W02023204308.

[0039] The preparation of N-tosylprolinamides is reported in Walther K. et al. (J. Prakt. Chem, 1987, 329(5), 859-870). Selected N-sulfonyl indoline derivatives having affinity for the vasopressin and ocytocin receptors are described in US 5,338,755, US 5,397,801 , US 5,481 ,005, and EP 0469984. Selected pyrrole sulfone derivatives are described as non-nucleoside reverse transcriptase inhibitors (Silvestri R. et al., II Farmaco, 2004, 59, 201-210; WO 2008 / 054605) and indole sulfones as modulators G-protein couple receptor GPR119 (WO 2009 / 105722). Certain thiazolidine sulfonamides are disclosed as prostaglandin F receptor modulators (US 2008 / 255094). WO 2016 / 004180 discloses quinoline and quinazoline sulfonamides as O-GIcNAc transferase inhibitors. Certain bicyclic sulfonamide derivatives are reported as inhibitors / antagonists of STAT3 (Lopez-Tapia F. et al., ACS Med. Chem. Lett., 2018, 9, 250-255; WO 2012 / 018868; WO 2018 / 136935; US 10,196,373 B2), of TRPA1 (Chen H. et al., J. Med. Chem., 2018, 61 , 3641-3659; WO 2013 / 108857 (US 2014 / 0329796; EP2805718); WO 2016 / 128529), of CCR-9 (WO 2004 / 073634; US 2004 / 180892; US 2005 / 49286; US 2007 / 293503), of gamma secretase (WO 2005 / 113542), or of bradykin B2 (US 6,071 ,917), or as binding VLA-4 (US 6,583,139 B1). Selected azetidine sulfonamides are further reported as STAT3 inhibitors (Brotherton-Pleiss C. et al., J. Med. Chem., 2021 , 64, 695- 710; WO 2021 / 016333). WO 2018 / 015411 discloses certain sulfonylcycloalkyl compounds as TRPA1 modulators. Selected thiol pyrrolidine derivatives are reported as metalloprotease inhibitors in US 2002 / 049243. The following compounds are known as chemical library compounds: • A / -benzyl-A / -(1 , 1-dioxidotetrahydrothiophen-3-yl)-1-tosylpyrrolidine-2-carboxamide (CAS 1101176-47-9);

[0040] • (R)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide (Pubchem CID (PID) 25620704);

[0041] • (S)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide (PID 25620707);

[0042] • (S)-A / -benzyl-A / -((S)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide (PID 51731021);

[0043] • (R)-A / -benzyl-A / -((S)-1 ,1 -dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide (PID 124809066);

[0044] • A / -(1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide (CAS 1100238-77-4);

[0045] • (2R)-A / -(1 , 1 -dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide (CAS 2180106-48-1);

[0046] • (2S)-A / -(1 , 1 -dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide (CAS 956630-44-7);

[0047] • (S)-A / -((R)-1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide (PID 26716027);

[0048] • (S)-A / -((S)-1 ,1 -dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide (PID 26716029); and

[0049] • A / -[(2-Methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-A / -[(tetrahydro-2-thienyl)methyl]-2- pyrrolidinecarboxamide (CAS 2716353-53-4).

[0050] 1) A first aspect of the invention relates to compounds of the Formula (I) wherein

[0051] Ring B is a 6-membered aromatic ring, wherein: • X1represents N or CRB2, wherein RB2represents hydrogen, halogen (especially fluoro), (Ci-s)alkyl (especially methyl), or (Ci-3)alkoxy (especially methoxy); (in particular X1represents CH, CF, or N); and

[0052] • RB1represents independently hydrogen, (Ci-4)alkyl (especially methyl or ethyl), (Ci-3)alkoxy (especially methoxy), halogen (especially fluoro, chloro, or iodo), monocyclic (C^cycloalkyl (especially cyclopropyl), or (Ci)fluoroalkyl (especially trifluoromethyl); [notably RB1represents independently hydrogen, (Ci-s)alkyl (especially methyl or ethyl), (Ci-3)alkoxy (especially methoxy), halogen (especially fluoro, chloro, or iodo), or monocyclic (C^cycloalky I (especially cyclopropyl); in particular RB1represents methyl, ethyl, methoxy, chloro, iodo, or cyclopropyl];

[0053] [notably Ring B represents p-tolyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6-methylpyridin-3-yl, 3-fluoro- 4-methoxyphenyl, 4-cyclopropylphenyl, 4-chlorophenyl, phenyl, 6-methoxypyridin-3-yl, 4-fluorophenyl, 3- fluorophenyl, 6-fluoropyridin-3-yl, 4-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,4-dimethylphenyl, or 3,4- difluorophenyl, or, in addition, 4-ethylphenyl, 4-iodophenyl, 4-isopropylphenyl, 4-propylphenyl, 4-(fert- butyl)phenyl, 4-(fert-butyl)-3-fluorophenyl, 4-bromophenyl, 4-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 4- bromo-3-fluorophenyl, 3-bromo-4-methylphenyl, or 3-chloro-4-methylphenyl; especially Ring B represents p- tolyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6-methylpyridin-3-yl, 3-fluoro-4-methoxyphenyl, 4- cydopropylphenyl, 4-chlorophenyl, phenyl, 6-methoxypyridin-3-yl, 4-fluorophenyl, 3-fluorophenyl, 6- fluoropyridin-3-yl, 4-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,4-dimethylphenyl, or 3,4-difluorophenyl, or, in addition, 4-ethylphenyl, 4-iodophenyl, 4-isopropylphenyl, 4-propylphenyl, 4-bromophenyl, 3,4-dichlorophenyl, 4-bromo-3-fluorophenyl, 3-bromo-4-methylphenyl, or 3-chloro-4-methylphenyl; in particular Ring B represents p-tolyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6-methylpyridin-3-yl, 3-fluoro-4-methoxyphenyl, 4- cydopropylphenyl, or 4-chlorophenyl, or, in addition, 4-ethylphenyl, or 4-iodophenyl];

[0054] X2represents 0 or NR4, wherein R4represents hydrogen, (Ci-s)alkyl (especially methyl, ethyl, or isopropyl), monocyclic (Cs-ejcycloalkyl or phenyl; [in particular X2represents 0, N-methyl, NH, or N-cyclopropyl];

[0055] X3represents CH or N such that:

[0056] • when X3represents CH, Ring A represents a monocyclic (Cs-ejcycloalkan-diyl or a monocyclic 5- or 6- membered heterocycloalkan-diyl comprising one ring 0 atom (especially tetrahydrofuran-diyl or tetrahydro- 2H-pyran-diyl); [in particular such Ring A represents cyclopentane-1 ,2-diyl]; or

[0057] • when X3represents N, Ring A represents:

[0058] • a 4- to 6-membered saturated monocyclic heterocycloalkan-diyl comprising X3and zero or one ring 0 atom (notably azetidin-diyl, pyrrolidin-diyl, oxazolidin-diyl, or oxazinan-diyl); wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted (notably unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), halogen (especially fluoro), (Ci-3)alkoxy (especially methoxy or ethoxy), hydroxy, and (Ci-3)alkylidene (especially H2C=); [notably such Ring A represents pyrrolidin-1,2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1,2-diyl, 3-methylenepyrrolidin-1,2-diyl, 5- methylpyrrolidin-1,2-diyl, oxazolidin-2,3-diyl, azetidin-1 ,2-diyl, 4-methylazetidin-1 ,2-diyl, 3- fl uoropy rrolidin- 1 ,2-diyl, 4-hydroxy pyrrolid i n-1 ,2-diyl, 4-methoxypy rrolidin- 1 ,2-diyl, 4-ethoxy pyrrol id in-

[0059] 1.2-diyl, 4,4-dimethylpyrrolidin-1,2-diyl, oxazolidin-3,4-diyl, or 1 ,3-oxazinan-2,3-diyl; in particular such Ring A represents pyrrolidin-1 ,2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1 ,2-diyl, 3- methylenepyrrol id i n-1 ,2-diyl, 5-methylpyrrolidin- 1 ,2-diyl, or oxazol id i n-2,3-diyl];

[0060] • a 4- to 6-membered (notably 5-membered) mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and zero or one additional ring N atom (especially dihydro-1 H-py rrol-diy I or dihydro-1 H- pyrazol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3); wherein said monounsaturated heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted (in particular is unsubstituted); wherein the substituents are independently (Ci_3)alkyl (especially methyl); [notably such Ring A represents 2,3-dihydro-1 H-pyrrol-1 ,2-diyl, 4,5-dihydro-1 H-pyrazol-1 ,5-diyl, or 3-methyl- 4,5-dihydro-1 / 7-pyrazol-1,5-diyl; in particular such Ring A represents 2, 3-dihydro-1 H-pyrrol-1 ,2-diyl]; or

[0061] • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3; wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or di-substituted (in particular is unsubstituted); wherein the substituents independently are (Ci_3)alkyl (especially methyl); (notably such Ring A represents azabicyclo[2.2.1]heptan-diyl, azabicyclo[3.1.0]hexan-diyl, or azaspiro[2.4]heptan-diyl, or, in addition, azabicyclo[3.2.0]heptan-diyl or 6,6-dimethyl-3- azabicyclo[3.1 ,0]hexan-d iyl; especially such Ring A represents 2-azabicyclo[2.2.1 ]heptan- 1 ,2-diyl, 2- azabicyclo[3.1.0]hexan-2,3-diyl, 3-azabicydo[3.1.0]hexan-2,3-diyl, or 5-azaspiro[2.4]heptan-4,5-diyl, or, in addition, 3-azabicyclo[3.2.0]heptan-2,3-diyl or 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2,3-diyl); [in particular such Ring A represents 2-azabicyclo[2.2.1 ]heptan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-

[0062] 2.3-diyl, or 3-azabicydo[3.1.0]hexan-2,3-diyl, or, in addition, 3-azabicyclo[3.2.0]heptan-2,3-diyl];

[0063] R1represents:

[0064] • 3-cyano-3,3-dimethylpropyl or 4-cyanobutyl [in particular 3-cyano-3, 3-di methylpropyl];

[0065] • a saturated monocyclic (C4-6)cycloalkyl (notably cydopentyl or cyclohexyl); wherein said (C^cycloalkyl is unsubstituted, or mono- or di-substituted (notably mono- or di-substituted); wherein the substituents are independently selected from the group consisting of: (Ci.3)alkyl (especially methyl or isopropyl), halogen (especially fluoro), (Ci-s)fluoroalkyl (especially difluoromethyl or trifluoromethyl), (Ci-3)alkoxy (especially methoxy), carbamoyl, hydroxy, and cyano; [notably such R1represents 3-cyanocyclopentyl, 3-cyano-3- methylcyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-2-hydroxycyclopentyl, 4-fluorocyclohexyl, 3-cyanocyclobutyl, 3- (trifluoromethyl)cyclobutyl, 3-hydroxy-3-(trifluoromethyl)cyclobutyl, 3-fluorocyclopentyl, 3- methoxycyclopentyl, 3-(difluoromethyl)cyclopentyl, 3-carbamoylcyclopentyl, 3-carbamoyl-3- methylcyclopentyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, 4-cyano-2-methoxycyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycydohexyl, 3-methoxycyclohexyl, 4-methylcyclohexyl, 4- isopropylcyclohexyl, 4-methoxycyclohexyl, 3,3-dimethylcyclohexyl, 2,2-difluorocyclohexyl, 3,3- difluorocyclohexyl, or 4-hydroxy-4-methylcyclohexyl, or, in addition, 2-methoxycydopentyl, or 3- hydroxycyclopentyl; in particular such R1represents 3-cyanocyclopentyl, 3-cyano-3-methylcydopentyl, 3- cyanocydohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-2-hydroxycydopentyl, or 4-fluorocyclohexyl];

[0066] • a mono-unsaturated monocyclic (Cs-ejcycloalkyl (especially cydohexenyl); wherein the double bond of said mono-unsaturated (C ejcycloalkyl does not contain the carbon atom attached to the group - N(CO)CH(R2)(R3); [in particular such R1represents cyclohex-3-en-1-yl];

[0067] • a saturated bicyclic (Ce-sjspirocycloalkyl (notably spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said (Ce-sjspirocycloalkyl is unsubstituted, or mono- or di-substituted (especially di-substituted); wherein the substituents are independently halogen (especially fluoro); [notably such R1represents 1,1-difluorospiro[2.3]hexan-5-yl, 1 ,1-difluorospiro[2.5]octan-6-yl, spiro[3.3]heptan-2-yl, 6,6-difluorospiro[3.3]heptan-2-yl, 1 , 1-difluorospiro[2.4]heptan-5-yl, or spiro[2.5]octan-6-yl; in particular such R1represents 1 ,1 -difluorospiro[2.3]hexan-5-yl or 1 ,1-difluorospiro[2.5]octan-6-yl];

[0068] • a saturated fused or bridged bicyclic (Ce-sjcycloal ky I (notably bicyclo[2.1.1 ]hexany I , bicyclo[4.1 ,O]heptanyl, or bicyclo[2.2.2]octanyl); wherein said (Ce-sjcycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro), cyano and carbamoyl; [notably such R1represents bicyclo[4.1.0]heptan-3-yl, 7,7-difluorobicyclo[4.1.0]heptan-3- yl, 4-carbamoylbicyclo[2.1.1]hexan-2-yl, or 4-cyanobicyclo[2.2.2]octan-1-yl; in particular such R1represents bicyclo[4.1 .0]heptan-3-y I or 7, 7-d if I uorobicyclo[4.1 ,0]heptan-3-yl]; or

[0069] • a 5- or 6-membered saturated monocyclic heterocycloalkyl comprising one ring heteroatomic group selected from 0, S, or SO2 (notably said one ring heteroatomic group is selected from 0 or SO2; notably said heterocycloalkyl is tetrahydrothiophen-1,1 -dioxide, tetrahydro-2 / - / -pyran, tetrahydro-2 / - / -thiopyran, tetrahydro-2 / 7-thiopyran-1,1 -dioxide); wherein said heterocycloalkyl 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), and (Ci-s)fluoroalkyl (especially trifluoromethyl); [notably such R1represents 1,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl, 1 ,1-dioxidotetrahydrothiophen-3-yl, tetrahydro-2 / - / -pyran-4-yl, 3-fluorotetrahydro-2 / - / -pyran-4-yl, 2-methyltetrahydro-2 / - / -pyran-4-yl, 2- (trifluoromethyl)tetrahydro-2 / 7-pyran-4-yl, 2,2-dimethyltetrahydro-2 / - / -pyran-4-yl, tetrahydro-2 / - / -thiopyran- 4-yl, or tetrahydro-2 / - / -pyran-3-yl, or, in addition, 6-methyltetrahydro-2 / - / -pyran-3-yl, 6,6-dimethyltetrahydro- 2H-pyran-3-yl, 3-methyltetrahydro-2 / - / -pyran-4-yl, 2,6-dimethyltetrahydro-2 / 7-pyran-4-yl, 1,1- d ioxidotetrahyd ro-2H-th iopyran-3-yl, or 6-methyl-1 , 1 -dioxidotetrahyd ro-2 / - / -thiopy ran-3-y I ; in particular such R1represents 1,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl, or, in addition, 1,1-dioxidotetrahydro-2 / 7-thiopyran- 3-yl, or 6-methyl-1 , 1-dioxidotetrahydro-2 / 7-thiopyran-3-yl];

[0070] R2represents hydrogen or methyl (especially hydrogen);

[0071] R3represents:

[0072] • an 8- to 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, or S (notably 2,3-dihydro-1 / 7-indenyl, 2,3- dihydrobenzofuranyl, benzo[d][1 ,3]dioxolyl, 6,7-dihydro-5 / 7-cyclopentapyridinyl, 2,3- dihydrofuro[3,2]pyridinyl, chromanyl, isochromanyl, or 2, 3-di hydrobenzo[b][1 ,4]dioxi ny I); wherein said 8- to 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 8- to 10-membered ring system 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), and oxo; [notably such R3represents 2,3-dihydro-1 / 7-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5- fluoro-2, 3-di hydrobenzofu ran-6-y I , benzo[d][1 , 3]d ioxol-5-y 1 , 4-fl uoro-2,3-dihydrobenzofuran-6-yl , 7-fluoro-

[0073] 2.3-dihydrobenzofuran-6-yl, 3-methyl-2,3-dihydrobenzofuran-6-yl, 2-methyl-2,3-dihydrobenzofuran-6-yl, 3- oxo-2, 3-dihydrobenzofuran-6-yl, benzo[d][1 , 3]d ioxol-4-yl, 2,2-difluorobenzo[d][1 , 3]dioxol-5-y 1 , 6,7-dihydro- 5 / - / -cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5 / - / -cydopenta[c]pyridin-3-yl, 2,3-dihydrofuro[3,2-b]pyridin-6-yl,

[0074] 2.3-dihydrofuro[3,2-c]pyridin-6-yl, chroman-6-yl, chroman-7-yl, isochroman-6-yl, isochroman-7-yl, or 2,3- dihydrobenzo[b][1.4]dioxin-6-yl; in particular such R3represents 2,3-dihydro-1 / 7-inden-5-yl, 2,3- dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1 ,3]dioxol-5-yl, or 4-fluoro-2,3- dihydrobenzofuran-6-yl];

[0075] • naphthyl or an 8- to 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S (notably benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, furopyridinyl, benzoxadiazolyl, thienopyridinyl, 1 / 7-indolyl, quinolinyl, or isoquinolinyl); wherein said 8- to 10-membered heteroaryl is unsubstituted, or mono- or di-substituted (especially unsubstituted or mono-substituted); wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl), halogen (especially fluoro or chloro), and (Ci-3)alkoxy (especially methoxy) [especially the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and halogen (especially fluoro or chloro)]; [notably such R3represents benzofuran-6-yl, benzo[d]oxazol-5-yl, 6-fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5- yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, 2- methylbenzo[d]thiazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[d]thiazol-6- yl, 6-fluoro-2-methylbenzo[cf]thiazol-5-yl, benzo[d]thiazol-2-yl, benzo[b]thiophen-2-yl, 2- methylbenzo[b]thiophen-5-yl, furo[3,2-b]pyridin-6-yl, furo[2,3-b]pyridin-6-yl, benzo[d]oxazol-2-yl, benzo[c][1,2,5]oxadiazol-5-yl, thieno[2,3-b]pyridin-2-yl, 1 / 7-indol-6-yl, naphthalen-2-yl, quinolin-7-yl, isoquinolin-3-yl, or isoquinolin-7-yl, or, in addition, 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5- yl, or 2-methoxybenzo[d]thiazol-5-yl; in particular such R3represents benzofuran-6-yl, benzo[d]oxazol-5-yl,

[0076] 6-fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, or 2-methylbenzo[d]thiazol-5-yl, or, in addition, 2-bromobenzo[d]thiazol-5-yl]; or

[0077] • phenyl or 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from N, 0, and S (notably pyridinyl, thiophenyl, oxazolyl, thiazolyl, isothiazolyl, or isoxazolyl); wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or, especially, mono-, di- or trisubstituted, wherein the substituents are independently selected from the group consisting of: (Ci.3)alkyl (especially methyl, ethyl, or isopropyl), halogen (especially fluoro, chloro, or bromo), (Ci-s)alkoxy (especially methoxy), (Ci-3)fluoroalkoxy (especially difluoromethoxy), monocyclic (Cs-ejcycloalkyl (especially cyclopropyl), (Ci-s)alkylthio (especially methylthio), (Ci-s)fluoroalkyl (especially trifluoromethyl), cyano, NRN1RN2, wherein RN1and RN2independently represent hydrogen or (Ci-4)alkyl (especially NRN1RN2represents dimethylamino), and 4- to 6-membered monocyclic heterocycloalkyl (especially azetidinyl or oxetanyl); wherein said heterocycloalkyl is unsubstituted or mono-substituted with halogen (especially fluoro); [notably such R3represents p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, 4-chloro- 2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2,4-difluorophenyl, 3-fluoro-4- methylphenyl, phenyl, 2-chlorophenyl, 3-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-

[0078] (difluoromethoxy)phenyl, 3-(azetidin-1-yl)phenyl, 3-(3-fluorooxetan-3-yl)phenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-(dimethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-

[0079] 3-methylphenyl, 2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4- methoxyphenyl, 2,5-difluorophenyl, 2-fluoro-5-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3,4- dimethylphenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4- methylphenyl, 3-cyano-4-methylphenyl, 3-fluoro-4-methoxyphenyl, 2,3-difluoro-4-methylphenyl, 4-chloro- 2,3-difluorophenyl, 4-chloro-2,6-difluorophenyl, 2,4-difluoro-5-methylphenyl, 5-chloropyridin-2-yl, 2- methylthiophen-3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5- isopropyloxazol-2-yl, 5-chlorothiazol-2-yl, 5-bromoothiazol-2-yl, 5-isopropylthiazol-2-yl, 2-isopropylthiazol-

[0080] 5-yl, 5-methylisothiazol-4-yl, 5-methylisoxazol-4-yl, 4-ethyl-5-methylisoxazol-3-yl, 5-cyclopropylisoxazol-3- yl, or 5-cyclopropyl-4-ethylisoxazol-3-yl; in particular such R3represents p-tolyl, 4-chlorophenyl, 4- bromophenyl, 4-(methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-fluoro-4- methylphenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, or 3-fluoro-4-methoxyphenyl]; with the exception of the following compounds: • A / -benzyl-A / -(1 , 1-dioxidotetrahydrothiophen-3-yl)-1-tosylpyrrolidine-2-carboxamide;

[0081] • (R)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0082] • (S)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0083] • (S)-A / -benzyl-A / -((S)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0084] • (R)-A / -benzyl-A / -((S)-1 ,1 -dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0085] • N-(1 ,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide;

[0086] • (2 R)- A / -( 1 , 1 -d ioxidotetrahydrothiophen-3-yl )- / -(f uran-2-yl methyl)- 1 -tosylpyrrolidine-2-carboxamide;

[0087] • (2S)-A / -(1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide;

[0088] • (S)-A / -((R)-1 ,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide;

[0089] • (S)-A / -((S)-1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide; and

[0090] • W-[(2-Methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-W-[(tetrahydro-2-thienyl)methyl]-2- pyrrolidinecarboxamide.

[0091] 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.

[0092] 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 / 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.

[0093] 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 (1 R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide encompasses enantiomerically enriched (1 R,2R,5S)-N-(benzofuran-6- ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, (1 R,2S,5S)-N-

[0094] (benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, (1S,2R,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide, or (1 S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide, or any mixture of these stereoisomers of said compound. Likewise, the compound (1 R*,5S*)-(2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide encompasses enantiomerically enriched (1S,2S,5R)-N-(benzo[d]thiazol- 5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, enantiomerically enriched (1 R, 2S, 5S)-N -(benzo[d]th i azol-5-y I methyl)-N -(4, 4-dif I uorocyclohexyl)-3-tosyl-3-azabicyclo[3.1 ,0]hexane- 2-carboxamide, or any mixture thereof.

[0095] 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).

[0096] 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 / the entirety of the respective other stereoisomers.

[0097] 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 / the entirety of the respective other stereoisomers. The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of Formula (I) according to embodiments 1) to 24), 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.

[0098] 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 2,3-dihydro-1 H-inden-5-yl group.

[0099] 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. For example the group 3-oxo-2,3-dihydrobenzofuran-6-yl is to be understood as also encompassing its tautomeric form 3-hydroxy-benzofuran-6-yl.

[0100] 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.

[0101] Any reference to compounds of Formula (I) according to embodiments 1) to 24) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

[0102] 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-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012. Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1) to 24), 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.

[0103] 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 / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.

[0104] The term “halogen” means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.

[0105] 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, tert-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-4)alkyl are especially (Ci-s)alkyl groups such as methyl or ethyl, especially methyl. When X1represents CRB2, an example of RB2representing (Ci_3)alkyl is methyl. An example of (Ci-s)alkyl as substituent of Ring A is methyl. Examples of (Ci-s)alkyl as substituent of a group R1are methyl and isopropyl (especially methyl). Examples of (Ci-s)alkyl as substituent of a group R3are methyl, ethyl, and isopropyl (especially methyl). When X2is NR4, examples of R4representing (Ci_3)alkyl are methyl, ethyl, and isopropyl (especially methyl).

[0106] 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, sec.- butoxy, and tert.-butoxy. Preferred are methoxy. An example of RB1representing (Ci.3)alkoxy is methoxy. When X1represents CRB2, an example of RB2representing (Ci.3)alkoxy is methoxy. An example of (Ci.3)alkoxy as substituent of a Ring A is methoxy or ethoxy. An example of (Ci.3)alkoxy as substituent of a group R1is methoxy. An example of (Ci-3)alkoxy as substituent of a group R3is methoxy.

[0107] 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.y)fluoroalkyl” (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)fluoroalkyl is trifluoromethyl. Examples of (Ci-s)fluoroalkyl as substituent of a group R1are difluoromethyl and trifluoromethyl. An example of (Ci.3)fluoroalkyl as substituent of a group R3is trifluoromethyl.

[0108] 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. An example of (Ci-3)fluoroalkoxy as substituent of a group R3isdifluoromethoxy.

[0109] The term "cyano" refers to a group -CN. A particular example of R1representing a saturated monocyclic (C^cydoalkyl with a cyano substituent is 3-cyanocyclopentyl; in particular, such cyano substituent of R1representing 3-cyanocyclopentyl is in relative cis configuration with respect to the bond, from the ring carbon at position 1 of 3-cyanocyclopentyl, linking R1to the rest of Formula (I) [notably such R1representing 3- cyanocyclopentyl is (1 R,3S)-3-cyanocydopentyl].

[0110] 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)-.

[0111] The term “(Cx y)alky I idene” (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-3)alkylidene is the methylidene (also referred to as methylene) group H2C=.

[0112] 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)cycloalkyl " (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms. For example, a (C3-6)cydoalkyl group contains from three to six carbon atoms.

[0113] The term "monocyclic (Cx y)cycloalkyl" or “saturated monocyclic (Cx-y)cycloalkyT’, 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. An example of RB1representing a monocyclic (C3-4)cycloalkyl is cyclopropyl. Preferred examples of R1representing a saturated monocyclic (C^cycloalkyl are cyclopentyl and cyclohexyl; wherein said groups are unsubstituted or substituted as explicitly defined. When X2is NR4, a preferred example of R4representing a monocyclic (Cs-ejcycloalkyl is cyclopropyl. An example of (C3- ejcycloalkyl as substituent of a group R3is cyclopropyl.

[0114] 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 X3represents CH and Ring A represents a monocyclic (Cs-ejcycloalkan-diyl, the points of attachment of said (Cs-ejcycloalkan-diyl in Formula (I) are on X3and on a carbon atom neighboring X3; examples are cydopentane-1 ,2-diyl and cyclohexane-1 ,2-diyl (especially cyclopentane-1 ,2-diyl).

[0115] The term "saturated bicyclic (Cx-y)spirocycloalkyl" (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 (Ce-sjspirocycloalkyl 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-sjspi rocycloal kyl are unsubstituted or substituted as explicitly defined. Particular examples of such R1representing a saturated bicyclic (Ce-sjspirocycloalkyl are 1 ,1- difluorospiro[2.3]hexan-5-yl, 1 ,1-difluorospiro[2.5]octan-6-yl, spiro[3.3]heptan-2-yl, 6,6-difluorospiro[3.3]heptan-2- yl, and 1,1-difluorospiro[2.4]heptan-5-yl, and spiro[2.5]octan-6-yl (especially 1 , 1 -difluorospiro[2.3]hexan-5-yl and 1 , 1 -dif I uorospiro[2.5]octan-6-y I) .

[0116] 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. Examples of R1representing a saturated bridged bicyclic (Ce-sjcycloalkyl are bicyclo[2.1.1]hexanyl, bicyclo[4.1.0]heptanyl, and bicyclo[2.2.2]octanyl (especially bicyclo[4.1.0]heptanyl); such R1are unsubstituted or substituted as explicitly defined. Particular examples of such R1representing a saturated fused bicyclic (Ce-sjcydoalkyl are bicyclo[4.1.0]heptan-3-yl, 7,7- dif I uorobicyclo[4.1 ,0]heptan-3-yl, 4-carbamoylbicydo[2.1 .1 ]hexan-2-yl, and 4-cyanobicyclo[2.2.2]octan-1 -yl (especially bicyclo[4.1.0]heptan-3-yl and 7,7-difluorobicyclo[4.1.0]heptan-3-yl). In one example when R1represents a bicyclo[4.1.0]heptanyl, the fused cyclopropyl ring of such bicyclo[4.1.0]heptanyl is such that its two bonds to the bridgehead ring carbon atoms of the fused cyclohexane ring of such bicyclo[4.1.0]heptanyl are in relative cis configuration; notably, such bicyclo[4.1.0]heptanyl may be a (1S,6S)-bicyclo[4.1.0]heptanyl. A particular example of R1representing bicydo[4.1.0]heptan-3-yl is (1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl; such R1is unsubstituted or substituted as explicitly defined. 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). In one embodiment when R1is a mono-unsaturated monocyclic (Cs-ejcycloalkyl, the unsaturated (double) bond of such (Cs-ejcycloalkyl does not contain the carbon atom attached to the group -N(CO)CH(R2)(R3); such an R1is unsubstituted or substituted as explicitly defined. An example of such an R1is cyclohexenyl, notably cydohex-3-en-1-yl.

[0117] The term "heterocycle”, “heterocycloalkyl”, or “saturated monocyclic heterocycloalkyl”, 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, and 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 / comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term “x- to y- membered heterocycloalkyl” or “x- to y-membered saturated monocyclic heterocycloalkyl” (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. When R1is a 5- or 6-membered saturated monocyclic heterocycloalkyl, such R1may be unsubstituted or substituted as explicitly defined; examples of such R1are tetrahydrothiophen-1,1 -dioxide, tetrahydro-2 / - / -pyran, and tetrahydro-2 / 7-thiopyran-1,1 -dioxide (particular examples of such R1are 1,1- dioxidotetrahyd ro-2 / 7-th iopy ran-4-y 1 , 1 , 1 -dioxidotetrahydrothiophen-3-yl, tetrahyd ro-2H-py ran-4-y 1 , 3- fluorotetrahydro-2 / 7-pyran-4-yl, 2-methyltetrahydro-2 / - / -pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2 / 7-pyran-4-yl, 2,2- dimethyltetrahydro-2 / 7-pyran-4-yl, tetrahydro-2 / 7-thiopyran-4-yl, and tetrahydro-2 / - / -pyran-3-yl; and, in addition to the before listed: 6-methyltetrahydro-2 / - / -pyran-3-yl, 6,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 3-methyltetrahydro-2 / - / - pyran-4-yl, 2,6-dimethyltetrahydro-2 / 7-pyran-4-yl, 1,1-dioxidotetrahydro-2 / 7-thiopyran-3-yl, and 6-methyl-1,1- dioxidotetrahyd ro-2H -th iopy ran-3-y I ; especially 1 , 1 -dioxidotetrahydro-2 / - / -thiopy ran-4-y 1 , 1 , 1 -dioxidotetrahyd ro-2 / - / - thiopyran-3-yl, and 6-methyl-1,1-dioxidotetrahydro-2H-thiopyran-3-yl). Examples of a 4- to 6-membered monocyclic heterocycloalkyl as a substituent of a group R3representing phenyl are notably 4-membered monocyclic heterocycloalkyl groups (especially azetidinyl or oxetanyl); wherein such heterocycloalkyl is unsubstituted or monosubstituted with halogen (especially fluoro); particular examples are azetidin-1-yl and 3-fluorooxetan-3-yl.

[0118] The term “x- to y-membered heterocycloalkan-diyl” or “monocyclic x- to y-membered 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 X3represents CH and Ring A represents a monocyclic 5- or 6-membered heterocycloalkan-diyl comprising one ring 0 atom, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X3and the carbon atom attached to the group-CO-N(R1)CH(R2)(R3); examples are tetrahydrofuran-2,3-diyl and tetrahydro-2 / - / -pyran-3,4-diyl. When X3represents N and Ring A represents a 4- to 6-membered saturated monocyclic heterocycloalkan-diyl comprising X3and zero or one ring 0 atom, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X3and on the carbon atom attached to the group -CO-N(R1)CH(R2)(R3); examples are azetidin-diyl, pyrrolidin-diyl, oxazolidin-diyl (notably oxazolidin-2,3-diyl or oxazolidin-3,4-diyl), and oxazinan-diyl (notably 1 ,3-oxazinan-2,3-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)CH(R2)(R3) is not further substituted.

[0119] 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, and S, and wherein said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds. When X3represents N and Ring A represents a 4- to 6- membered (notably 5-membered) mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and zero or one additional ring N atom, and no further ring heteroatoms (notably a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl; especially dihydro-1 H-pyrrol-d iyl or dihydro-1 H-pyrazol-d iyl), the points of attachment of said mono-unsaturated heterocycloalkan-diyl in Formula (I) are on X3and on the carbon atom attached to the group - CO-N(R1)CH(R2)(R3), e.g., are in 1,2 arrangement, and the unsaturated (double) bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3). Such Ring A may be unsubstituted or substituted as explicitly defined; particular examples are 2,3-dihydro-1 / 7-pyrrol- 1,2-diyl, 4,5-dihydro-1 H-pyrazol-1 ,5-diyl, and 3-methyl-4,5-dihydro-1 / 7-pyrazol-1,5-diyl (especially 2,3-dihydro-1 H- pyrrol-1 ,2-diyl). In a particular embodiment, the carbon atom of Ring A attached to the group -CO-N(R1)CH(R2)(R3) is not further substituted.

[0120] The term “x- to y-membered saturated spiro, fused, or bridged bicyclic heterocycloalky I” refers to a 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, and S. The term “x- to y-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl” refers to a 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, and S, wherein the saturated spiro, fused, or bridged bicyclic hydrocarbon ring is bivalently bound. Such saturated spiro, fused, or bridged bicyclic heterocycloalkyl or heterocycloalkan-diyl are unsubstituted or substituted as explicitly defined. When Ring A is a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3representing N, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X3and on the carbon atom attached to the group -CO-N(R1)CH(R2)(R3), e.g., are in 1 ,2 arrangement. Accordingly, the term "x- to y-membered saturated spiro bicyclic heterocycloalkyl" (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 ring atoms of which one or two (especially one) ring atoms are heteroatoms independently selected from N, 0, and S (especially N). Likewise the term "x- to y- membered saturated spiro bicyclic heterocycloalkan-diyl" refers to an x- to y-membered saturated spiro bicyclic heterocycloalkyl as defined before which is bivalently bound. An example of such Ring A representing a 6- to 8- membered saturated spiro bicyclic heterocycloalkan-diyl is azaspiro[2.4]heptane-diyl (especially 5- azaspiro[2.4]heptane-4,5-diyl). Accordingly, the term "x- to y-membered saturated fused bicyclic heterocycloalkyl" (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-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, and S (especially N). Likewise the term "x- to y-membered saturated fused bicyclic heterocycloalkan-diyl" refers to an x- to y-membered saturated fuse bicyclic heterocycloalkyl as defined before which is bivalently bound. When Ring A is a 6- to 8-membered saturated fused bicyclic heterocycloalkan-diyl comprising X3representing N, the carbon atom of Ring A attached to the group -CO-N(R1)CH(R2)(R3) is not shared between the two cycles of such bicycle. An example of such Ring A representing a 6- to 8-membered saturated fused bicyclic heterocycloalkan-diyl is azabicydo[3.1.0]hexan-diyl (especially 2-azabicyclo[3.1.0]hexan-2,3-diyl or 3-azabicyclo[3.1.0]hexan-2,3-diyl); an additional example of such Ring A representing a 6- to 8-membered saturated fused bicyclic heterocycloalkan-diyl is azabicyclo[3.2.0]heptan- diyl (especially 3-azabicyclo[3.2.0]heptan-2,3-diyl). Accordingly the term "x- to y-membered saturated bridged bicyclic heterocycloalkyl" (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 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, and S (especially N). Likewise the term "x- to y-membered saturated bridged bicyclic heterocycloalkan-diyl" refers to an x- to y-membered saturated bridged bicyclic heterocycloalkyl as defined before which is bivalently bound. When Ring A is a 6- to 8-membered bridged saturated bicyclic heterocycloalkan-diyl comprising X3representing N, the carbon atom of Ring A attached to the group-CO-N(R1)CH(R2)(R3) is not a bridgehead atom. An example of such Ring A representing a 6- to 8-membered bridged saturated bicyclic heterocycloalkan-diyl is azabicyclo[2.2.1 ]heptan-diyl (especially 2-azabicyclo[2.2.1 ]heptan-1 ,2-diyl). In a particular case of a 6- to 8- membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3representing N, such group contains 6 to 8 ring atoms, including X3representing nitrogen, and no further heteroatoms.

[0121] 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.

[0122] When R3represents phenyl, such phenyl may be unsubstituted or substituted as explicitly defined. Whenever R3represents phenyl, notably such phenyl groups are mono-, di- or tri-substituted, wherein especially one of said substituents is attached in para or meta (in particular in para) position with regard to the point of attachment of the rest of the molecule. In one embodiment wherein R3represents phenyl, such phenyl groups are mono-substituted in para position with regard to the point of attachment of the rest of the molecule, or are independently di-substituted in para and one meta position, or in para and one ortho position, with regard to the point of attachment of the rest of the molecule. Especially such substituent in para position is (Ci_3)alkyl (notably methyl, ethyl, or isopropyl), halogen (notably fluoro, chloro, or bromo), (Ci-3)alkoxy (notably methoxy), (Ci-3)fluoroalkoxy (notably difluoromethoxy), (Ci-s)alkylthio (notably methylthio), (Ci-s)fluoroalkyl (notably trifluoromethyl), or NRN1RN2, wherein RN1and RN2independently represent hydrogen or (Ci-4)alkyl (especially NRN1RN2represents dimethylamino). The remaining substituent(s), if present, especially are independently selected from (Ci_3)alkyl (especially methyl), halogen (notably fluoro or chloro), and cyano. Particular examples of R3representing phenyl are p-tolyl, 4- chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2- fluoro-4-methylphenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, phenyl, 2-chlorophenyl, 3-methylphenyl, 3- fluorophenyl, 3-methoxyphenyl, 3-(difluoromethoxy)phenyl, 3-(azetidin-1-yl)phenyl, 3-(3-fluorooxetan-3-yl)phenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-(dimethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-3-methylphenyl, 2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4- methoxyphenyl, 2,5-difluorophenyl, 2-fluoro-5-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3,4-dimethylphenyl, 4- fluoro-3-methylphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 3-cyano-4- methylphenyl, 3-fluoro-4-methoxyphenyl, 2,3-difluoro-4-methylphenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-2,6- difluorophenyl, and 2,4-difluoro-5-methylphenyl. Examples of such R3representing a para-substituted phenyl are p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4- methoxyphenyl, 2-fluoro-4-methylphenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-(dimethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 2,4- dimethylphenyl, 4-fluoro-2-methylphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-methoxyphenyl, 3,4-dimethylphenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 3-cyano-4- methylphenyl, 4-fluoro-4-methoxyphenyl, 2,3-difluoro-4-methylphenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-2,6- difluorophenyl, and 2,4-difluoro-5-methylphenyl (especially p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4- (methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2,4- difluorophenyl, and 3-fluoro-4-methylphenyl, and, in addition to the before listed: 3-fluoro-4-methoxyphenyl).

[0123] 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, and 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 R3represents a 5- or 6-membered heteroaryl, such heteroaryl as used for R3comprises one to three ring heteroatoms independently selected from N, 0, and S, wherein such heteroaryl is especially linked to the rest of the molecule via a ring carbon atom. Such R3is notably pyridinyl, thiophenyl, oxazolyl, thiazolyl, isothiazolyl, or isoxazolyl; such 5- or 6-membered heteroaryl is unsubstituted or, especially, substituted as explicitly defined. Examples of such R3are 5-chloropyridin-2-yl, 2-methylthiophen-3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5-isopropyloxazol-2-yl, 5-chlorothiazol-2-yl, 5-bromoothiazol-2-yl, 5-isopropylthiazol-2-yl, 2- isopropylthiazol-5-yl, 5-methylisothiazol-4-yl, 5-methylisoxazol-4-yl, 4-ethyl-5-methylisoxazol-3-yl, 5- cyclopropylisoxazol-3-yl, and 5-cyclopropyl-4-ethylisoxazol-3-yl (especially 5-chloropyridin-2-yl, 2-methylthiophen-

[0124] 3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5-isopropyloxazol-2-yl, 5-chlorothiazol-2- yl, 5-bromoothiazol-2-yl, 5-isopropylthiazol-2-yl, 2-isopropylthiazol-5-yl, 5-methylisothiazol-4-yl, 5-methylisoxazol-

[0125] 4-yl, and 4-ethyl-5-methylisoxazol-3-yl).

[0126] The term "8- to 10-membered heteroaryl" refers to a bicyclic heteroaryl group as defined before, wherein said 8- to 10-membered heteroaryl especially comprises in total one to a maximum of three (in particular one or two) heteroatoms independently selected from N, 0, and S. Notably, the such term refers to a 9- or 10-membered heteroaryl groups, such as especially indazolyl, benzoimidazolyl, indolyl, benzotriazolyl, benzooxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl, pyrrolopyridinyl, and imidazopyridinyl. The above groups are unsubstituted or substituted as explicitly defined. Examples of R3representing an 8- to 10-membered heteroaryl are benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, furopyridinyl, benzoxadiazolyl, thienopyridinyl, 1 / -indolyl, quinolinyl, and isoquinolinyl (especially benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, and furopyridinyl); wherein such 8- to 10-membered heteroaryl is unsubstituted or substituted as defined. Particular examples of such R3are benzofuran-6-yl, benzo[d]oxazol-5-yl, 6-fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin- 6-yl, 2-methylbenzo[d]thiazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[cf]thiazol-6-yl, 6-fluoro-2-methylbenzo[c / ]thiazol-5-yl, benzo[d]thiazol-2-yl, benzo[b]thiophen-2-yl, 2-methylbenzo[b]thiophen-5-yl, furo[3,2-b]pyridin-6-yl, furo[2,3-b]pyridin-6-yl, benzo[d]oxazol-2-yl, benzo[c][1,2,5]oxadiazol-5-yl, thieno[2,3- b]pyridin-2-yl, 1 H-indol-6-yl, quinolin-7-yl, isoquinolin-3-yl, and isoquinolin-7-yl; and, in addition to the before listed: 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[cf]thiazol-5-yl, and 2-methoxybenzo[d]thiazol-5-yl (especially benzofuran-6-yl, benzo[d]oxazol-5-yl, 6-fluorobenzo[c(]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, 2- chlorobenzo[cf]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, and 2- methylbenzo[d]thiazol-5-yl; and, in addition to the before listed: 2-bromobenzo[d]thiazol-5-yl).

[0127] The term "8- to 10-membered partially aromatic fused bicyclic ring system" refers to a 5- or 6-membered aromatic ring (especially a 6-membered aromatic ring) which is fused to a (C5-6)cycloalkyl or to a 5- or 6-membered heterocycle, as defined before, wherein said fused ring system comprises in total zero to a maximum of three heteroatoms independently selected from N, 0, and S. When R3represents an 8- to 10-membered partially aromatic fused bicyclic ring system, such ring system is linked to the rest of the molecule at the aromatic ring moiety, especially at an aromatic ring carbon; such 8- to 10-membered partially aromatic fused bicyclic ring system is unsubstituted or substituted as explicitly defined; wherein it is understood that any oxo substituent is attached to the non-aromatic ring of such ring system. Examples of R3representing an 8- to 10-membered partially aromatic fused bicyclic ring system are phenyl or pyridine which are fused to a (Cs-ejcycloalkyl or 5- or 6-membered heterocycloalkyl ring, as defined before (wherein it is understood that the total of heteroatoms comprised in the thus-formed bicyclic ring system is zero to three); notably, examples of R3representing an 8- to 10-membered partially aromatic fused bicyclic ring system are 2,3-dihydro-1 / 7-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][1 ,3]dioxolyl, 6,7-dihydro-5 / 7-cyclopentapyridinyl, 2,3-dihydrofuro[3,2]pyridinyl, chromanyl, isochromanyl, and 2,3-dihyd robenzo[b][1 ,4]dioxiny I); wherein such ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein such ring system is unsubstituted or substituted as explicitly defined. Examples of such R3representing an 8- to 10-membered partially aromatic fused bicyclic ring system are 2, 3-d i hydro- 1 H-i nden-5-yl, 2,3- dihydrobenzofuran-6-yl, 5-fl uoro-2,3-dihydrobenzofu ran-6-y I, benzo[d][1 , 3]d ioxol-5-y 1 , 4-fluoro-2,3- dihydrobenzofuran-6-yl, 7-fluoro-2,3-dihydrobenzofuran-6-yl, 3-methyl-2,3-dihydrobenzofuran-6-yl, 2-methyl-2,3- dihydrobenzofuran-6-yl, 3-oxo-2,3-dihydrobenzofuran-6-yl, benzo[d][1 ,3]dioxol-4-yl, 2,2- difluorobenzo[d][1 ,3]dioxol-5-yl, 6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5 / - / -cyclopenta[c]pyridin-3- yl2,3-dihydrofuro[3,2-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-c]pyridin-6-yl, chroman-6-yl, chroman-7-yl, isochroman-6- yl, isochroman-7-yl, and 2,3-dihydrobenzo[b][1.4]dioxin-6-yl; particular examples of such R3are 2,3-dihydro-1 H- inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1 ,3]dioxol-5-yl, and 4-fluoro- 2,3-dihydrobenzofuran-6-yl. For avoidance of doubt, certain groups having tautomeric forms which are considered predominantly non-aromatic, such as for example 3-oxo-2,3-dihydrobenzofuran-6-yl, are defined herein as 8- to 10-membered partially aromatic fused bicyclic heterocyclyl groups, even though the corresponding tautomeric form (3-hydroxy-benzofuran-6-yl) could in some instances be considered as a 8- to 10-membered heteroaryl; such tautomeric form being encompassed in the scope.

[0128] 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.

[0129] 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:

[0130] 2) Another embodiment relates to compounds according to embodiment 1), wherein X1represents CH, CF, or N (in particular X1represents CH or CF).

[0131] 3) Another embodiment relates to compounds according to embodiment 1) or 2), wherein RB1represents independently (Ci-3)alkyl, (Ci-3)alkoxy, halogen, or monocyclic (C3-4)cycloalkyl; [especially RB1represents independently methyl, ethyl, methoxy, chloro, iodo, or cyclopropyl; in particular RB1represents independently methyl or methoxy],

[0132] 4) Another embodiment relates to compounds according to embodiment 1), wherein

[0133] Ring B represents p-tolyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6-methylpyridin-3-yl, 3-fluoro-4- methoxyphenyl, 4-cyclopropylphenyl, 4-chlorophenyl, phenyl, 6-methoxypyridin-3-yl, 4-fluorophenyl, 3- fluorophenyl, 6-fluoropyridin-3-yl, 4-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,4-dimethylphenyl, or 3,4- difluorophenyl, or, in addition, 4-ethylphenyl, 4-isopropylphenyl, 4-propylphenyl, 4-(tert-butyl)phenyl, 4-(fert-butyl)- 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-bromophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 4-bromo-3- fluorophenyl, 3-bromo-4-methylphenyl, or 3-chloro-4-methylphenyl [notably p-tolyl, 4-ethylphenyl, 4- isopropylphenyl, 4-propylphenyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6-methylpyridin-3-yl, 3-fluoro-4- methoxyphenyl, 4-cyclopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, phenyl, 6-methoxypyridin-3- yl, 4-fluorophenyl, 3-fluorophenyl, 6-fluoropyridin-3-yl, 4-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,4- dimethylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 4-bromo-3-fluorophenyl, 3-bromo-4-methylphenyl, or 3- chloro-4-methylphenyl; especially Ring B represents p-tolyl, 3-fluoro-4-methylphenyl, 4-methoxyphenyl, 6- methylpyridin-3-yl, 3-fluoro-4-methoxyphenyl, 4-cyclopropylphenyl, or 4-chlorophenyl, or, in addition, 4-ethylphenyl, or 4-iodophenyl; in particular Ring B represents p-tolyl, 3-fluoro-4-methylphenyl, or 4-methoxyphenyl],

[0134] 5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein X2represents 0 or NR4, wherein R4represents hydrogen, methyl, or cyclopropyl [in particular X2represents 0 or NR4, wherein R4represents hydrogen or methyl],

[0135] 6) Another embodiment relates to compounds according to any one of embodiments 1 ) to 4), wherein X2represents 0.

[0136] 7) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein X3represents CH or N such that:

[0137] • when X3represents CH, Ring A represents a monocyclic (Cs-ejcycloalkan-diyl or a monocyclic 5- or 6- membered heterocycloalkan-diyl comprising one ring 0 atom (especially tetrahydrofuran-diyl or tetrahydro- 2H-pyran-diyl); [in particular such Ring A represents cyclopentane-1 ,2-diyl]; or when X3represents N, Ring A represents: • a 4- or 5-membered saturated monocyclic heterocycloal kan-d iy I comprising X3and zero ring 0 atoms (notably azetidin-diyl or pyrrolidin-diyl); wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted (notably unsubstituted or mono-substituted); wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl), halogen (especially fluoro), (Ci-s)alkoxy (especially methoxy or ethoxy), hydroxy, and (Ci-3)alkylidene (especially H2C=); [especially such Ring A represents pyrrolidin-1 ,2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4-f I uoropyrrol idi n- 1 ,2-diyl, 3-methy lenepyrrol id i n- 1 ,2-diyl, 5-methy I pyrrol idi n- 1 ,2-diyl, azetidin-1 ,2- diyl, 4-methylazetidin-1, 2-diyl, 3-fluoropyrrolidin-1 ,2-diyl, 4-hydroxypyrrolidin-1 ,2-diyl, 4- methoxypyrrolidin-1 ,2-diyl, 4-ethoxypyrrolidin-1, 2-diyl, or 4, 4-dimethylpyrrolidin-1, 2-diyl; in particular Ring A represents pyrrolidin-1 , 2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1 ,2-diyl, 3- methylenepyrrolidin-1 ,2-diyl, or 5-methylpyrrolidin-1 , 2-diyl];

[0138] • an unsubstituted 5- or 6-membered saturated monocyclic heterocycloalkan-diyl comprising X3and one ring 0 atom (notably oxazolidin-diyl or oxazinan-diyl, especially oxazolidin-diyl); [especially such Ring A represents oxazolidin-2,3-diyl, oxazolidin-3,4-diyl, or 1 ,3-oxazinan-2,3-diyl; in particular such Ring A represents oxazolidin-2,3-diyl];

[0139] • a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and zero additional ring N atoms (notably dihydro-1 H-pyrrol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group — CO-N(R1)CH(R2)(R3); [in particular such Ring A represents 2, 3-dihydro-1 H-pyrrol-1 , 2-diyl];

[0140] • a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and one additional ring N atom (especially dihydro-1 H-pyrazol-diyl); wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO- N(R1)CH(R2)(R3); wherein said heterocycloalkan-diyl is unsubstituted or mono-substituted with (Ci-s)alkyl (especially methyl); [in particular such Ring A represents 4,5-dihydro-1 / 7-pyrazol-1,5-diyl or 3-methyl-4,5-dihydro-1 H-pyrazol-1 ,5-diyl]; or

[0141] • a 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3; wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or di-substituted (in particular is unsubstituted); wherein the substituents independently are (Ci-s)alkyl (especially methyl); (notably such Ring A represents azabicyclo[2.2.1]heptan-diyl, azabicyclo[3.1.0]hexan-diyl, or azaspiro[2.4]heptan-diyl, or, in addition, azabicyclo[3.2.0]heptan-diyl; especially such Ring A represents 2-azabicyclo[2.2.1]heptan-1, 2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3- azabicyclo[3.1.0]hexan-2,3-diyl, or 5-azaspiro[2.4]heptan-4,5-diyl, or, in addition, 3- azabicyclo[3.2.0]heptan-2,3-diyl, or 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2,3-diyl); [in particular such Ring A represents 2-azabicyclo[2.2.1 ]heptan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, or 3- azabicyclo[3.1.0]hexan-2,3-diyl, or, in addition, 3-azabicyclo[3.2.0]heptan-2,3-diyl],

[0142] 8) Another embodiment relates to compounds according to any one of embodiments 1 ) to 7), wherein X3represents CH.

[0143] 9) Another embodiment relates to compounds according to embodiment 8), wherein Ring A is:

[0144] (in particular Ring wherein the asterisks indicate the point of attachment of the substituent -C(=O)NR1-CH2(R2)(R3).

[0145] 10) Another embodiment relates to compounds according to embodiment 8) or 9), wherein the substituents -S(=O)(=X2)-(Ring B) and -C(=O)NR1-CH2(R2)(R3) of Ring A are in relative trans configuration.

[0146] When X3represents CH, the compounds of Formula (I) contain at least two stereogenic centers which are situated at the two carbon atoms of Ring A that link Ring A to -S(=O)(=X2)-(Ring B) and to -C(=O)NR1-CH2(R2)(R3). 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)):

[0147] Formula (II) Formula (III).

[0148] In such a case, in the present application, the relative configuration of stereoisomers is thus denoted as follows: for example the compound (1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1- difluoro-spiro[2.5]oct-6-yl)-amide having the relative configuration (1 R*,2S*) refers to the compounds (1 R,2S)-2- (T oluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-ch loro-benzy l)-( 1 , 1 -dif I uoro-spiro[2 ,5]oct-6-y l)-amide, or (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 , 1-difluoro-spiro[2.5]oct-6-yl)- amide, or any mixture of these stereoisomers including the racemate (denominated rac-(1 R*,2S*)-2-(Toluene-4- sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct-6-yl)-amide).

[0149] 11) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein X3represents N.

[0150] 12) Another embodiment relates to compounds according to embodiment 11), wherein Ring A represents:

[0151] • pyrrolidin-diyl; wherein said pyrrolidin-diyl is unsubstituted, or mono-substituted with (Ci-s)alkyl

[0152] (especially methyl), halogen (especially fluoro), (Ci-s)alkoxy (especially methoxy or ethoxy), hydroxy, or (Ci-3)alkylidene (especially H2C=); or di-substituted with (Ci-s)alkyl (especially methyl) or halogen (especially fluoro); [especially such Ring A represents pyrrolidin-1, 2-diyl, 4-methylpyrrolidin-1, 2-diyl, 4-fluoropyrrolidin-1, 2-diyl, 3-methylenepyrrolidin-1 ,2-diyl, 5-methylpyrrolidin-1,2-diyl, 4,4- dimethylpyrrolidin-1 ,2-diyl, 3-fluoropyrrolidin-1, 2-diyl, 4-hydroxypyrrolidin-1 ,2-diyl, 4- methoxypyrrolidin-1 ,2-diyl, or 4-ethoxypyrrolidin-1 ,2-diyl; in particular such Ring A represents pyrrolidin-1 ,2-diyl, 4-methy I py rrol id i n- 1 ,2-diyl, 4-fl uoropyrrol id i n- 1 ,2-diyl, 3-methy lenepy rrol idi n- 1 ,2- diyl, or 5-methyl pyrrol id i n-1 ,2-diyl];

[0153] • oxazolidin-diyl; [in particular such Ring A represents oxazol id in-2,3-diyl];

[0154] • dihydro-1 / 7-pyrrol-diyl; wherein the double bond of said dihydro-1 H-pyrrol-diyl does not contain X3or the carbon atom attached to the group — CO-N(R1)CH(R2)(R3); [in particular such Ring A represents 2, 3-d i hydro- 1 H-pyrrol- 1 ,2-diyl]; or

[0155] • a 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3; wherein said bicyclic heterocycloalkan-diyl is unsubstituted, or di-substituted (in particular is unsubstituted); wherein the substituents independently are (Ci-s)alkyl (especially methyl); (notably such Ring A represents azabicyclo[2.2.1]heptan-diyl, azabicyclo[3.1.0]hexan-diyl, or azaspiro[2.4]heptan-diyl, or, in addition, azabicyclo[3.2.0]heptan-diyl; especially such Ring A represents 2-azabicyclo[2.2.1]heptan-1,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3- azabicyclo[3.1.0]hexan-2,3-diyl, or 5-azaspiro[2.4]heptan-4,5-diyl, or, in addition, 3- azabicyclo[3.2.0]heptan-2,3-diyl, or 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2,3-diyl); [in particular such Ring A represents 2-azabicyclo[2.2.1 ]heptan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, or 3- azabicyclo[3.1.0]hexan-2,3-diyl, or, in addition, 3-azabicyclo[3.2.0]heptan-2,3-diyl],

[0156] 13) Another embodiment relates to compounds according to embodiment 11), wherein Ring A represents pyrrolidin-1, 2-diyl, 4-methylpyrrolidin-1 ,2-diyl, 4-fluoropyrrolidin-1, 2-diyl, 3-methylenepyrrolidin-1, 2-diyl, 2,3- dihydro-1 H-pyrrol-1 ,2-diyl, 2-azabicyclo[2.2.1 ]heptan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, or 3- azabicyclo[3.1.0]hexan-2,3-diyl, or, in addition, 3-azabicyclo[3.2.0]heptan-2,3-diyl.

[0157] 14) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein

[0158] R1represents:

[0159] • 3-cyano-3,3-dimethylpropyl or 4-cyanobutyl (notably 3-cyano-3,3-dimethylpropyl);

[0160] • a saturated monocyclic (C^Jcycloalkyl; wherein said (C^cycloalkyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl (especially methyl or isopropyl), halogen (especially fluoro), (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), (Ci-3)alkoxy (especially methoxy), carbamoyl, hydroxy, and cyano;

[0161] • a mono-unsaturated monocyclic (Cs-ejcycloalkyl (especially cydohexenyl); wherein the double bond of said mono-unsaturated (C ejcycloalkyl does not contain the carbon atom attached to the group - N(CO)CH(R2)(R3); [in particular such R1represents cyclohex-3-en-1-yl];

[0162] • a saturated bicyclic (Ce-sjspirocycloalkyl (notably spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said (Ce-sjspirocycloalkyl is unsubstituted or di-substituted with fluoro; [in particular such R1represents 1,1-difluorospiro[2.3]hexan-5-yl, 1,1-difluorospiro[2.5]octan-6-yl, spi ro[3.3]heptan-2-y I, 6, 6-d if I uorospi ro[3.3]heptan-2-yl , 1 , 1 -d ifl uorospi ro[2.4]heptan-5-yl , or spiro[2.5]octan-6-yl];

[0163] • a saturated fused or bridged bicyclic (C6-8)cyclo al ky I (notably bicyclo[2.1.1 ]hexany I , bicyclo[4.1 ,O]heptanyl, or bicyclo[2.2.2]octanyl); wherein said (Ce-sjcycloalkyl is unsubstituted or di-substituted with fluoro; [in particular such R1represents bicyclo[4.1.0]heptan-3-yl, 7,7-difluorobicyclo[4.1.0]heptan-3-yl]; or

[0164] • a 6-membered saturated monocyclic heterocycloalkyl comprising one ring heteroatomic group selected from 0, S, and SO2 (notably said heterocycloalkyl is tetrahydro-2 / - / -pyran, tetrahydro-2 / - / -thiopyran, or tetrahydro-2 / 7-thiopyran-1,1 -dioxide); wherein said heterocycloalkyl 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), and (Ci-3)fluoroalkyl (especially trifluoromethyl); [in particular such R1represents 1,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl, tetrahydro-2 / - / -pyran-4-yl, 3- fluorotetrahydro-2 / 7-pyran-4-yl, 2-methyltetrahydro-2 / - / -pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2 / - / -pyran- 4-yl, 2,2-dimethyltetrahydro-2 / - / -py ran-4-y I , or tetrahydro-2 / - / -pyran-3-yl, or, in addition, 3-methyltetrahydro- 2H-pyran-4-yl, 6-methyltetrahydro-2 / - / -pyran-3-yl, 6,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6- d imethy ltetrahydro-2 / 7-py ran-4-y I , or 1 , 1 -dioxidotetrahydro-2 / - / -thiopyran-3-y I] .

[0165] 15) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein

[0166] R1represents: 3-cyano-3,3-dimethylpropyl or 4-cyanobutyl (notably 3-cyano-3,3-dimethylpropyl);

[0167] • cyclobutyl; wherein said cyclobutyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl), halogen (especially fluoro), (Ci-3)fluoroalkyl (especially trifluoromethyl), hydroxy, and cyano; [in particular such R1represents 3- cyanocyclobutyl, 3-(trifluoromethyl)cyclobutyl, or 3-hydroxy-3-(trifluoromethyl)cyclobutyl];

[0168] • cyclopentyl; wherein said (C^cycloalkyl is 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)fluoroalkyl (especially difluoromethyl), (Ci-3)alkoxy (especially methoxy), carbamoyl, hydroxy, and cyano; [especially such R1represents 3-cyanocyclopentyl, 3-cyano-3-methylcyclopentyl, 4-cyano-2- hydroxycyclopentyl, 3-fluorocyclopentyl, 3-methoxycyclopentyl, 3-(difluoromethyl)cyclopentyl, 3- carbamoylcyclopentyl, 3-carbamoyl-3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, or 4-cyano-2-methoxycyclopentyl, or, in addition, 2-methoxycyclopentyl, or 3-hydroxycyclopentyl; in particular such R1represents 3-cyanocyclopentyl, 3-cyano-3-methylcyclopentyl, or 4-cyano-2- hydroxycyclopentyl];

[0169] • cyclohexyl; wherein said (C^cycloalkyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl (especially methyl or isopropyl), halogen (especially fluoro), (Ci-3)alkoxy (especially methoxy), carbamoyl, hydroxy, and cyano; [especially such R1represents 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocydohexyl, 4,4-dimethylcyclohexyl, 4,4- difluorocyclohexyl, 4-fluorocyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-methoxycyclohexyl, 4- methylcyclohexyl, 4-isopropylcyclohexyl, 4-methoxycyclohexyl, 3,3-dimethylcyclohexyl, 2,2- difluorocyclohexyl, 3,3-difluorocyclohexyl, or 4-hydroxy-4-methylcyclohexyl; in particular such R1represents 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocydohexyl, 4,4-dimethylcyclohexyl, 4,4- difluorocyclohexyl, or 4-fluorocyclohexyl];

[0170] • cyclohexenyl; wherein the double bond of said cyclohexenyl does not contain the carbon atom attached to the group -N(CO)CH(R2)(R3); [in particular such R1represents cyclohex-3-en-1 -yl];

[0171] • a saturated bicyclic (Ce-sjspirocycloalkyl (notably spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, or spiro[2.5]octanyl); wherein said (Ce-sjspirocycloalkyl is unsubstituted or di-substituted with fluoro; [in particular such R1represents 1,1-difluorospiro[2.3]hexan-5-yl, 1,1-difluorospiro[2.5]octan-6-yl, spi ro[3.3]heptan-2-y I, 6, 6-d if I uorospi ro[3.3]heptan-2-yl , 1 , 1 -d ifl uorospi ro[2.4]heptan-5-yl , or spiro[2.5]octan-6-yl];

[0172] • a saturated fused or bridged bicyclic (C6-a)cycloal ky I (notably bicyclo[2.1.1 ]hexany I , bicyclo[4.1 ,O]heptanyl, or bicyclo[2.2.2]octanyl); wherein said (Ce-sjcycloalkyl is unsubstituted or di-substituted with fluoro; [in particular such R1represents bicyclo[4.1.0]heptan-3-yl, 7,7-difluorobicyclo[4.1.0]heptan-3-yl]; or • a 5- or 6-membered (preferably 6-membered) saturated monocyclic heterocycloalkyl comprising one ring heteroatomic group selected from 0, S, and SO2 (notably said heterocycloalkyl is tetrahydrothiophen-1 , 1- dioxide, tetrahydro-2 / - / -pyran, tetrahydro-2 / - / -thiopyran, or tetrahydro-2 / 7-thiopyran-1,1 -dioxide); wherein said heterocycloalkyl 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), and (Ci-s)fluoroalkyl (especially trifluoromethyl); [in particular such R1represents 1,1- d ioxidotetrahyd ro-2H-th iopyran-4-y I, 1 , 1 -dioxidotetrahydrothiophen-3-yl, tetrahydro-2H-py ran-4-y I, 3- fluorotetrahydro-2 / 7-pyran-4-yl, 2-methyltetrahydro-2 / - / -pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2 / - / -pyran- 4-yl, 2,2-dimethyltetrahydro-2 / - / -py ran-4-y I , or tetrahydro-2 / - / -pyran-3-yl, or, in addition, 3-methyltetrahydro- 2H-pyran-4-yl, 6-methyltetrahydro-2 / - / -pyran-3-yl, 6,6-dimethyltetrahydro-2 / 7-pyran-3-yl, 2,6- d imethy ltetrahydro-2 / 7-py ran-4-y I , or 1 , 1 -dioxidotetrahydro-2 / - / -thiophen-3-y I] .

[0173] 16) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein

[0174] R1represents:

[0175] • 3-cyano-3-methylbutyl;

[0176] • a saturated monocyclic (Cs-ejcycloalkyl; wherein said (Cs-ejcycloalkyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: methyl, fluoro, hydroxy, and cyano; [especially such R1represents 3-cyanocyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4- cyanocydohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-2-hydroxycyclopentyl, or 4- fluorocyclohexyl];

[0177] • cyclohex-3-en-1-yl;

[0178] • a saturated bicyclic (Ce-sjspirocycloalkyl (notably spiro[2.3]hexanyl or spiro[2.5]octanyl); wherein said (Ce-sjspirocycloalkyl is di-substituted with fluoro; [notably such R1represents 1 , 1 -difluorospiro[2.3]hexan-5- yl, 1 , 1 -d ifl uorospi ro[2.5]octan-6-y I];

[0179] • a saturated fused or bridged bicyclic (Ce-sjcycloalkyl (notably bicyclo[4.1.0]heptanyl); wherein said (Ce-sjcycloalkyl is unsubstituted or di-substituted with fluoro; [notably such R1represents bicyclo[4.1.0]heptan-3-yl, 7,7-difluorobicyclo[4.1 ,0]heptan-3-yl]; or

[0180] • tetrahyd ro-2 / - / -thiopyran-1 , 1 -dioxide.

[0181] 17) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein

[0182] R1represents: a saturated monocyclic (Cs-ejcycloalkyl; wherein said (Cs-ejcycloalkyl is mono-substituted with cyano or hydroxy; or di-substituted with methyl or di-substituted with fluoro; [in particular such R1represents 3- cyanocyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocydohexyl, 4,4-dimethylcyclohexyl, or 4,4-difluorocyclohexyl];

[0183] • a saturated bicyclic (Ce-sjspirocycloalkyl (notably spiro[2.3]hexanyl or spiro[2.5]octanyl); wherein said (Ce-sjspirocycloalkyl is di-substituted with fluoro; [in particular such R1represents 1,1- d if I uorospiro[2.3]hexan-5-y 1 , 1 , 1 -dif I uorospi ro[2.5]octan-6-y I]; or

[0184] • bicyclo[4.1.0]heptan-3-yl;

[0185] • or, in addition, 1 ,1-dioxidotetrahydro-2H-thiopyran-3-yl.

[0186] 18) Another embodiment relates to compounds according to any one of embodiments 1) to 17), wherein

[0187] R3represents:

[0188] • a 9- or 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, and S (notably 2,3-dihydro-1 / 7-indenyl, 2,3- dihydrobenzofuranyl, benzo[d][1 ,3]dioxolyl, 6,7-dihydro-5 / 7-cyclopentapyridinyl, 2,3- dihydrofuro[3,2]pyridinyl, chromanyl, isochromanyl, or 2, 3-d i hydrobenzo[b][1 ,4]dioxi nyl); wherein said 9- or 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 9- or 10-membered ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro) and oxo; [in particular such R3represents 2,3-dihydro-1 H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1 , 3]dioxol-5-y 1 , 4-fl uoro-2,3-di hydrobenzof uran-6-y I, 7-f I uoro-2, 3-d i hyd robenzof uran-6-y 1 , 3- methyl-2,3-dihydrobenzofuran-6-yl, 2-methyl-2,3-dihydrobenzofuran-6-yl, 3-oxo-2,3-dihydrobenzofuran-6- yl, benzo[d][1 ,3]dioxol-4-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5 / - / -cyclopenta[c]pyridin-3-yl2,3-dihydrofuro[3,2-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-c]pyridin-6- yl, chroman-6-yl, chroman-7-yl, isochroman-6-yl, isochroman-7-yl, or 2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl];

[0189] • naphthyl or a 8- to 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S (notably such R3represents a 9- or 10-membered heteroaryl; especially benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, furopyridinyl, benzoxadiazolyl, thienopyridinyl, 1 / 7-indolyl, quinolinyl, or isoquinolinyl); wherein said naphthyl or 8- to 10-membered heteroaryl is independently unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl (especially methyl) and halogen (especially fluoro or chloro): [in particular such R3represents benzofuran-6-yl, benzo[d]oxazol-5-yl, 6- fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[b]thiophen-2-yl, 2-methylbenzo[b]thiophen-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2- methylbenzofuran-6-yl, benzo[d]thiazol-2-yl, benzo[d]oxazol-2-yl, thieno[2,3-b]pyridin-2-yl, 1 H-indol-6-yl, furo[3,2-b]pyridin-6-yl, furo[2,3-b]pyridin-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[c][1 ,2,5]oxadiazol-5-yl, naphthalen-2-yl, quinolin-7-yl, isoquinolin-3-yl, or isoquinolin-7-yl, or, in addition, 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, or 2-methoxybenzo[d]thiazol-5-yl];

[0190] • phenyl; wherein said phenyl is mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl, ethyl, or isopropyl), halogen (especially fluoro, chloro, or bromo), (Ci-3)alkoxy (especially methoxy), (Ci-3)fluoroalkoxy (especially difluoromethoxy), a monocyclic 4- to 6-membered heterocycloalkyl (especially azetidinyl or oxetanyl); wherein heterocycloalkyl is unsubstituted or mono-substituted with halogen (especially fluoro), monocyclic (C3- ejcycloalkyl (especially cyclopropyl), (Ci-s)alkylthio (especially methylthio), (Ci_3)fluoroalkyl (especially trifluoromethyl), cyano, and NRN1RN2, wherein RN1and RN2independently represent hydrogen or (Ci-4)alkyl (especially NRN1RN2represents dimethylamino); [in particular such R3represents p-tolyl, 4-chlorophenyl, 4- bromophenyl, 4-(methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-fluoro-4- methylphenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-chlorophenyl, 3-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-(difluoromethoxy)phenyl, 3-(azetidin-1-yl)phenyl, 3-(3-fluorooxetan-3-yl)phenyl, 4- ethylphenyl, 4-isopropylphenyl, 4-(dimethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4- (trifluoromethyl)phenyl, 2-fluoro-3-methylphenyl, 2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 2-chloro-4- fluorophenyl, 2-fluoro-4-methoxyphenyl, 2,5-difluorophenyl, 2-fluoro-5-methoxyphenyl, 3-fluoro-5- methoxyphenyl, 3,4-dimethylphenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl,

[0191] 3-chloro-4-methylphenyl, 3-cyano-4-methylphenyl, 4-fluoro-4-methoxyphenyl, 2,3-difluoro-4-methylphenyl,

[0192] 4-chloro-2,3-difluorophenyl, 4-chloro-2,6-difluorophenyl, or 2,4-difluoro-5-methylphenyl]; or

[0193] • a 5- or 6-membered heteroaryl comprising one to three ring heteroatoms independently selected from N, 0, and S (notably pyridinyl, thiophenyl, oxazolyl, thiazolyl, or isoxazolyl); wherein said 5- or 6-membered heteroaryl is independently mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci.3)alkyl (especially methyl, ethyl, or isopropyl), halogen (especially fluoro, chloro, or bromo), (Ci-3)alkoxy (especially methoxy), (Ci-3)fluoroalkoxy (especially difluoromethoxy), monocyclic (Cs-ejcycloalkyl (especially cyclopropyl), (Ci-s)alkylthio (especially methylthio), (Ci-3)fluoroalkyl (especially trifluoromethyl), cyano, NRN1RN2, wherein RN1and RN2independently represent hydrogen or (C1- 4)alkyl (especially NRN1RN2represents dimethylamino), and 4- to 6-membered monocyclic heterocycloalkyl (especially azetidinyl or oxetanyl); wherein said heterocycloalkyl is unsubstituted or mono-substituted with halogen (especially fluoro); [in particular such R3represents 5-ch loropyrid i n-2-y 1 , 2-methylthiophen-3-yl, 5- methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5-isopropyloxazol-2-yl, 5-chlorothiazol- 2-yl, or 5-bromoothiazol-2-yl],

[0194] 19) Another embodiment relates to compounds according to any one of embodiments 1) to 17), wherein

[0195] R3represents: • a 9- or 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, and S (notably 2,3-dihydro-1 H-inden-5-yl, 2,3- dihydrobenzofuran-6-yl, benzo[d][1,3]dioxol-5-yl, benzo[d][1,3]dioxol-4-yl, 6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5 / - / -cyclopenta[c]pyridin-3-yl, 2,3-dihydrofuro[3,2-b]pyridin-6-yl, 2,3- dihydrofuro[3,2-c]pyridin-6-yl, chroman-6-yl, chroman-7-yl, isochroman-6-yl, isochroman-7-yl, or 2,3- dihydrobenzo[b][1.4]dioxin-6-yl); wherein said 9- or 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 9- or 10-membered ring system is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro) and oxo; [in particular such R3represents 2,3-dihydro-1 / 7-inden-5-yl, 2,3- dihydrobenzofuran-6-yl, 5-fl uoro-2, 3-di hydrobenzof uran-6-y I , benzo[d][1 ,3]dioxol-5-yl, 4-f I uoro-2, 3- dihydrobenzofuran-6-yl, 7-fluoro-2,3-dihydrobenzofuran-6-yl, 3-methyl-2,3-dihydrobenzofuran-6-yl, 2- methyl-2,3-dihydrobenzofuran-6-yl, 3-oxo-2,3-dihydrobenzofuran-6-yl, benzo[d][1 ,3]d ioxol-4-y 1 , 2,2- d ifl uorobenzo[d][1 , 3]dioxol-5-y 1 , 6, 7-di hydro-5 / - / -cyclopenta[b]py rid i n-2-y 1 , 6,7-dihydro-5H- cyclopenta[c]pyridin-3-yl, 2,3-dihydrofuro[3,2-b]pyridin-6-yl, 2,3-dihydrofuro[3,2-c]pyridin-6-yl, chroman-6- yl, chroman-7-yl, isochroman-6-yl, isochroman-7-yl, or 2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl];

[0196] • a 9- or 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S (notably benzofuran-2-yl, benzofuran-5-yl, benzofuran-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-2-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, furo[3,2- b]pyridin-6-yl, benzo[c][1,2,5]oxadiazol-5-yl, thieno[2,3-b]pyridin-2-yl, 1 H-indol-6-yl, quinolin-7-yl, isoquinolin-3-yl, or isoquinolin-7-yl); wherein said 9- or 10-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and halogen (especially fluoro or chloro): [in particular such R3represents benzofuran-6-yl, benzo[d]oxazol-5-yl, 6-fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5- yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2-c]pyridin-6-yl, 2- methylbenzo[d]thiazol-5-yl, benzo[b]thiophen-2-yl, 2-methylbenzo[b]thiophen-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[d]thiazol-2-yl, benzo[d]oxazol-2-yl, thieno[2,3-b]pyridin-2- yl, 1 H-indol-6-yl, furo[3,2-b]pyridin-6-yl, furo[2,3-b]pyridin-6-yl, 6-fluoro-2-methylbenzo[c / ]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[c][1 ,2,5]oxadiazol-5-yl, quinolin-7-yl, isoquinolin-3-yl, or isoquinolin-7-yl], or, in addition, 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, or 2-methoxybenzo[d]thiazol-5-yl;

[0197] • phenyl; wherein said phenyl is mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl, ethyl, or isopropyl), halogen (especially fluoro, chloro, or bromo), (Ci-3)alkoxy (especially methoxy), (Ci-3)fluoroalkoxy (especially difluoromethoxy), (Ci-3)alkylthio (especially methylthio), (Ci-s)fluoroalkyl (especially trifluoromethyl), cyano, and NRN1RN2, wherein RN1and RN2independently represent hydrogen or (Ci-4)alkyl (especially NRN1RN2represents dimethylamino); [in particular such R3represents p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4- (methylthio)phenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-fluoro-4-methylphenyl,

[0198] 2.4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-chlorophenyl, 3-methylphenyl, 3-fluorophenyl, 3- methoxyphenyl, 3-(difluoromethoxy)phenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-(dimethylamino)phenyl, 4- (difluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-3-methylphenyl, 2,4-dimethylphenyl, 4-fluoro- 2-methylphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-methoxyphenyl, 2,5-difluorophenyl, 2-fluoro-5- methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3,4-dimethylphenyl, 4-fluoro-3-methylphenyl, 3,4- difluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 3-cyano-4-methylphenyl, 4-fluoro-4- methoxyphenyl, 2,3-difluoro-4-methylphenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-2,6-difluorophenyl, or

[0199] 2.4-difluoro-5-methylphenyl]; or

[0200] • a 5-membered heteroaryl comprising one to three ring heteroatoms independently selected from N, 0, and S (notably thiophen-3-yl, thiophen-2-yl, oxazol-2-yl, thiazol-2-yl, thiazol-5-yl, isothiazol-4-yl, isoxazol-3-yl, or isoxazol-4-yl); wherein said 5-membered heteroaryl is independently mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl (especially methyl, ethyl, or isopropyl) and halogen (especially chloro, or bromo); [in particular such R3represents 2- methylthiophen-3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5- isopropyloxazol-2-yl, 5-chlorothiazol-2-yl, 5-bromoothiazol-2-yl, 5-isopropylthiazol-2-yl, 2-isopropylthiazol- 5-yl, 5-methylisothiazol-4-yl, 4-ethyl-5-methylisoxazol-3-yl, or 5-methylisoxazol-4-yl]; or

[0201] • pyridinyl (especially pyridin-2-yl); wherein said pyridinyl is mono-substituted with halogen (especially chloro); [in particular such R3represents 5-chloropyridi n-2-yl],

[0202] 20) Another embodiment relates to compounds according to any one of embodiments 1) to 17), wherein

[0203] R3represents:

[0204] • a 9- or 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, and S (notably 2,3-dihydro-1 H-inden-5-yl, 2,3- dihydrobenzofuran-6-yl, or benzo[d][1 ,3]dioxol-5-yl); wherein said 9- or 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 9- or 10-membered ring system is unsubstituted, or mono-substituted with halogen (especially fluoro); [in particular such R3represents 2,3- d i hydro- 1 H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2, 3-d i hydrobenzofu ran-6-y I, benzo[d][1 , 3]dioxol-5-y I , or 4-fluoro-2,3-dihydrobenzofuran-6-yl;

[0205] • a 9- or 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S (notably benzofuran-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, or furo[3,2-c]pyridin-6-yl); wherein said 9- or 10-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl (especially methyl) and halogen (especially chloro): [in particular such R3represents benzofuran-6-yl, benzo[c(]oxazol-5-yl, 6-fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[cf]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furo[3,2- c]pyridin-6-yl, or 2-methylbenzo[d]thiazol-5-yl, or, in addition, 2-bromobenzo[d]thiazol-5-yl]; or

[0206] • phenyl; wherein said phenyl is mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl (especially methyl), halogen (especially fluoro, chloro, or bromo), (Ci-3)alkoxy (especially methoxy), and (Ci-3)alkylthio (especially methylthio); [in particular such R3represents p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, 4-chloro-2-fluorophenyl, 4- fluorophenyl, 4-methoxyphenyl, 2-fluoro-4-methylphenyl, 2,4-difluorophenyl, or 3-fluoro-4-methylphenyl, or, in addition, 3-fluoro-4-methoxyphenyl],

[0207] 21) Another embodiment relates to compounds according to any one of embodiments 1) to 17), wherein

[0208] R3represents:

[0209] • a 9- or 10-membered partially aromatic fused bicyclic ring system selected from 2, 3-d i hyd ro- 1 H-i nden-5-y I , 2,3-dihydrobenzofuran-6-yl, and benzo[d][1 ,3]dioxol-5-yl; wherein said 9- or 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 9- or 10-membered ring system is unsubstituted, or mono-substituted with halogen (especially fluoro); [in particular such R3represents 2,3- dihydro-1 H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, or benzo[d][1 , 3]dioxol-5-y I];

[0210] • a 9- or 10-membered heteroaryl selected from benzofuran-6-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, and benzo[d]thiazol-5-yl; wherein said 9- or 10-membered heteroaryl is unsubstituted, or mono-substituted with halogen (fluoro or chloro): [in particular such R3represents benzofuran-6-yl, benzo[d]oxazol-5-yl, 6- fluorobenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-5-yl, or 2-chlorobenzo[d]thiazol-5-yl]; or

[0211] • phenyl; wherein said phenyl is mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), halogen (especially fluoro, chloro, or bromo), (Ci-3)alkoxy (especially methoxy), and (Ci-s)alkylthio (especially methylthio); (wherein especially the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), halogen (especially fluoro, chloro, or bromo), and (Ci-s)alkylthio (especially methylthio)); [in particular such R3represents p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, or 4-chloro-2-fluorophenyl, or, in addition, 3-fluoro-4-methoxyphenyl],

[0212] 22) Another aspect of the invention relates to compounds of the Formula (I) according to any one of embodiments 1) to 21) which are also compounds of the Formula (IV) (i.e., the absolute configuration of the ring carbon atom to which the group -C(=O)NR1-CH2(R2)(R3) is attached, is as depicted in Formula (IV) below):

[0213] Formula (IV).

[0214] 23) Another embodiment relates to compounds according to embodiment 1) which are selected from the following compounds:

[0215] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0216] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide;

[0217] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cydohexyl)-amide;

[0218] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl-cydohexyl)-amide;

[0219] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-6-ylmethyl-(4,4-difluoro-cydohexyl)- amide;

[0220] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide;

[0221] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide;

[0222] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cydohexyl)-amide;

[0223] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cydohexyl)-amide;

[0224] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-dimethyl-cydohexyl)-amide;

[0225] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(1, 1-dioxo-hexahydro-1X6- thiopyran-4-yl)-amide;

[0226] (1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0227] (1S,2S,5R)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;

[0228] (1 R,2S,5S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcydohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0229] (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;

[0230] (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide; (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;

[0231] (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;

[0232] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4-fluoro-cyclohexyl)-amide;

[0233] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4-hydroxy-cyclohexyl)- amide;

[0234] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)- amide;

[0235] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0236] (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0237] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;

[0238] (2S)-N-(benzofuran-6-ylmethyl)-N-(cyclohex-3-en-1-yl)-1-tosylpyrrolidine-2-carboxamide;

[0239] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzooxazol-5-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;

[0240] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzooxazol-6-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;

[0241] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4- difluoro-cydohexyl)-amide;

[0242] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cydohexyl)-amide;

[0243] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzooxazol-5-ylmethyl-(4,4- difluoro-cydohexyl)-amide;

[0244] (1 R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0245] (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0246] (1 R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0247] (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro- cyclohexyl)-amide; (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;

[0248] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzooxazol-6-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;

[0249] (2S)-N-(benzo[b]thiophen-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0250] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6- ylmethyl)-amide;

[0251] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4-dimethyl- cyclohexyl)-amide;

[0252] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(1,1-dioxo- hexahydro-1X6-thiopyran-4-yl)-amide;

[0253] (1 R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;

[0254] (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0255] (1 R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0256] (1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicydo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;

[0257] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide;

[0258] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4-hydroxy-cyclohexyl)-amide;

[0259] (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0260] (2S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;

[0261] (2S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;

[0262] (2S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1 -tosylpyrrolidine-2-carboxamide;

[0263] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4-hydroxy- cyclohexyl)-amide;

[0264] (1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0265] (1S,2S,5R)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;

[0266] (1 R,2S,5S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0267] (1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide; (1 S,2S,5R)-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1 ,0]hexane-2- carboxamide;

[0268] (1 R,2S,5S)-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0269] (1 R*,5S*)-(2RS)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;

[0270] (1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0271] (1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0272] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;

[0273] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0274] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;

[0275] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0276] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0277] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4- dimethyl-cyclohexyl)-amide;

[0278] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0279] (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;

[0280] (25.45)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0281] (S)-N-(4,4-Difluorocydohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-1 -tosylpyrrolidine-2-carboxamide;

[0282] (25.45)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-4-fluoro-1 -tosylpyrrolidine-2-carboxamide;

[0283] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(5-fluoro-2,3-dihydro-benzofuran- 6-ylmethyl)-amide;

[0284] (1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;

[0285] (25.45)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-4-fluoro-1-tosylpyrrolidine-2-carboxamide; (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(4-fluoro-2,3-dihydro-benzofuran- 6-ylmethyl)-amide;

[0286] (2S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;

[0287] (2S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;

[0288] (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;

[0289] (2S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide;

[0290] (S)-4-Methylene-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0291] (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0292] (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0293] (2S,4S)-4-Fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1 R,3R,6R)-bicyclo[4.1.0]hept-3-yl-

[0294] (2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0295] (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0296] (S)-N-(4,4-difluorocydohexyl)-N-(furo[3,2-c]pyridin-6-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide;

[0297] (1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cydohexyl)- (2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0298] (1 R*,5S*)-(2RS)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5- ylmethyl-(4,4-difluoro-cydohexyl)-amide;

[0299] (1 S,2S,5R)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;

[0300] (1 R,2S,5S)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;

[0301] (1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;

[0302] (1 R,3S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-tosyl-2-azabicyclo[3.1.0]hexane-3- carboxamide;

[0303] (1 R,3S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-((4-methoxyphenyl)sulfonyl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide; (1 R,3S,5R)-N-(bicyclo[4.1 .0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-tosyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide;

[0304] (1 R,3S,5R)-N-(bicyclo[4.1 .0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((4-methoxyphenyl)sulfonyl)- 2-azabicyclo[3.1 ,0]hexane-3-carboxamide;

[0305] (1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid benzooxazol-5-ylmethyl-

[0306] (4,4-difluoro-cydohexyl)-amide;

[0307] (1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;

[0308] (1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;

[0309] (1 R,2S,5S)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;

[0310] (1S,2S,5R)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;

[0311] (1 R,2S,5S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-tosyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0312] (1S,2S,5R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-tosyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0313] (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methoxyphenylsulfonimidoyl)pyrrolidine-2- carboxamide ;

[0314] (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxyphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0315] (1 R*,5S*)-(2RS)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-d ifluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0316] (1 S,2S,5R)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4 ,4-dif I uoro-cyclohexy I)- (2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0317] (1 R,2S,5S)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-

[0318] (2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0319] (1R* 5S*)-(2RS)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0320] (1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0321] (1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicydo[4.1 .0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide; (1 R*,5S*)-(2RS)-N-(bicyclo[4.1 ,0]heptan-3-y l)-N-((2, 3-di hyd robenzofu ran-6-yl) methy l)-3-((4- methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

[0322] (1S,2S,5R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0323] (1 R,2S,5S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;

[0324] (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-(N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0325] (1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0326] (1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0327] (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0328] (S)-1-(3-Fluoro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0329] (S)-1-(4-Chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran- 6-ylmethyl)-amide;

[0330] (S)-1-(4-Cyclopropyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0331] (2S,5R)-5-Methyl-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0332] (2S)-N-(4,4-difluorocydohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1 -tosylpyrrolidine-2-carboxamide;

[0333] (S)-1-(Toluene-4-sulfonyl)-2,3-dihydro-1 H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;

[0334] (1 R,3S,4S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((6-methylpyridin-3- yl)sulfonyl)-2-azabicydo[2.2.1 ]heptane-3-carboxamide;

[0335] (1 R,3S,4S)-2-(6-Methyl-pyridine-3-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide;

[0336] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0337] (2S)-N-(benzo[d][1 , 3]dioxol-5-y I methy l)-N -(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0338] (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0339] (2S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-(3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0340] (2S)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0341] (2S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-(methylthio)benzyl)pyrrolidine-2- carboxamide;

[0342] (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;

[0343] (2S)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4-difluorocyclohexyl)-N-((2,3- dihydrobenzofuran-6-yl)methyl)pyrrolidine-2-carboxamide;

[0344] (2S)-N-(benzo[d]thiazol-5-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;

[0345] (1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0346] (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methoxyphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;

[0347] (2S)-N-(4-chlorobenzyl)-1-(N-cyclopropyl-4-methylphenylsulfonimidoyl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2- carboxamide;

[0348] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0349] (1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;

[0350] (1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0351] (2S)-N-(4-chlorobenzyl)-N-(4,4-dimethylcyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0352] (2S)-N-(4-chlorobenzyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-((4-ethynyl-2-hydroxycyclopentyl)pyrrolidine- 2-carboxamide;

[0353] (2S)-N-(4-chlorobenzyl)-N-(1 , 1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0354] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide;

[0355] (2S)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine- 2-carboxamide; (1 S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;

[0356] (2S)-N-((3S,5R)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4- methylbenzyl)pyrrolidine-2-carboxamide;

[0357] (2S)-N-(4-chlorobenzyl)-N-((3S,5R)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0358] (2S)-N-(4-chlorobenzyl)-N-(1 , 1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0359] (2S)-N-(4-chlorobenzyl)-N-((3S,6R)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0360] (1S,2R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-tosylcyclopentane-1- carboxamide;

[0361] (1S,2R)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-tosylcyclopentane-1 -carboxamide;

[0362] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro-cydohexyl)- amide;

[0363] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct-6-yl)- amide;

[0364] (2S)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0365] (2S)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;

[0366] (2S)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0367] (2S)-N-(4-Chlorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0368] (2S)-N-(4-Chloro-2-fluorobenzyl)-N-((3S,5r)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0369] (2S)-N-(4-Chloro-2-fluorobenzyl)-N-((3S,6r)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0370] (2S)-N-((3S,6r)-1 , 1 -D if I uorospiro[2.5]octan-6-y I)- 1 -(( R)-N , 4-d i methy Iphenylsu Ifon i midoy l)-N -(4- methylbenzyl)pyrrolidine-2-carboxamide;

[0371] (1S,2R)-N-(4-chlorobenzyl)-N-((1S*,3R*)-3-cyanocydopentyl)-2-tosylcydopentane-1-carboxamide;

[0372] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct-6-yl)- amide; (1 S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methoxy-benzyl)- amide;

[0373] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(4-cyano-cyclohexyl)-amide;

[0374] (2S)-N-(4-Chlorobenzyl)-N-((1 R*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0375] (25.45)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- methylpyrrolidine-2-carboxamide;

[0376] (25.45)-N-(4-chlorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- methylpyrrolidine-2-carboxamide;

[0377] (25.45)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-(N,4-dimethylphenylsulfonimidoyl)-4-methylpyrrolidine-2- carboxamide;

[0378] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzooxazol-5-ylmethyl-(1 ,1-difluoro-spiro[2.5]oct-6- yl)-amide;

[0379] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methyl-benzyl)- amide;

[0380] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methylsulfanyl- benzyl)-amide;

[0381] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct- 6-yl)-amide;

[0382] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(1 ,1-difluoro- spiro[2.5]oct-6-yl)-amide;

[0383] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(2-fluoro-4-methyl-benzyl)- amide;

[0384] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(4-cyano-cyclohexyl)- amide;

[0385] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(2,4-difluoro-benzyl)-amide;

[0386] (1S,2R)-N-(4-Cyanocyclohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1 -carboxamide;

[0387] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methylsulfanyl-benzyl)- amide;

[0388] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methyl-benzyl)-amide;

[0389] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-bromo-benzyl)-(4-cyano-cyclohexyl)-amide;

[0390] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-fluoro-benzyl)-amide;

[0391] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(3-cyano-3,3-dimethyl-propyl)- amide; (1 S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (7,7-difluoro-bicyclo[4.1.0]hept-3-yl)-(4-methyl- benzyl)-amide;

[0392] (25.45)-N-(4-chlorobenzyl)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- fluoropyrrolidine-2-carboxamide;

[0393] (25.45)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)- 4-methylpyrrolidine-2-carboxamide;

[0394] (S)-N-((1 R*,3S*)-3-cyanocydopentyl)-N-(4-methylbenzyl)-1-tosylpyrrolidine-2-carboxamide;

[0395] (S)-N-(4-chlorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-1-tosylpyrrolidine-2-carboxamide;

[0396] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic add ((1S*,3R*)-3-cyano-cyclopentyl)-(4-methyl-benzyl)- amide;

[0397] (25.45)-N-(4-Chlorobenzyl)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-(R)-(N,4-dimethylphenylsulfonimidoyl)- 4-methylpyrrolidine-2-carboxamide;

[0398] (2RS)-N-((1 R*,3S*)-3-Cyanocydopentyl)-N-(4-methylbenzyl)-3-tosyloxazolidine-2-carboxamide;

[0399] (2RS)-N-((1 R*,3S*)-3-Cyanocydopentyl)-N-(4-chlorobenzyl)-3-tosyloxazolidine-2-carboxamide;

[0400] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-(4-methyl-benzyl)- amide;

[0401] (1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-indan-5-ylmethyl- amide;

[0402] (1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(3-cyano-3,3-dimethyl- propyl)-amide;

[0403] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-bromo-benzyl)-(3-cyano-3,3-dimethyl-propyl)- amide;

[0404] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1 R*,3R*)-3-cyano-cyclohexyl)-(4-methyl-benzyl)- amide;

[0405] (1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-((1 R,3S)-3-cyano-cyclopentyl)- amide;

[0406] (1S,2R)-N-((1 R*,3S*)-3-Cyanocyclopentyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;

[0407] (1S,2R)-N-(7,7-Difluorobicyclo[4.1 ,0]heptan-3-yl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;

[0408] (1S,2R)-N-((1 R*,3R*)-3-Cyanocydohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;

[0409] (1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid ((1 R*,3S*)-3-cyano-cyclopentyl)-(3-fluoro-4-methyl- benzyl)-amide; (25.45)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)- 4-fluoropyrrolidine-2-carboxamide;

[0410] (25.45)-N-(4,4-difluorocydohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4-methyl-N-(4- methylbenzyl)pyrrolidine-2-carboxamide;

[0411] (1S,2R)-N-((1r,4S)-4-cyanocyclohexyl)-N-(4-(methyl-d3)benzyl)-2-tosylcyclopentane-1-carboxamide;

[0412] (1S,2R)-N-(4-Chloro-2-fluorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-2-tosylcyclopentane-1-carboxamide;

[0413] (1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cydohexyl)- amide;

[0414] (1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (4,4-difluoro-cyclohexyl)-(6-fluoro-benzooxazol-5- ylmethyl)-amide;

[0415] (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-2-((R)-4- methylphenylsulfonimidoyl)cydopentane-1 -carboxamide;

[0416] (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-2-((S)-4- methylphenylsulfonimidoyl)cydopentane-1 -carboxamide;

[0417] (2S)-N-(4-chlorobenzyl)-N-((1 R)-3-cyano-3-methylcyclopentyl)-1-tosylpyrrolidine-2-carboxamide;

[0418] (1S,2R)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocyclopentyl)-2-((R)-4-methylphenylsulfonimidoyl)cydopentane-1- carboxamide;

[0419] (1S,2R)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocyclopentyl)-2-((S)-4-methylphenylsulfonimidoyl)cyclopentane-1- carboxamide;

[0420] (1S,2R)-N-(4-chlorobenzyl)-N-((1 R)-3-cyano-3-methylcyclopentyl)-2-tosylcyclopentane-1 -carboxamide;

[0421] (S)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-N-(4-methylbenzyl)-1-((S)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0422] (S)-N-((3S,5r)-1 ,1-difluorospiro[2.3]hexan-5-yl)-N-(4-methylbenzyl)-1-((S)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0423] (S)-N-((1S*,3R*)-3-Cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;

[0424] (S)-N-((1S*,3S*)-3-Cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;

[0425] (S)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocydopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0426] (S)-N-((1 R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;

[0427] (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;

[0428] (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)-1 -tosylpyrrolidine-2-carboxamide; (S)-N -(benzo[d]th iazol-5-y I methy l)-N-((3R, 5s)- 1 , 1 -dif I uorospi ro[2.3]hexan-5-yl)-1 -tosylpyrrolidine-2-carboxamide;

[0429] (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((3-fluoro-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;

[0430] (S)-N -(benzo[d]th iazol-5-y I methy l)-N-((3R, 5s)- 1 , 1 -dif I uorospi ro[2.3]hexan-5-yl)-1 -((3-fluoro-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;

[0431] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methyl-benzothiazol-5- ylmethyl)-amide;

[0432] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;

[0433] (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4- difluoro-cyclohexyl)-amide;

[0434] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;

[0435] (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide;

[0436] (S)-N-(benzo[d]th i azol-5-y I methy l)-N -((3R, 5s)- 1 , 1 -dif I uorospi ro[2 ,3]hexan-5-yl)-1 -((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; and

[0437] (1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1 ,0]hexane-2- carboxamide.

[0438] 24) Further compounds according to embodiment 1) are selected from the following compounds: (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1 -((R)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;

[0439] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1 -((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine- 2-carboxamide;

[0440] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0441] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0442] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0443] (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)- bicyclo[4.1 ,0]hept-3-yl-amide;

[0444] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3- yl-amide; (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 S,3R,6S)-bicyclo[4.1.0]hept-3- yl-amide;

[0445] (S)-1 -(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzoth iazol-5-y I methyl-( 1 S,3S,6S)- bicyclo[4.1.0]hept-3-yl-amide;

[0446] (S)-1 -(4-lodo-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cydohexyl)-amide;

[0447] (S)-1 -(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro- cyclohexyl)-amide;

[0448] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0449] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 , 1-difluorospiro[2.3]hexan-5-yl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0450] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0451] (S)-1-(4-Ethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide;

[0452] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1 S,3S,6S)-bicyclo[4.1.0]heptan-3-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0453] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicydo[4.1.0]heptan-3-yl)-1 -((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0454] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicydo[4.1.0]heptan-3-yl)-1 -((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0455] (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0456] (1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothi azol-5-y I methy l-( 1 , 1 - difluoro-spiro[2.5]oct-6-yl)-amide;

[0457] (1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothi azol-5-y I methy l-( 1 , 1 - difluoro-spiro[2.3]hex-5-yl)-amide;

[0458] (1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2- methyl-benzothiazol-5-ylmethyl)-amide;

[0459] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;

[0460] (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4- difluoro-cydohexyl)-amide;

[0461] (S)-1 -(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(3-methoxy-cydohexyl)-amide;

[0462] (S)-1 -(3-Fluoro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide; (S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0463] (S)-N-((2-Bromobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0464] (S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0465] (S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0466] (S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;

[0467] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(6-methyl-1 ,1 -dioxo-hexahydro-1 X6- thiopyran-3-yl)-amide;

[0468] (S)-1 -(T ol uene-4-su lfonyl)-py rrol idi ne-2-carboxy I ic acid (4-ch loro-benzy l)-( 1 , 1 -dioxo-hexahydro-1 X6-thiopy ran-3- yl)-amide;

[0469] (1S*,2S*,5R*)-3-(Toluene-4-sulfonyl)-3-azabicydo[3.2.0]heptane-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;

[0470] (1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;

[0471] (1 R*,2S*,5S*)-N-Benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide; and

[0472] (1 R,2S,5S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-((R)-N,4-dimethylphenylsulfonimidoyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide.

[0473] The compounds of Formula (I) according to embodiments 1) to 24) 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).

[0474] 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.

[0475] The present invention also relates to a method for the prevention / 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 24). For avoidance of any doubt, if compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.

[0476] The compounds of Formula (I) according to any one of embodiments 1) to 24) are useful for the prevention / prophylaxis or treatment of diseases or disorders relating to the 0X2R receptor, and notably in disease and disorders in which agonism of 0X2R plays a role. Disease and disorders in which agonism of 0X2R 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).

[0477] Thus, the compounds of Formula (I) according to embodiments 1) to 24) are useful for improving wakefulness in a subject (especially in a subject having hypersomnia or narcolepsy, or presenting excessive daytime sleepiness (EDS)).

[0478] The term “improving wakefulness in a subject” refers to improving symptoms of, or to the prevention / prophylaxis or treatment of:

[0479] • hypersomnia, particularly prevention / prophylaxis or treatment of:

[0480] • narcolepsy; including especially narcolepsy type 1 and narcolepsy type 2;

[0481] • secondary narcolepsy associated with inherited disorders (such as Prader-Willi syndrome, Niemann- Pick C disease, or myotonic dystrophy);

[0482] • secondary narcolepsy associated with tumors, especially symptoms of narcolepsy associated with tumors that involve the hypothalamus area;

[0483] • secondary narcolepsy associated with head trauma, especially symptoms of narcolepsy associated with head trauma affecting the hypothalamic area;

[0484] • idiopathic hypersomnia; or

[0485] • Kleine-Levin syndrome;

[0486] • excessive daytime sleepiness (EDS), particularly:

[0487] • 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; • 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:

[0488] ■ Improving symptoms of EDS associated with objective sleep disturbances (notably sleep apnea);

[0489] ■ improving symptoms of EDS associated with obesity and / or diabetes;

[0490] ■ 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;

[0491] ■ improving symptoms reminiscent of narcolepsy in subjects having an auto-immune disorder (especially neuromyelitis optica, multiple sclerosis, Guillain-Barre syndrome, or anti-Ma2 encephalitis);

[0492] ■ improving symptoms of EDS / treatment of hypersomnia associated with a psychiatric disorder, such as depression; or

[0493] ■ improving symptoms of EDS / treatment of hypersomnia associated with insufficient sleep syndrome; or

[0494] • improving symptoms of EDS / treatment of hypersomnia due to a medication or substance; or

[0495] • fatigue (especially including chronic fatigue), particularly:

[0496] • fatigue accompanied by mental fatigue with poor concentration and memory;

[0497] • fatigue associated with infections (viral or bacterial), chronic inflammatory diseases, cancer, or neurodegeneration; or

[0498] • fatigue associated with autoimmune disease primary Sjogren's syndrome.

[0499] The term “narcolepsy type 1” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep disruption and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions).

[0500] The term “narcolepsy type 2” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep disruption and without cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions).

[0501] Fatigue is characterized by a lack of energy ("an overwhelming sense of tiredness, a feeling of exhaustion").

[0502] Further disease and disorders in which agonism of OX2R plays a role include: eating disorders; obesity, particularly obesity in narcoleptic subjects; attention deficit disorders; • neuropsychiatric disorders, notably mood disorders, particularly depression (such as major depressive disorder (MDD));

[0503] • pain, particularly inflammatory pain, or chronic neuropathic pain;

[0504] • inflammation, particularly inflammation following cardiac arrest, intracerebral hemorrhage, or septic shock; and

[0505] • cognitive impairments, particularly age-related deficits in learning and memory or cognitive impairments due to sleep loss.

[0506] Additionally, agonism of OX2R plays a role in:

[0507] • disorders of consciousness, notably coma, vegetative state and minimally conscious state induced by traumatic brain injury;

[0508] • recovery of arousal following unconsciousness associated with cardiac arrest or acute alcohol intoxication, or following anesthetic-induced unconsciousness.

[0509] It is to be understood that in the context of using compounds of Formula (I) according to embodiments 1) to 24) for improving wakefulness in a subject (especially in a subject having hypersomnia or narcolepsy, or presenting excessive daytime sleepiness (EDS)), other symptoms or disease characteristics of that subject may be concurrently improved. For example, in the context of using compounds of Formula (I) according to embodiments 1) to 24) for improving symptoms of EDS due to or associated with diabetes, other symptoms or disease characteristics of that subject may be concurrently improved, e.g., in addition to improving wakefulness in a diabetic subject, diabetic parameters may be improved.

[0510] 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.

[0511] The compounds of Formula (I) according to any one of embodiments 1) to 24) are in particular useful as therapeutic agents for the prevention / 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 Maski K. et al. J Clin Sleep Med. 2021, 17(9), 1881-1893; Bassetti C. et al. Eur J Neurol. 2021, 00, 1-16).

[0512] The invention, thus, also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material, and:

[0513] • a compound of Formula (I) according to any one of embodiments 1) to 24);

[0514] • and one or more additional therapeutic agents.

[0515] The invention, thus, further relates to a kit comprising • a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and:

[0516] • a compound of Formula (I) according to any one of embodiments 1) to 24);

[0517] • and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).

[0518] 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).

[0519] 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 bioavailability 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.

[0520] 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, R3, R4, RB1, X1, X2, X3, 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, R3, R4, RB1, X1, X2and X3might 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.

[0521] Compound 11 , belonging to Formula (I) wherein X2=O and X3= 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 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 or similar and a base such as DIPEA, TEA or N-methylmorpholine (Scheme 1). 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 in solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DI PEA to give 11. Alternatively, an amino acid with structure 7 can be reacted with a sulfonyl chloride 6 in a solvent mixture such as DMF / Water and an inorganic base such as NaHCOs to give 10. Acid 10 can be converted into compound with structure 11 either 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 (or similar) and a base such as DIPEA, TEA or N-methylmorpholine or by conversion of 10 into its corresponding acid chloride by reaction with a reagent such as oxalyl chloride and DMF or thionyl chloride in a solvent such as toluene followed by condensation with 3 (or the corresponding salt, like HCI or TFA salts) in a solvent such as DCM and in presence of an organic base as TEA or DIPEA. Compounds having structure 10 can alternatively be prepared by sulfonamide formation from ester 8 with sulfonyl chloride 6 in a solvent such as DCM, DMF, MeCN and in presence of a base as TEA or DIPEA, followed by ester hydrolysis using a base such as LiOH or NaOH in a mixture of solvents such as THF / Water. Compounds with structure 2, 6, 7 and 8 are either commercially available or prepared as described in the literature.

[0522]

[0523] Scheme 1 . Synthesis of sulfonamide compound 11

[0524] Amines of structure 3 can be synthesized by reductive amination reaction between an aldehyde or a ketone (12 or 15) and a primary amine such as 13 or 14 (or the corresponding salt, like HCI or TFA salts) as described in the Scheme 2 using a solvent such as MeOH or THF and in presence of a reducing agent such as NaBF , NaBHsCN or Na(AcO)3BH. Starting materials 12, 13, 14 and 15 are either commercially available or prepared from commercially available reagents using conventional reactions well known in the art. Alternatively, amine with structure 3 can be prepared by SN2 reaction between primary amines 16 or 19 (or the corresponding salt, like HCI or TFA salts) and 17 or 18 (where LG is either a halide, OMs, OTs, OTf or any appropriate leaving group) in a solvent such as MeCN and in presence of a base as K2CO3. In an other aspect, amine 3, wherein R2= H, can be prepared by Suzuki-Miyaura cross-coupling between an organotrifluoroborate (21) and an alkyl bromide (22) as described by Molander ef al. (Chemistry, 2012, 18(31), 9564-70) in presence of a catalyst such as P(tBu)sPd G2 and a base such as CS2CO3 in a solvent mixture such as THF / Water. Organotrifluoroborate 21 can be prepared as described in the literature by reaction between 16 (or the corresponding salt, like HCI or TFA salts) and potassium bromotrifluoroborate 20 in a solvent mixture such as THF / t-BuOH.

[0525] H2N R2°^1+ T

[0526] Scheme 2. Synthesis of amines with general structure 3

[0527] Sulfonimidamide (SIA) compounds with structure 31, belonging to Formula (I) wherein X2= NR4and X3= N can be prepared as described in Scheme 3. A commercially available arylthiol 23 can be oxidized into its corresponding sulfinate ester 24 by reaction with NBS and MeOH in a solvent such as DCM. Sulfinate ester 24 can be converted into sulfinamide with general structure 25 by reaction with LiHMDS in a solvent like THF and hydrolysis with sat. aq. NH4CI. The resulting sulfinamide can be protected with an appropriate protecting group (PG) to yield 26 using standard protection methods known in the literature and familiar to the person skilled in the art. Compound 26 can be condensed with 8 in presence of a chlorinating agent such as tert-butyl hypochlorite or W-chlorosuccinimide in a solvent such as DCM or 1,2-dichloroethane to give SIA intermediate 27. The ester functional group can be hydrolysed into the corresponding carboxylic acid (28) in presence of aq. LiOH soln, and a solvent such as THF. Subsequent amide coupling between 28 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 (or similar) and a base such as DIPEA, TEA or N-methylmorpholine yields 29. Protecting group cleavage using standard protection methods known in the literature and familiar to the person skilled in the art leads to derivative 30. Alkylation of 30 can be performed with a base such as NaH or KOtBu and an alkyl halide as alkylating agent to obtain 31. If not commercially available, arylthiol 23 can be prepared with methodologies described in the literature or as described here below in the experimental part.

[0528] Alternatively, the -NR4group can be introduced in an early stage by condensation between primary amine 32 (or the corresponding salt, like HCI or TFA salts) and 24 using a base as n-BuLi in THF to yield sulfinamide 33. SIA formation between 33 and 5 using similar conditions as described herein before yields final compounds 31. Diastereomers can be separated either by prep HPLC, flash chromatography (FC) or chiral SFC chromatography at the final step (31) or at the level of 27, 29 or 30.

[0529]

[0530] Scheme 3. Synthesis of SIA compound 31

[0531] Sulfone compounds with structure 38, belonging to Formula (I) wherein X2= 0 and X3= C can be prepared as described in Scheme 4. Michael addition between arylthiol 23 and commercially available a,p-unsaturated ester 34 in a solvent such as piperidine yields racemic thioether 35. Intermediate 35 can be oxidized in presence of an oxidant such as MCPBA and in a solvent such as DCM to lead to sulfone 36. Derivative 36 can be hydrolysed using standard methods as described herein before into its corresponding carboxylic acid 37. Subsequent amide coupling between 37 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 38.

[0532]

[0533] Scheme 4. Synthesis of sulfone compound 38

[0534] Sulfoximine compounds with structure 45, belonging to Formula (I) wherein X2=NH and X3= C can be prepared as described in Scheme 5. Compound 35 can be hydrolysed into 43 using a base such as LiOH in a solvent mixture as H2O / THF. Amide coupling between acid 43 and 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 (or similar) and a base such as DI PEA, TEA or N-methylmorpholine gives 44. Thioether 44 is treated with an oxidant such as iodobenzene diacetate and ammonium carbamate in a solvent like MeOH to yield sulfoximine 45. Alternatively, 35 can be oxidized in the first step using hydrogen peroxide in a solvent as hexafluoro-2-propanol to yield 39. Sulfoxide 39 can be treated with iodobenzene diacetate and magnesium peroxide in presence of tert-butyl carbamate and rhodium (II) acetate in a solvent such as DCM to give Boc-protected sulfoximine 40. Ester 40 can be hydrolysed as described herein before to yield carboxylic acid 41. Amide coupling between 41 and amine 3 (or the corresponding salt, like HCI or TFA salts) in a similar way as described in this paragraph can yield to Boc- protected intermediate 42. Deprotection of the Boc protecting group can be performed in a presence of an acid such as HCI or TFA and in a solvent such as 1 ,4-dioxane to lead to desired product 45. Generated diastereomers (40, 41, 42 or 45) can be separated either by prep HPLC, Flash chromatography or chiral SFC chromatography.

[0535]

[0536] Scheme 5. Synthesis of sulfoximine compound 45

[0537] Experimental Part

[0538] Abbrevations (as used herein and in the description above): Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)

[0539] AcOH Acetic acid

[0540] Al BN 2,2'-Azobis(2-methylpropionitrile) anh. Anhydrous aq. aqueous atm Atmosphere tBME tert-Butylmethylether

[0541] Boc tert-Butoxycarbonyl

[0542] BOC2O di-fert-Butyl dicarbonate tBuOCI tert-Buthyl hypochlorite BSA Bovine serum albumine

[0543] Bu Butyl such as in tBu = tert-butyl = tertiary butyl cone. Concentrated

[0544] DCE 1,2-Dichloroethane

[0545] DCM Dichloromethane

[0546] DEA Diethylamine

[0547] DI PEA Diisopropylethylamine

[0548] DME Dimethoxyethane

[0549] DMEM Dulbecco’s modified eagle medium

[0550] DMF W,W-Dimethylformamide

[0551] DMSO Dimethyl sulfoxide dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene

[0552] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0553] ELSD Evaporative Light-Scattering Detection eq Equivalent(s)

[0554] ES Electron spray

[0555] Et Ethyl

[0556] Etl Ethyl Iodide

[0557] Et2O Diethyl ether

[0558] EtOAc Ethyl acetate

[0559] EtOH Ethanol

[0560] Ex. Example

[0561] FBS Fetal bovine serum

[0562] FC Flash Chromatography on silica gel

[0563] FCS Foatal calf serum h Hour(s)

[0564] HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0565] HBSS Hank’s balanced salt solution

[0566] HBTU 2-(1 H-benzotriazol-1-yl)-1 ,1,3,3-tetramethyluronium hexafluorophosphate

[0567] HEK293 Human embryonic kidney 293 cells

[0568] HEPES 4-(2-Hydroxyethyl)-piperazine-1 -ethanesulfonic acid

[0569] Hept Heptane

[0570] 1H-NMR Nuclear magnetic resonance of the proton

[0571] HPLC High performance liquid chromatography HTRF Homogeneous Time Resolved Fluorescence

[0572] IP1 Intracellular inositol-1 -phosphate

[0573] LC-MS Liquid chromatography - Mass Spectroscopy

[0574] □HMDS Lithium hexamethyldisilazide

[0575] Lit. Literature

[0576] LG Leaving group

[0577] M Exact mass (as used for LC-MS)

[0578] M Molarity [mol E1]

[0579] MCPBA 3-Chloroperbenzoic acid

[0580] Me Methyl

[0581] MeCN Acetonitrile

[0582] MeOH Methanol

[0583] Mel Methyl iodide

[0584] MHz Megahertz il Microliter p.m Micrometer min Minute(s)

[0585] MS Mass spectroscopy

[0586] Ms Mesyl such as OMs

[0587] N Normality

[0588] NaH Sodium hydride

[0589] NMP N-Methyl-2-pyrrolidone

[0590] Pd(OAc)2 Palladium diacetate

[0591] Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)

[0592] PG Protecting group

[0593] PL-HCO3 Polymer supported hydrogen carbonate

[0594] Ph Phenyl

[0595] Prep Preparative

[0596] PTFE Polytetrafluoroethylene

[0597] PyCloP Chlorotripyrrolidinophosphonium hexafluorophosphate

[0598] PyrSO3Sulfur trioxide pyridine complex

[0599] Rf Retention factor rac racemic or racemate rt Room temperature sat. aq. saturated aqueous SIA Sulfonimidamide compound(s)

[0600] SFC Supercritical fluid chromatography soln. Solution

[0601] TBME fert-Butyl methyl ether

[0602] TBTU 2-(1 H-Benzotriazole-1 -yl)-1 , 1 ,3,3-tetramethylaminium tetrafluoroborate fBu fert-Butyl

[0603] TEA Triethylamine

[0604] Tf Triflate such as OTf

[0605] TFA Trifluoroacetic acid

[0606] THF Tetrahydrofuran tRRetention time

[0607] Ts Tosyl such as OTs

[0608] UPLC Ultra performance liquid chromatography

[0609] I. Chemistry

[0610] 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. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time tRis given in min; molecular weight obtained from the mass spectrum is given in g / mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC- MS spectra, the retention time of the most abundant conformer is given. Racemates can be separated into their enantiomers by preparative HPLC or SFC

[0611] LC-MS conditions

[0612] LC-MS (1)

[0613] 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 p.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 tRis given in min.

[0614] LC-MS (2) LC-MS- conditions: Analytical UPLC on a Agilent Zorbax RRHD SB-Aq (2.1x50mm, 1.8 p.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):

[0615] LC-MS (3)

[0616] LC-MS- conditions: Analytical UPLC on a Waters BEH C18 (2.1x50 mm, 2.5 p.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):

[0617] Preparative LC-MS methods used:

[0618] Preparative HPLC / MS purifications (prep. HPLC) 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 conditions) or water / ammonia 0.02% (A) and MeCN (B) (basic prep. HPLC conditions).

[0619] Preparative chiral SFC methods used:

[0620] Preparative chiral SFC purifications were performed on a Sepiatec Prep SFC 360 system. Following parameters were used:

[0621] Preparative chiral SFC 1: A ChiralPak AD-H column (30 x 250mm, 5um) was used. The modifier was MeCN / MeOH 1 :1 , run for 4 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 Preparative chiral SFC 2'. A ChiralCel OZ-H column (30 x 250mm, 5um) was used. The modifier was EtOH / MeCN 1 :1 , run for 4 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 4 °C, temperature fraction module 20 °C, and temperature column department 40 °C.

[0622] Preparative chiral SFC 3: A ChiralPak IC column (30 x 250 mm, 5 p.m) was used. The modifier was EtOH (25%), run for 4.5 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.

[0623] Preparative chiral SFC 4: A ChiralPak AD-H column (30 x 250 mm, 5 p.m) was used. The modifier was EtOH (25%), run for 4:45 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.

[0624] Preparative chiral SFC 5'. A ChiralPak IB column (30 x 250 mm, 5 p.m) was used. The modifier was MeCN / EtOH / DEA 50:50:0.1 (20%), run for 6.94 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.

[0625] Preparative chiral SFC 6: A ChiralPak IE column (30 x 250 mm, 5 p.m) was used. The modifier was MeCN / EtOH / DEA 50:50:0.1 (45%), run for 5.62 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.

[0626] Preparative chiral SFC 7: A ChiralPak AZ-H column (30 x 250 mm, 5 p.m) was used. The modifier was MeOH (10%), run for 6 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.

[0627] Preparative chiral SFC 8: A ChiralPak ID column (30 x 250 mm, 5 p.m) was used. The modifier was AcCN / EtOH 1 :1 (45%), run for 6 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.

[0628] Preparative chiral SFC 9'. A ChiralPak ID column (30 x 250 mm, 5 p.m) was used. The modifier was AcCN / EtOH 1 :1 (35%), run for 6 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.

[0629] Preparative chiral SFC 10'. A ChiralPak ID column (30 x 250 mm, 5 p.m) was used. The modifier was AcCN / EtOH 1 :1 (50%), run for 6 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

[0630] FC (Flash Chromatography) was performed using a combiflash from Teledyne ISCO.

[0631] Phase-separator

[0632] Phase separator cartriges used were Isolute® purchased from Biotage

[0633] Solid Phase Extraction

[0634] Ion exchange was performed using cationic exchange sorbent (Isolute® SXC) purchased from Biotage.

[0635] Preparation of Examples:

[0636] Methods for the preparation of sulfonamides compounds (Examples 1.x)

[0637] Example 1.1 : (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (1,1-dioxo-hexahydro-l6-thiopyran- 4-yl)-(4-fluoro-benzyl)-amide:

[0638] 4-((4-Fluorobenzyl)amino)tetrahydro-2H-thiopyran 1 ,1-dioxide: A soln, of 4-aminotetrahydro-2H-thiopyran 1,1- dioxide hydrochloride (2500 mg, 13.2 mmol, 1 eq) and TEA (3.67 mL, 26.4 mmol, 2 eq) in DMF / THF 1 :1 (80 mL) was stirred at rt under nitrogen atmosphere. 4-Fluorobenzaldehyde (1.45 mL, 13.2 mmol, 1 eq) and AcOH (1.51 mL, 26.4 mmol, 2 eq) were added and stirred at rt for 1 h. Sodium triacetoxyborohydride (6639 mg, 39.6 mmol, 3 eq) was then added portionwise. The reaction mixture was stirred overnight at rt. Water and aq. 2M HCI. were added and the mixture was washed with EtOAc. The aq. layer was basified with aq. 1 M NaOH and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to DCM / MeOH 99:1) to give the title compound (1059 mg, 47%) as a white solid. LC-MS (2): tR= 0.43 min; [M+H]+: 257.97.

[0639] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (1,1-dioxo-hexahydro-16-thiopyran-4-yl)-(4-fluoro- benzyl)-amide: A soln, of tosyl-L-proline (700 mg, 2.57 mmol), 4-((4-fluorobenzyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide, HATU (1468 mg, 3.86 mmol) and DIPEA (1.87 mL, 10.9 mmol) in DMF (25 mL) was stirred at rt overnight. HATU (294 mg, 0.772 mmol) was added again and the soln, stirred for 2 supplementary hours. Aq. 2M HCI soln, was added and the mixture extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound (855 mg, 65%) as a white solid. LC-MS (1): tR= 1.025 min; [M+H]+: 509.3.

[0640] Example 1.2: (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-5-ylmethyl-(1,1-dioxo- hexahydro-1X6-thiopyran-4-yl)-amide

[0641] 4-((Benzofuran-5-ylmethyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide: A soln, of 4-aminotetrahydro-2H- thiopyran 1 ,1-dioxide (1500 mg, 9.55 mmol) and TEA (1.33 mL, 9.55 mmol) in DMF / THF 1 :1 (45 mL) was stirred at rt under nitrogen. 1-Benzofuran-5-carbaldehyde (1424 mg, 9.55 mmol) and AcOH (1.09 mL, 19.1 mmol) were added. After 1h sodium triacetoxyborohydride (4173 mg, 19.1 mmol) was added portionwise. The reaction mixture was stirred overnight at it Aq. 2M HCI soln, was added and the mixture extracted with EtOAc. The organic layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to DCM / MeOH 99:1) to give the title compound (1587 mg, 59%) as a yellow solid. LC-MS (2): tR= 0.49 min; [M+H]+: 280.19.

[0642] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-5-ylmethyl-(1,1-dioxo-hexahydro-1X6- thiopyran-4-yl)-amide: The product was synthesized as described in Example 1.1 using 4-((benzofuran-5- ylmethyl)amino)tetrahydro-2H-thiopyran 1 ,1 -dioxide and N-tosyl-L-proline to give the title compound as a white solid. LC-MS (1): tR= 1.036 min; [M+H]+: 531.3.

[0643] Example 1.3: (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)- amide:

[0644] N-benzyl-4,4-dimethylcyclohexan-1-amine hydrochloride: At rt, to a soln, of 4,4-dimethylcyclohexan-1-amine (23 mg, 0.18 mmol) and DIPEA (31.4 iL, 0.18 mmol) in MeOH (0.550 mL) was added a soln, of benzaldehyde (15.5 p.L, 0.15 mmol) in MeOH (0.1 mL) and the solution was stirred at rt for 4h. NaBH4 (7.50 mg, 0.197 mmol) was added and the mixture was stirred at rt overnight. Aq. 2M HCI was added and the mixture was washed with EtOAc. The aq. layer was basified with sat. aq. NaHCOs and extracted with EtOAc. A 1.25 M soln, of HCI in MeOH (0.500 mL) was added and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS (2): tR= 0.57 min; [M+H]+: 226.18.

[0645] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: Was synthesized as described in Example 1.1 using N-benzyl-4,4-dimethylcyclohexan-1-amine hydrochloride salt and N-tosyl-L-proline to give the title compound as a white solid. LC-MS (1): tR= 1.437 min; [M+H]+: 469.2.

[0646] Example 1.4 to Example 1.23 were synthesized using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone as described in Example 1.3. LC-MS data of Example 1.4 to Example 1.23 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0647] Example 1.24: (S)-N-((RS)-1-(4-chlorophenyl)ethyl)-N-(4,4-difluorocyclohexyl)-1-tosylpyrrolidine-2- carboxamide Tosyl-L-prolinoyl chloride: To a suspension of tosyl-L-proline (3.00 g, 11.1 mmol, 1 eq) in toluene (78 mL) was added oxalyl chloride (2.68 mL, 30.4 mmol, 2.733 eq) and DMF (0.028 mL). The reaction was stirred for 1h at room temperature. The reaction mixture was evaporated under reduced pressure to give the title compound (2.90 g, 91 %) as an off-white solid.

[0648] N-(1-(4-Chlorophenyl)ethyl)-4,4-difluorocyclohexan-1-amine: A mixture of rac-4-chloro-alpha- methylbenzylamine (125 mg, 0.798 mmol), 4,4-difluorocyclohexan-1-one (160 mg, 1.2 mmol), AcOH (0.167 mL, 1.2 mmol) and sodium triacetoxyborohydride 97% (534 mg, 2.39 mmol) in THF (4.00 mL) was stirred at rt overnight. The reaction mixture was partitioned between aq. 1 M HCI and EtOAc. The layers were separated and the aq. layer was basified with solid NaHCCL and extracted with EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil. LC- MS (2): tR= 0.70 min; [M+H]+: 274.08.

[0649] (S)-N-((RS)-1-(4-Chlorophenyl)ethyl)-N-(4,4-difluorocyclohexyl)-1-tosylpyrrolidine-2-carboxamide: A solution of tosyl-L-prolinoyl chloride (35.7 mg, 0.124 mmol, 1 eq), N-(1-(4-chlorophenyl)ethyl)-4,4- difluorocydohexan-1 -amine (33.9 mg, 0.124 mmol, 1 eq) and DIPEA (0.0499 mL, 0.291 mmol, 2.35 eq) in DCM (1 .2 mL) was stirred at rt over 3 days. The reaction mixture was washed with brine. The organic layer was separated through a phase-separator cartridge and concentrated under reduced pressure. The crude residue was purified by prep. HPLC to give the title compound as a white solid. LC-MS (1): tR= 1.365 min; [M+H]+: 525.3.

[0650] Example 1.25 to Example 1.32 were synthesized using the appropriate amine or amine salt derivative and the appropriate aldehyde or ketone as described in Example 1.3. LC-MS data of Example 1.25 to Example 1.32 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0651] Example 1.33 (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl-(4,4-dimethyl- cyclohexyl)-amide: tert-Butyl (2S,4S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate: tert-Butyl

[0652] (25.45)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidine-1 -carboxylate ( 48 mg, 0.2 mmol, 1 eq) was dissolved in DMF (1.00 mL). HATU (80 mg, 0.21 mmol, 1.05 eq) and DIPEA (0.11 mL, 0.6 mmol, 3 eq) were added followed after 15 min by N-benzyl-4,4-dimethylcyclohexan-1 -amine (45 mg, 0.2 mmol, 1 eq). The reaction was stirred at rt overnight. The mixture was purified by prep. HPLC to give the title compound (78 mg, 90%). LC- MS (2): tR= 1.11 min; [M+H]+: 434.13.

[0653] (25.45)-N-Benzyl-N-(4,4-dimethylcyclohexyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride: tert-Butyl

[0654] (25.45)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (77.9 mg, 0.18 mmol, 1.00 eq) was dissolved in DCM (6.00 mL). 4M HCI in 1 ,4-dioxane (3.00 mL) was added and the mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give the title compound (66.3 mg, 100%) as a yellow solid. LC-MS (2): tR= 0.79 min; [M+H]+: 333.36.

[0655] (25.45)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)- amide: To a soln, of (2S,4S)-N-benzyl-N-(4,4-dimethylcyclohexyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (66.3 mg, 0.18 mmol, 1.00 eq) in DCM (2 mL) at 0°C was added TEA (0.052 mL, 0.38 mmol, 2.1 eq) followed by p-toluenesulfonyl chloride (38.5 mg, 0.20 mmol, 1.1 eq), and the mixture was stirred at rt overnight. The mixture was purified by prep. HPLC to give the title compound (68 mg, 78%) as a white solid. LC-MS (1): tR= 1.388 min; [M+H]+: 487.3.

[0656] Example 1.34 to Example 1.42 were synthesized using the appropriate amine or amine salt derivative and the appropriate aldehyde or ketone as described in Example 1 .3. LC-MS data of Example 1 .34 to Example 1 .42 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0657] Example 1.43 (1 R*,5S*)-(2RS)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzyl- (4,4-dimethyl-cyclohexyl)-amide:

[0658] (1R*,5S*)-(2RS)-3-Tosyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid: Asoln. of cis-3-azabicyclo[3.1 0]hexane- 2-carboxylic acid (90 mg, 0.708 mmol, 1 eq) in sat. aq. NaHCOs (4.00 mL) and DMF (4.00 mL) was cooled to 0°C and p-toluenesulfonyl chloride (207 mg, 1 .06 mmol, 1 .5 eq) was added at 0°C. The mixture was then warmed to rt and stirred for 17h. DMF was removed under reduced pressure. The residue was acidified with aq. 1 M HCI and extracted with DCM. The combined organic layers were washed with water, dried over MgSC , filtered, and concentrated under reduced pressure to give the title compound (192 mg, 96%) as a white solid. LC-MS (2): IR= 0.76 min; [M+H]+: 282.16.

[0659] (1R*,5S*)-(2RS)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzyl-(4,4-dimethyl- cyclohexyl)-amide: Was synthesized as described in Example 1.1 using N-benzyl-4,4-dimethylcyclohexan-1- amine hydrochloride and (1 R*,5S*)-(2RS)-3-tosyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give the title compound as a white solid. LC-MS (1): IR= 1.456 min; [M+H]+: 481.4. Example 1.44 to Example 1.46 were synthesized using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate carboxylic acid as described in Example 1 .33. LC-MS data of Example 1.44 to Example 1.46 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0660] Example 1.47 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide:

[0661] 5-(Bromomethyl)benzo[d]oxazole: To a soln, of 5-methylbenzoxazole (1000 mg, 7.47 mmol, 1 eq) and N- bromosuccinimide (1729 mg, 9.71 mmol, 1.3 eq) in bromobenzene (20 mL) was added AIBN (25 mg, 0.149 mmol, 0.02 eq) and the soln, was stirred at 90°C for 16h. The reaction mixture was concentrated. The residue was purified by FC (Hept to Hept / EtOAc 9:1) to give the title compound (0.785 g, 50%) as a yellow solid. Rf(Hept / EtOAc)= 0.55. LC-MS (2): tR= 0.78 min; [M+H]+: 212.04.

[0662] N-(Benzo[d]oxazol-5-ylmethyl)-4,4-difluorocyclohexan-1-amine: 4,4-Difluoro-cyclohexylamine hydrochloride (2455 mg, 13.9 mmol, 1 eq) and potassium carbonate (4843 mg, 34.7 mmol, 2.5 eq) were suspended in MeCN (100 mL) and the resulting beige suspension was stirred at rt. 5-(Bromomethyl)benzo[d]oxazole (2942 mg, 13.9 mmol, 1 eq) in MeCN (40 mL) was then added and the reaction mixture was stirred at rt for 20h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by FC (Hept to Hept / (EtOAc + 2% EtsN) 6:4) to give the title compound (3.037 g, 79%) as a pale yellow oil that solidified upon standing. LC-MS (3): tR= 0.78 min; [M+H]+: 267.20.

[0663] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide: N-(Benzo[d]oxazol-5-ylmethyl)-4,4-difluorocyclohexan-1-amine (205 mg, 0.77 mmol, 1 eq) was dissolved in DMF (7 mL) and DI PEA (0.329 mL, 1 .92 mmol, 2.5 eq) followed by tosyl-L-prolinoyl chloride (233 mg, 0.77 mmol, 1 eq). The resulting pale yellow solution was stirred at rt for 3.5 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (357 mg, 90%) as a white solid. Rf (Hept / EtOAc 2:8)= 0.50. LC-MS (1): tR= 1.133 min; [M+H]+: 518.2.

[0664] Example 1.48 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide: N-(Benzo[d]oxazol-5-ylmethyl)-4,4-dimethylcyclohexan-1-amine: Was synthesized using 4,4- dimethylcyclohexan-1 -amine and 5-(bromomethyl)benzo[d]oxazole as described in Example 1.47 to give the title compound as an orange oil. LC-MS (2): IR = 0.66 min; [M+H]+: 259.32.

[0665] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl-cyclohexyl)- amide: Was synthesized using N-(benzo[d]oxazol-5-ylmethyl)-4,4-dimethylcyclohexan-1-amine and N-tosyl-L- proline as described in Example 1.1 to give the title compound as a white solid. LC-MS (1): IR = 1.314 min; [M+H]+: 510.2.

[0666] Example 1.49 to Example 1.51 were synthesized using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, N-toluenesulfonyl-L-proline as described in Example 1.33. LC-MS data of Example 1.49 to Example 1.51 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0667] Example 1.52 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide:

[0668] Benzofuran-6-ylmethanol: Ethyl chloroformate (0.179 mL, 1.82 mmol, 1 eq) was added dropwise to the iced- cooled soln, of benzofuran-6-carboxylic acid (301 mg, 1.82 mmol, 1 eq) and TEA (0.297 mL, 2.09 mmol, 1.15 eq) in THF (7.3 mL). The resulting soln, was stirred at 0 °C for 1 h. A soln, of sodium borohydride (206 mg, 5.45 mmol, 3 eq) in water (2.90 mL) was added dropwise at 0 °C to the reaction mixture and stirring was continued at the same temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with aq. 1 M HCI, sat aq. NaHCOs and brine. The organic layer was 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 as a light yellow oil. LC-MS (2): IR = 0.64 min; mass not seen.

[0669] Benzofuran-6-carbaldehyde: A suspension of benzofuran-6-ylmethanol (140 mg, 0.841 mmol, 1 eq) and manganese(IV) oxide (activated, 185 mg, 2.1 mmol, 2.5 eq) in DCM (8.4 mL) was stirred at rt overnight. Manganese(IV) oxide (185 mg, 2.1 mmol, 2.5 eq) was added again to the mixture and stirring was continued at rt for 3h. The reaction mixture was filtered over a poly proply lene fritted cartridge and the solid was washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS (2): tR= 0.77 min; mass not seen.1H NMR (500 MHz, DMSO) 5: 10.07 (s, 1 H), 8.28 (d, J = 2.2 Hz, 1 H), 8.16 (m, 1 H), 7.87 (m, 1 H), 7.83 (m, 1 H), 7.13 (dd, Ji = 1.0 Hz, J2= 2.2 Hz, 1 H).

[0670] N-(Benzofuran-6-ylmethyl)-4,4-dimethylcyclohexan-1-amine: Was synthesized using benzofuran-6- carbaldehyde and 4,4-dimethylcyclohexan-1-amine as described in Example 1.1 to give the title compound. LC- MS (2): tR= 0.77 min; [M+H]+: 258.11.

[0671] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)- amide: Was synthesized using N-(benzofuran-6-ylmethyl)-4,4-dimethylcyclohexan-1 -amine and N-toluenesulfonyl- L-proline as described in Example 1.1 to give the title compound. LC-MS (1): tR= 1.441 min; [M+H]+: 509.4.

[0672] Example 1.53 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro- cyclohexyl)-amide:

[0673] N-(Benzofuran-6-ylmethyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using benzofuran-6- carbaldehyde and 4,4-difluorocydohexan-1-amine as described in Example 1 .1 to give the title compound. LC-MS (2): tR= 0.65 min; [M+H]+: 266.21.

[0674] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)- amide: Was synthesized using N-(benzofuran-6-ylmethyl)-4,4-difluorocyclohexan-1-amine and N-toluenesulfonyl- L-proline as described in Example 1.1 to give the title compound. LC-MS (1): tR= 1.265 min; [M+H]+: 517.2.

[0675] Example 1.54 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide:

[0676] N-(Benzo[d]thiazol-5-ylmethyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using 4,4- difluorocyclohexan-1 -amine and benzothiazole-5-carbaldehyde as described in Example 1.1 to give the title compound. LC-MS (2): tR= 0.56 min; [M+H]+: 283.23.

[0677] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide: Was synthesized using N-(benzo[d]thiazol-5-ylmethyl)-4,4-difluorocydohexan-1-amine and N- toluenesulfonyl-L-proline as described in Example 1.1 to give the title compound. LC-MS (1): tR= 1. 167 min; [M+H]+: 534.2.

[0678] Example 1.55 to Example 1.60 were synthesized using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, N-toluenesulfony l-L-prol i ne as described in Example 1.1. LC-MS data of Example 1.55 to Example 1.60 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0679] Example 1.61 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(tetrahydro- pyran-4-yl)-amide: Was synthesized using 4-aminotetrahydropyran, 5-(bromomethyl)benzo[d]oxazole and N- toluenesulfonyl-L-proline as described in Example 1.47. LC-MS (1): 1R= 0.965 min; [M+H]+: 484.2. Example 1.62 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(tetrahydro- pyran-4-yl)-amide: Was synthesized as described in Example 1.47 using 4-aminotetrahydropyran, 6- (bromomethyl)benzo[d]oxazole (US2006173183A1) and N-toluenesulfonyl-L-proline. LC-MS (1): IR = 0.946 min; [M+H]+: 484.3.

[0680] Examples 1.63 to Example 1.65 were synthesized as described in Example 1 .47 using the appropriate amine or amine salt derivative, 6-(bromomethyl)benzo[d]oxazole and N-toluenesulfonyl-L-proline. LC-MS data of Example 1.63 to Example 1.65 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0681] Example 1.66 (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4- difluoro-cyclohexyl)-amide: Was synthesized using the appropriate amine or amine salt to give the title compound as described in Example 1.33. LC-MS (1): IR = 1.291 min; [M+H]+: 529.2. Example 1.67 to Example 1.68 were synthesized as described in Example 1.1 using the appropriate amine or amine salt derivative and N-toluenesulfonyl-L-proline. LC-MS data of Example 1.67 to Example 1.68 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0682] Example 1.69 (2S)-N-(Benzofuran-6-ylmethyl)-N-(tetrahydro-2H-pyran-3-yl)-1-tosylpyrrolidine-2- carboxamide: Was synthesized using oxan-3-amine hydrochloride, benzofuran-6-carbaldehyde and N- toluenesulfonyl-L-proline as described in Example 1.53 to give the title compound as a white solid. LC-MS (1): tR= 1.154 min; [M+H]+: 483.2.

[0683] Example 1.70 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(1,1-dioxo- hexahydro-1X6-thiopyran-4-yl)-amide: was synthesized as described in Example 1.47 using 5- (bromomethyl)benzo[d]oxazole, 4-aminotetrahydro-2h-thiopyran 1,1 -dioxide and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (2): tR= 0.84 min; [M+H]+: 532.17.

[0684] Example 1.71 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (5-bromo-thiazol-2-ylmethyl)-(4,4- difluoro-cyclohexyl)-amide: Was synthesized as described in Example 1 .24 using 4,4-difluorocydohexylamine, 5-bromo-1,3-thiazole-2-carbaldehyde and tosyl-L-prolinoyl chloride to give the title compound as a white solid. LC- MS (1): tR= 1.257 min; [M+H]+: 562.2.

[0685] Example 1.72 (1 R*,5S*)-(2RS)-N-(Benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide:

[0686] N-(Benzo[d]oxazol-6-ylmethyl)-4,4-dimethylcyclohexan-1-amine: Was synthesized as described in Example 1.47 using 6-(bromomethyl)benzo[d]oxazole (US2006173183A1) and 4,4-dimethylcyclohexan-1-amine to give the title compound as a pale brown solid. LC-MS (2): tR= 0.67 min; [M+H]+: 259.33.

[0687] (1R*,5S*)-(2RS)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide: Was synthesized as described in Example 1.1 using N- (benzo[d]oxazol-6-ylmethyl)-4,4-dimethylcyclohexan-1-amine and (1 R*,5S*)-(2RS)-3-Tosyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid to give the title compound as a white solid. LC-MS (1): tR= 1.337 min;

[0688] [M+H]+: 522.3.

[0689] Example 1.73 (2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6- ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: Was synthesized as described in Example 1.33 using N- (benzo[d]oxazol-6-ylmethyl)-4,4-dimethylcyclohexan-1 -amine and N-boc-cis-4-fluoro-L-proline to give the title compound as a white solid. LC-MS (1): IR= 1.264 min; [M+H]+: 528.2.

[0690] Example 1.74 to Example 1.95 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone and the appropriate substituted proline or proline ester. LC-MS data of Example 1 .74 to Example 1.95 are listed in the table below.

[0691] Example 1.96 (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-dimethyl-cyclohexyl)- (4-methyl-benzyl)-amide:

[0692] Methyl ((4-methoxyphenyl)sulfonyl)-L-prolinate: To a soln, of L-proline methyl ester hydrochloride (607 mg, 3.56 mmol, 2.5 eq) and DIPEA (0.731 mL, 4.27 mmol, 3 eq) in MeCN (27.5 mL, 526 mmol, 369.9 eq) was added

[0693] 4-methoxybenzenesulfonyl chloride (300 mg, 1.42 mmol, 1 eq) at rt and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSC , filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 1 :1) to give the title compound (350 mg, 82%) as a yellow solid. LC-MS (2): IR= 0.82 min; [M+H]+: 300.24.

[0694] Lithium ((4-methoxyphenyl)sulfonyl)-L-prolinate: To a solution of methyl ((4-methoxyphenyl)sulfonyl)-L- prolinate (350 mg, 1.15 mmol, 1 eq) in THF (7.5 mL, 91.3 mmol, 79.23 eq) was added aq. 1 M LiOH soln. (1.44 mL, 1.44 mmol, 1.25 eq) and the resulting mixture was stirred at rt over 3 days. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to give the title compound (350 mg, 98%) as a white solid. LC-MS (2): tR= 0.69 min; [M+H]+: 286.21.

[0695] 4,4-Dimethyl-N-(4-methylbenzyl)cyclohexan-1-amine: Was synthesized using p-tolualdehyde and 4,4- dimethylcyclohexan-1 -amine as described in Example 1.3 to give the title compound as a colorless oil. LC-MS (2): tR= 0.75 min; [M+H]+: 232.35.

[0696] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-dimethyl-cyclohexyl)-(4-methyl- benzyl)-amide: A soln, of lithium ((4-methoxyphenyl)sulfonyl)-L-prolinate (20 mg, 0.0659 mmol, 1 eq), HATU (28.8 mg, 0.0758 mmol, 1.15 eq) and DI PEA (0.0339 mL, 0.198 mmol, 3 eq) in DMF (0.2mL) was stirred for 1 h at rt. 4,4- dimethyl-N-(4-methylbenzyl)cyclohexan-1-amine (0.0725 mmol, 1.1 eq) in DMF (0.2 mL) was added and the reaction mixture was stirred for 1h. The reaction mixture was purified by acidic prep. HPLC to give the title compound (20.5 mg, 62%) as an orange solid. LC-MS (1): tR= 1.444 min; [M+H]+: 499.2.

[0697] Examples 1.97 to Example 1.100 were synthesized using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone and lithium ((4-methoxyphenyl)sulfonyl)-L-prolinate following the procedure described in Example 1.96. LC-MS data of Example 1.97 to Example 1.100 are listed in the table below. The LC- MS conditions used were LC-MS (1).

[0698] Example 1.101 to Example 1.145 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, tosyl-L-prolinoyl chloride or the appropriate substituted proline or proline ester. LC-MS data of Example 1.101 to Example 1.145 are listed in the table below.

[0699] Example 1.146 (S)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-[3-(3- fluoro-oxetan-3-yl)-benzyl]-amide: 3-(3-(Diethoxymethyl)phenyl)oxetan-3-ol: To a soln, of 3-bromobenzaldehyde diethyl acetal (0.787 mL, 3.78 mmol, 1 eq) in THF (12 mL) cooled to -78°C was added under nitrogen n-butyllithium (1.6 M in hexanes, 2.84 mL, 4.54 mmol, 1.2 eq). The mixture was stirred at -78°C for 40 min. 3-Oxetanone (545 mg, 7.56 mmol, 2 eq) in THF (3 mL) was added dropwise and the reaction mixture was stirred at -78°C for 30 min. The mixture was allowed to warm up to rt and stirred for 30 min. The reaction mixture was quenched with sat. aq. NH4CI and extracted with EtOAc. The organic layer was washed twice with brine, dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (0.373 g, 39%) as a colorless glue.1H NMR (500 MHz, DMSO) 5: 7.64 (t, J = 1.6 Hz, 1 H), 7.58 (m, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.33 (m, 1 H), 6.38 (s, 1 H), 5.51 (s, 1 H), 4.78 (d, J = 6.8 Hz, 2 H), 4.66 (d, J = 6.8 Hz, 2 H), 3.53 (m, 4 H), 1.15 (t, J = 7.0 Hz, 6 H). LC-MS (2): tR= 0.77 min; [M+H]+: not seen.

[0700] 3-(3-Fluorooxetan-3-yl)benzaldehyde: Diethylaminosulfur trifluoride (0.121 mL, 0.892 mmol, 1.5 eq) was added at - 78°C to a stirred solution of 3-(3-(diethoxymethyl)phenyl)oxetan-3-ol in DCM (8.5 mL) and was stirred for 15 min. The reaction mixture was allowed to warm to 0 °C. Aq. 1 M NaOH was added carefully and extracted with DCM. The organic layer was separated and washed twice with brine. The organic layer was 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 (39.5 mg, 37%) as a white solid. Rf(Hept / EtOAc 9:1)= 0.18.1H NMR (500 MHz, de- DMSO) 5: 10.09 (s, 1 H), 8.10 (d, J = 1.5 Hz, 1 H), 7.97-7.99 (m, 1 H), 7.92 (m, 1 H), 7.74 (t, J = 7.7 Hz, 1 H), 4.93- 5.05 (m, 4 H). LC-MS (2): tR= 0.71 min; [M+H]+: not seen.

[0701] 4,4-Difluoro-N-(3-(3-fluorooxetan-3-yl)benzyl)cyclohexan-1-amine: A mixture of 4,4-difluorocyclohexan-1- amine (13.9 mg, 0.1 mmol, 1 eq), 3-(3-fluorooxetan-3-yl)benzaldehyde (18 mg, 0.1 mmol, 1 eq) and sodium triacetoxyborohydride (44.6 mg, 0.2 mmol, 2 eq) in THF (1 mL) was stirred at rt for 4h. The reaction mixture was partitioned between DCM and aq. sat. NaHCOs. The organic layer was separated through a phase separator cartridge and concentrated under reduced pressure to give the title compound (34 mg, 100 %) as a yellow oil. LC- MS (2): tR= 0.61 min; [M+H]+: 300.27.

[0702] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-[3-(3-fluoro-oxetan-3-yl)- benzyl]-amide: Was synthesized using 4,4-difluoro-N-(3-(3-fluorooxetan-3-yl)benzyl)cyclohexan-1-amine and tosyl-L-prolinoyl chloride as described in Example 1.24 to give the title compound. LC-MS (1): tR= 1.212 min; [M+H]+: 551.2.

[0703] Examples 1.147 (1 R*,5S*)-(2RS)-N-(Benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide: Was synthesized using cis-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, p-toluenesulfonyl chloride and N-(benzo[d]oxazol-5-ylmethyl)-4,4-dimethylcyclohexan-1 -amine as described in Example 1.1 to give the title compound. LC-MS (1): tR= 1.341 min; [M+H]+: 522.2.

[0704] Example 1.148 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (5-cyclopropyl-4-ethyl-isoxazol-3- ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: tert-Butyl ((5-cyclopropylisoxazol-3-yl)methyl)carbamate: A soln. of 1 -(5-cyclopropyl-3- isoxazolyl)methanamine (800 mg, 5.79 mmol, 1 eq), di-tert-butyl dicarbonate (1.61 mL, 6.95 mmol, 1.2 eq) and TEA (0.806 mL, 5.79 mmol, 1 eq) was stirred in DCM (14.5 mL) for 5 min at 0°C. The soln, was then warmed up to rt and stirred overnight. The soln, was diluted with EtOAc and washed with water, aq. sat. NaHCOs, and brine. The organic layer was dried with MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept / EtOAc 6:4) to give the title compound (896 mg, 65%) as a off white solid. LC-MS (2): IR= 0.85 min; [M+H]+: 239.17. tert-Butyl ((5-cyclopropyl-4-iodoisoxazol-3-yl)methyl)carbamate: In a 25 ml double neck flask tert-butyl ((5- cyclopropylisoxazol-3-yl)methyl)carbamate (202 mg, 0.848 mmol, 1 eq) was added to a suspension of silver trifluoroacetate (225 mg, 1 .02 mmol, 1 .2 eq) in DCM (4 mL), and stirred for 30 min at rt. I2(264 mg, 1.02 mmol, 1.2 eq) was added to the suspension and stirred at rt. After 30 min the suspension was heated under reflux for 5 h and stirred overnight at rt. The suspension was diluted with DCM and filtered. The clear solution was washed with aq. 5% NaHSOs, aq. sat. NaHCOs, H2O, and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified with FC (Hexanes / EtOAc 8:2) to give the title compound as a white solid. LC-MS (2): IR= 0.95 min; [M+H]+: 365.01. tert-Butyl ((5-cyclopropyl-4-vinylisoxazol-3-yl)methyl)carbamate: tert-Butyl ((5-cyclopropyl-4-iodoisoxazol-3- yl)methyl)carbamate (102 mg, 0.28 mmol, 1 eq), K2CO3 (77.4 mg, 0.56 mmol, 2 eq), Pd(PPh3)4 (32.4 mg, 0.028 mmol, 0.1 eq) and 2,4,6-trivinylcyclotriboroxane pyridine complex (67.4 mg, 0.28 mmol, 1 eq) were dissolved in DME (2.60 mL) and water (0.90 mL) and the reaction mixture was degassed for 3 min then stirred at 100°C for 1h. The reaction mixture was cooled down to rt, diluted with DCM, and washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 8:2) to give the title compound (67 mg, 91 %) as a brown solid. Rf(Hept / EtOAc 7:3)= 0.43; LC-MS (3): IR= 1.01 min; [M+H]+: 265.28. tert-Butyl ((5-cyclopropyl-4-ethylisoxazol-3-yl)methyl)carbamate: tert-Butyl ((5-cyclopropyl-4-vinylisoxazol-3- yl)methyl)carbamate (66 mg, 0.25 mmol, 1 eq) was dissolved in EtOH (6 mL) and Pd / C (10% Pd, -50% H2O, 26.6 mg, 0.025 mmol, 0.1 eq) was added. The reaction mixture was degassed under vacuum and filled in with H2 with the help of a balloon. The reaction mixture was then stirred at rt for 16h. The reaction mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure to give the title compound (64.7 mg; 97%) as a pale solid which was used as such in the next step without further purification. LC-MS (3): IR= 1.01 min; [M+H]+: 267.23.

[0705] (5-Cyclopropyl-4-ethylisoxazol-3-yl)methanamine hydrochloride: HCI (4M in dioxane, 1.36 mL, 5.45 mmol, 22 eq) was added dropwise to a solution of tert-butyl ((5-cyclopropyl-4-ethylisoxazol-3-yl)methyl)carbamate (66 mg, 0.248 mmol, 1 eq) in DCM (2.5 mL) and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure to give the title compound (62.7 mg, 100%) as a yellow oil which was used as such in next step without further purification. LC-MS (3): IR= 0.67 min; [M+H]+: 167.14.1H NMR (500 MHz, de- DMSO) 5 8.56 (s, 2 H), 4.11 (bs, 2 H), 2.46 (q, J = 7.6 Hz, 2 H), 1.09 (t, J = 7.5 Hz), 2.11-2.21 (m, 1 H), 1.09 (t, J = 7.5 Hz), 1.05-1.08 (m), 0.91-0.94 (m, 2 H).

[0706] N-((5-Cyclopropyl-4-ethylisoxazol-3-yl)methyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using (5- cyclopropyl-4-ethylisoxazol-3-yl)methanamine hydrochloride and 4,4-difluorocyclohexanone as described in Example 1.146 to give the title compound. LC-MS (3): IR= 1.04 min; [M+H]+: 285.25.

[0707] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (5-cyclopropyl-4-ethyl-isoxazol-3-ylmethyl)-(4,4- difluoro-cyclohexyl)-amide: Was synthesized using N-((5-cyclopropyl-4-ethylisoxazol-3-yl)methyl)-4,4- difluorocydohexan-1 -amine and tosyl-L-prolinoyl chloride as described in Example 1 .24 to give the title compound. LC-MS (1): tR= 1.305 min; [M+H]+: 536.04.

[0708] Examples 1.149 to Example 1.152 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone and the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.149 to Example 1.152 are listed in the table below.

[0709] Example 1.153 (S)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-ethyl-5- methyl-isoxazol-3-ylmethyl)-amide: tert-Butyl ((5-methylisoxazol-3-yl)methyl)carbamate: A soln, of 1-(5-methylisoxazol-3-yl)methanamine (270 mg, 2.41 mmol, 1 eq), di-tert-butyl dicarbonate (0.67 mL, 2.89 mmol, 1.2 eq), and TEA (0.335 mL, 2.41 mmol, 1 eq) was stirred in DCM (5.5 mL) for 5 min at 0°C. The solution was then warmed up to rt and stirred overnight. The soln, was diluted with EtOAc and washed with water, aq. sat. NaHCOs, and brine. The organic layer was dried with MgSC , filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (455 mg, 89%) as an off white solid. LC-MS (3): IR= 0.78 min; [M+H]+: 213.28. tert-Butyl ((4-iodo-5-methylisoxazol-3-yl)methyl)carbamate: In a 25 ml double neck flask tert-butyl ((5- methylisoxazol-3-yl)methyl)carbamate (454 mg, 2.14 mmol, 1 eq) was added to a suspension of silver trifluoroacetate (579 mg, 2.57 mmol, 1.2 eq) in DCM (10 mL), and stirred for 30 min at rt. I2(653 mg, 2.57 mmol, 1.2 eq) was added to the suspension and stirred at rt overnight. After 30 min the suspension was heated under reflux for 5 h and stirred overnight at rt. The suspension was diluted with DCM and filtered. The clear soln, was washed with NaHSO3, NaHCOs, H2O, and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified with FC (Hexanes / EtOAc 9:1) to give the title compound (0.508 g, 70%) as a white solid. LC-MS (3): tR= 0.93 min; [M+H]+: 339.12. tert-Butyl ((5-methyl-4-vinylisoxazol-3-yl)methyl)carbamate: tert-Butyl ((4-iodo-5-methylisoxazol-3- yl)methyl)carbamate (150 mg, 0.444 mmol, 1 eq), K2CO3 (123 mg, 0.887 mmol, 2 eq), Pd(PPh3)4 (51.3 mg, 0.0444 mmol, 0.1 eq) and 2,4,6-trivinylcyclotriboroxane pyridine complex (107 mg, 0.444 mmol, 1 eq) were dissolved in DME (4.1 mL) and water (1.4 mL) and the reaction mixture was degassed for 3 min then stirred at 100°C for 30 min. The reaction mixture was cooled to rt, diluted with DCM, and washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 9 / 1) to give the title compound (94 mg; 89%) as a pale brown solid. LC-MS (3): tR= 0.90 min; [M+H]+: 239.22. tert-Butyl ((4-ethyl-5-methylisoxazol-3-yl)methyl)carbamate: tert-Butyl ((5-methyl-4-vinylisoxazol-3- yl)methyl)carbamate (46.5 mg, 0.195 mmol, 1 eq) was dissolved in EtOH (4.5 mL) and Pd / C (10% Pd, -50% H2O, 20.8 mg, 0.0195 mmol, 0.1 eq) was added. The reaction mixture was degassed with vacuum and then filled with H2 with a balloon. The reaction mixture was then stirred at rt for 16h. The reaction mixture was filtered through Celite® pad and the solvent was removed under reduced pressure to give the title compound (43 mg; 92%) as a pale solid which was used as such in the next step without further purification. LC-MS (3): tR= 0.91 min; [M+H]+: 241.25.

[0710] (4-Ethyl-5-methylisoxazol-3-yl)methanamine hydrochloride: HCI (4M in dioxane, 0.955 mL, 3.82 mmol, 22 eq) was added dropwise to a soln, of (4-ethyl-5-methylisoxazol-3-yl)methanamine (46.9 mg, 0.195 mmol, 1 eq) in DCM (2.0 mL) and the reaction mixture was stirred at rt for 3h. The reaction mixture was concentrated under reduced pressure to give the title compound (62.7 mg, 100%) as a yellow oil which was used as such in next step without further purification. LC-MS (3): tR= 0.54 min; [M+H]+: 141.16.

[0711] N-((4-Ethyl-5-methylisoxazol-3-yl)methyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using (4-ethyl-5- methylisoxazol-3-yl)methanamine hydrochloride and 4,4-difluorocydohexanone as described in Example 1.146 to give the title compound. LC-MS (3): tR= 0.95 min; [M+H]+: 259.32. (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-ethyl-5-methyl- isoxazol-3-ylmethyl)-amide: Was synthesized using N-((4-ethyl-5-methylisoxazol-3-yl)methyl)-4,4- difluorocydohexan-1 -amine and tosyl-L-prolinoyl chloride as described in Example 1 .24 to give the title compound. LC-MS (1): tR= 1.241 min; [M+H]+: 510.2. Example 1.154 to Example 1.164 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde and the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1 .154 to Example 1.164 are listed in the table below. Example 1.165 (1S,2S,5R)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3- azabicyclo[3.1.0]hexane-2-carboxamide: Was prepared as described herein before using (1S,2S,5R)-3- azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride and N-(benzo[d]thiazol-5-ylmethyl)-4,4- difluorocyclohexan-1 -amine to give the title compound as a white solid. LC-MS (2): IR= 1.05 min, [M+H]+: 546.08. Example 1.166 to Example 1.188 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde and the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.166 to Example 1.188 are listed in the table below.

[0712] Example 1.189 (S)-1-Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide:

[0713] Potassium (((4,4-difluorocyclohexyl)amino)methyl)trifluoroborate: An oven-dried microwave vial equipped with a stirrer bar was charged with potassium (bromomethyl)trifluoroborate (3347 mg, 15 mmol, 1 eq), sealed and put under a N2 atmosphere. Then THF (5 mL), t-BuOH (3.75 mL) and 4,4-difluorocyclohexan-1-amine (2508 mg, 18 mmol, 1 .2 eq) in THF (2.5 mL) were added. The resulting mixture was placed in an oil bath at rt and then gradually heated to 60 °C and stirred at this temperature overnight. The suspension was cooled down to rt and concentrated, the solid was suspended in hot (~ 50-60 °C) MeCN (120 mL). The white precipitate was filtered off on a 0.45 micron Whatmann filter. The filtrate was concentrated and the same operation was repeated. The filtrate was concentrated and dissolved in a minimal amount of hot MeCN (30 mL). Then, Et2O was added dropwise. The precipitate was filtered off and washed with Et2O / Heptane. The white powder was dried under high vacuum to give the title compound (2.03 g, 62%) as a white solid. LC-MS (3): tR= 0.46 min; [M-H]+: 215.98;1H NMR (500 MHz, d6-DMSO) 5: 7.67 (s, 2 H), 2.87-3.09 (m, 1 H), 2.05-2.11 (m, 4 H), 1.79-1.98 (m, 2 H), 1.75 (m, 2 H), 1.48-1.56 (m, 2 H).

[0714] 4.4-Difluoro-N-((5-fluorobenzofuran-6-yl)methyl)cyclohexan-1-amine: An oven-dried microwave vial equipped with a stirrer bar was charged with 6-bromo-5-fluorobenzofuran (WO20140274695) (148 mg, 0.69 mmol, 1 eq), potassium (((4,4-difluorocyclohexyl)amino)methyl)trifluoroborate (193 mg, 0.889 mmol, 1.289 eq), P(tBu)3Pd G2 (35.4 mg, 0.069 mmol, 0.1 eq) and CS2CO3 (674 mg, 2.07 mmol, 3 eq), sealed, and placed under N2atmosphere. Then, THF (7 mL) and water (7 mL) were added and the resulting mixture was degassed for 5 min under a nitrogen stream and then stirred at 90 °C (pre-heated heating block) overnight. The residue was purified by cation exchange resin. The basic fractions were further purified by prep. HPLC to give the title compound (25.2 mg, 13%) as a yellow oil. LC-MS (2): tR= 0.65 min; [M+H]+: 284.25.

[0715] 4.4-Difluoro-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexan-1-amine: To a solution of 4,4- difluoro-N-((5-fluorobenzofuran-6-yl)methyl)cyclohexan-1 -amine (24 mg, 0.0846 mmol, 1 eq) in EtOH (1 mL) was added Pd / C (10% Pd, 50% H2O, 9 mg, 0.0085 mmol, 0.1 eq) and the mixture was stirred at rt under a H2atmosphere overnight. The mixture was filtered over Celite®, and wahed with EtOH. The filtrate was concentrated under reduced pressure to give the title compound (23.7 mg, 97 %) as a light yellow oil. LC-MS (2): tR= 0.62 min; [M+H]+: 286.24.

[0716] (S)-N-(4,4-Difluorocyclohexyl)-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)-1-tosylpyrrolidine-2- carboxamide: Was synthesized using 4,4-difluoro-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexan-1 - amine and tosyl-L-prolinoyl chloride as described in Example 1.24 to give the title compound as a white solid. LC- MS (1): tR= 1.260 min; [M+H]+: 537.2.

[0717] Example 1.190 to Example 1.196 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.190 to Example 1.196 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0718] Example 1.197 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide:

[0719] 2-(2,5-Dibromo-3-fluorophenoxy)ethan-1-ol: 2,5-Dibromo-1,3-difluorobenzene (2500 mg, 9.01 mmol, 1 eq) was dissolved in NMP (1.9 mL) and ethylene glycol (2.53 mL, 45.1 mmol, 5 eq) was added. Potassium tert-butoxide (1217 mg, 10.8 mmol, 1.203 eq) was added portionwise at 0 °C and the resulting mixture was stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (1.402 g, 50%) as a white solid. LC-MS (2): tR= 0.86 min; [M+H]+: not seen;1H NMR (500 MHz,d6-DMSO) 6 7.31 (dd, Ji = 2.0 Hz, J2= 8.1 Hz, 1 H), 7.23 (t, J = 1.8 Hz, 1 H), 4.92 (t, J = 5.3 Hz, 1 H), 4.15 (m, 2 H), 3.74 (m, 2 H).

[0720] 2,5-Dibromo-1-(2-bromoethoxy)-3-fluorobenzene: PBr3(0.214 mL, 2.24 mmol, 0.5013 eq) was added dropwise to a solution of 2-(2,5-dibromo-3-fluorophenoxy)ethan-1-ol (1400 mg, 4.46 mmol, 1 eq) in toluene (9.2 mL) at 0°C. The resulting yellow solution was stirred at 90 °C for 4h. The reaction mixture was cooled to 0 °C and aq. 1 M NaOH was added dropwise. The white suspension was filtered on a Celite® pad and the cake was washed with EtOAc. The filtrates were washed 3x with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 95:5) to give the title compound (1.126 g, 67%) as as a white solid. LC-MS (2): tR= 1.06 min; [M+H]+: not seen;1H NMR (400 MHz, d6-DMSO) 6 7.36 (d, J = 8.1 Hz, 1 H), 7.24-7.28 (m, 1 H), 4.44-4.53 (m, 2 H), 3.80-3.87 (m, 2 H).

[0721] 4-Fluoro-2,3-dihydrobenzofuran-6-carbaldehyde: To a stirred solution of 2,5-dibromo-1-(2-bromoethoxy)-3- fluorobenzene (900 mg, 2.39 mmol, 1 eq) in dry THF (8.4 mL) at -78 °C, n-butyllithium 1.6 M in hexanes (1.65 mL, 2.64 mmol, 1 .106 eq) was added dropwise under nitrogen for 45 min. After this time n-Butyllithium 1 .6 M in hexanes (1.65 mL, 2.64 mmol, 1.106 eq) was added again and the resulting mixture was stirred for additional 45min at -78 °C. DMF (0.368 mL, 4.78 mmol, 2 eq) was then added dropwise at -78 °C and the mixture was stirred at this temperature for 30min. The reaction mixture was allowed to reach rt and was then quenched with sat. aq. NH4CI and extracted with EtOAc. The organic layer was washed twice with brine, dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified with FC (Hept to Hept / EtOAc 9:1) to give the title compound (270 mg, 68%) as a white solid. LC-MS (2): IR = 0.79 min; [M+H]+: not seen;1H NMR (500 MHz, de- DMSO) 6 9.89 (d, J = 1.5 Hz, 1 H), 7.27 (dd, Ji = 1.0 Hz, J2= 8.5 Hz, 1 H), 7.14 (d, J = 0.9 Hz, 1 H), 4.70 (t, J = 8.8 Hz, 2 H), 3.33 (t, J = 9.0 Hz, 2 H).

[0722] 4,4-Difluoro-N-((4-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexan-1-amine: Was synthesized using 4- fluoro-2,3-dihydrobenzofuran-6-carbaldehyde and 4,4-difluorocyclohexan-1-amine as described in Example 1.146 to give the title compound as a light yellow oil. LC-MS (2): IR = 0.64 min; [M+H]+: 286.32.

[0723] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-2,3-dihydro- benzofuran-6-ylmethyl)-amide: Was synthesized using 4,4-difluoro-N-((4-fluoro-2,3-dihydrobenzofuran-6- yl)methyl)cyclohexan-1 -amine and tosyl-L-prolinoyl chloride as described in Example 1.24 to give the title compound as a white solid. LC-MS (1 ): IR = 1 .256 min; [M+H]+: 537.4.

[0724] Example 1.198 to Example 1.208 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.198 to Example 1.208 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0725] Example 1.209 (2S,4S)-4-Fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1 S,3R,6S)- bicyclo[4.1.0]hept-3-yl-(2,3-dihydro-benzofuran-6-ylmethyl)-amide, Example 1.210 (2S,4S)-4-fluoro-1 -(4- methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1 R,3R,6R)-bicyclo[4.1.0] h ept-3-y I -(2,3-d i hyd ro- benzofuran-6-ylmethyl)-amide and Example 1.211 (2S,4S)-4-fluoro-1-(4-methoxy-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (1 S,3R,6S)-bicyclo[4.1.0]hept-3-yl-(2,3-dihydro-benzofuran-6-ylmethyl)- amide: Were obtained by preparative chiral separation (SFC 1 method) of (2S,4S)-N-(bicyclo[4.1.0]heptan-3-yl)- N-((2,3-dihydrobenzofuran-6-yl)methyl)-4-fluoro-1 -((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide (Example 1.184) to give Example 1.209 (first eluting), 1.210 (second eluting) and Example 1.21 1 (third eluting). Stereochemistry was arbitrarily assigned. Example 1.209: LC-MS (1): tR= 1.246 min; [M+H]+: 529.2; Example 1.210: LC-MS (1): tR= 1.240 min; [M+H]+: 529.2 and Example 1.21 1 : LC-MS (1 ): tR= 1.234 min; [M+H]+: 529.2.

[0726] Example 1.212 to Example 1.234 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.212 to Example 1.234 are listed in the table below.

[0727] Example 1.235 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(7-fluoro-

[0728] 2.3-dihydro-benzofuran-6-ylmethyl)-amide:

[0729] 4.4-Difluoro-N-((7-fluorobenzofuran-6-yl)methyl)cyclohexan-1-amine: Was synthesized using potassium (((4,4-difl uorocyclohexy I) amino) methy l)trifl uoroborate and 6-bromo-7-fluoro-2,3-dihydrobenzofuran as described in

[0730] Example 1.189 to give the title compound as a yellow oil. LC-MS (2): IR = 0.66 min; [M+H]+: 284.20.

[0731] 4.4-Difluoro-N-((7-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexan-1-amine: Was synthesized using

[0732] 4.4-difluoro-N-((7-fluorobenzofuran-6-yl)methyl)cyclohexan-1-amine as described in Example 1 .189 to give the title compound as a yellow oil. LC-MS (2): IR = 0.62 min; [M+H]+: 286.35. (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(7-fluoro-2,3-dihydro- benzofuran-6-ylmethyl)-amide: Was synthesized using 4,4-difluoro-N-((7-fluoro-2,3-dihydrobenzofuran-6- yl)methyl)cyclohexan-1 -amine and tosyl-L-prolinoyl chloride as described in Example 1.189 to give the title compound as a white solid. LC-MS (1): tR= 1.249 min; [M+H]+: 537.3.

[0733] Example 1.236 to Example 1.266 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.236 to Example 1.266 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0734] Example 1.267 (S)-2-(Toluene-4-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide: Was synthesized using (S)-1 -(tert-butoxycarbonyl)- 4,5-dihydro-1 H-pyrazole-5-carboxylic acid (WO2012122450), N-((2,3-dihydrobenzofuran-6-yl)methyl)-4,4- difluorocyclohexan-1 -amine, and 4-methylbenzenesulfonyl chloride as described in Example 1.33 to give the title compound as a white solid. LC-MS (2): tR= 1.01 min; [M+H]+: 518.33.

[0735] Example 1.268 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5- isopropyl-thiazol-2-ylmethyl)-amide:

[0736] 4,4-Difluoro-N-((5-isopropylthiazol-2-yl)methyl)cyclohexan-1-amine: Was synthesized using 4,4- difluorocydohexan-1 -amine and 5-(propan-2-yl)-1 ,3-thiazole-2-carbaldehyde as described in Example 1.1 to give the title compound as a yellow oil. LC-MS (2): tR= 1.02 min; [M+H]+: 275.08.

[0737] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-isopropyl-thiazol-2- ylmethyl)-amide: Was synthesized using 4,4-difluoro-N-((5-isopropylthiazol-2-yl)methyl)cyclohexan-1-amine and tosyl-L-prolinoyl chloride as described in Example 1.189 to give the title compound as a off-white solid. LC-MS (1): tR= 1.281 min; [M+H]+: 526.3.

[0738] Example 1.269 (2S)-N-(4,4-Difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-tosylpyrrolidine- 2-carboxamide:

[0739] (2S)-N-(1-(Benzofuran-6-yl)ethyl)-N-(4,4-difluorocyclohexyl)-1-tosylpyrrolidine-2-carboxamide: Was synthesized using 1-(benzofuran-6-yl)ethan-1-one, 4,4-difluorocyclohexan-1-amine, and tosyl-L-prolinoyl chloride as described in Example 1.189 to give the title compound as a off-white solid. LC-MS (2): tR= 0.67 min; [M+H]+: 280.25.

[0740] (2S)-N-(4,4-Difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-tosylpyrrolidine-2-carboxamide:

[0741] To a soln, of (2S)-N-(1 -(benzofuran-6-yl)ethyl)-N-(4,4-difluorocyclohexyl)-1 -tosylpyrrolidine-2-carboxamide (26 mg, 0.049 mmol, 1 eq) in EtOH (0.5 mL) was added Pd / C (10%, 5.2 mg, 0.0049 mmol, 0.1 eq) and the reaction mixture was stirred under a H2 atmosphere overnight. The reaction mixture was filtered over Celite®, and the cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give the title compound (21.6 mg, 83%) as a light yellow glue. LC-MS(1): tR= 1.290 min; [M+H]+: 533.4.

[0742] Example 1.270 (S)-1-(Toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (4,4-difluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide: Methyl (S)-2-((4-Methylphenyl)sulfonamido)pent-4-ynoate: p-Toluenesulfonyl chloride (320 mg, 1.66 mmol, 1.1 eq) was added at rt to a stirred solution of L-propargylglycine methyl ester hydrochloride (250 mg, 1.51 mmol, 1 eq) and DIPEA (0.647 mL, 3.78 mmol, 2.5 eq) in DCM (10 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and washed once with brine. The organic layer was separated through a phase separator cartridge and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (305 mg, 72 %) as a white solid. LC-MS (2): tR= 0.83 min; [M+H]+: 282.21.

[0743] (S)-1-Tosyl-2,3-dihydro-1H-pyrrole-2-carboxylic acid: A microwave vial equipped with a stirrer bar was charged with methyl (S)-2-((4-methylphenyl)sulfonamido)pent-4-ynoate (96 mg, 0.341 mmol, 1 eq), Pd (II) acetate (7.66 mg, 0.0341 mmol, 0.1 eq), triphenylphosphine (18.1 mg, 0.0682 mmol, 0.2 eq) and K2CO3 (236 mg, 1.71 mmol, 5 eq), and then sealed. THF (3.4 mL) was added under nitrogen and the resulting mixture was degassed for 5 min under a nitrogen stream and then stirred at 45 °C for 24h. Lithium hydroxide monohydrate (21 .5 mg, 0.512 mmol, 1 .5 eq) was added and the mixture was stirred at rt for 4h and then diluted with EtOAc and water. The layers were separated. The aq. layer was slowly acidified to pH=1-2 using aq. 1 M HCI and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (88 mg, 97%) as a beige solid, which was used as such in the next step without further purification. LC-MS (2): tR= 0.74 min; [M+H]+: 268.23.

[0744] (S)-1-(Toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide: Was synthesized using (S)-1 -tosyl-2,3-dihydro-1 H-pyrrole-2-carboxylic acid and N-((2,3-dihydrobenzofuran-6-yl)methyl)-4,4-difluorocyclohexan-1-amine as described in Example 1.33 to give the title compound as a beige solid. LC-MS(1): tR= 1.228 min; [M+H]+: 517.2.

[0745] Example 1.271 to Example 1.301 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.271 to Example 1.301 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0746] Example 1.302 rac-5-Methyl-2-(toluene-4-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro- cyclohexyl)-(4-methyl-benzyl)-amide: l-(tert-Butyl) 5-ethyl 3-methyl-4,5-dihydro-1H-pyrazole-1,5-dicarboxylate: Copper(ll) chloride (26.9 mg, 0.2 mmol, 0.2 eq) was added to a solution of tert-butyl (E)-2-(1-chloropropan-2-ylidene)hydrazine-1 -carboxylate (207 mg, 1 mmol, 1 eq), ethyl diazoacetate (0.363 mL, 3 mmol, 3 eq), and Na2CO3 (530 mg, 5 mmol, 5 eq) in DCM (8 mL), and the reaction mixture was stirred at rt for 5h. 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 (200 mg, 78%) as a yellow oil. 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, 3H), 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.

[0747] 5-(Ethoxycarbonyl)-3-methyl-4,5-dihydro-1H-pyrazol-1-ium trifluoroacetate: TFA (0.3 mL) was added to a soln, of 1 -(tert-butyl) 5-ethyl 3-methyl-4,5-dihydro-1 H-pyrazole-1 ,5-dicarboxylate (80 mg, 0.312 mmol, 1 eq) in DCM (3 mL). The resulting brownish soln, was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil which was used as such in the next step without further purification. LC-MS (2): tR= 0.39 min; [M+H]+: 157.28.

[0748] Ethyl 3-methyl-1-tosyl-4,5-dihydro-1H-pyrazole-5-carboxylate: 5-(Ethoxycarbonyl)-3-methyl-4,5-dihydro-1 H- pyrazol-1-ium trifluoroacetate (84.3 mg, 0.312 mmol, 1 eq) was dissolved in MeCN (2.6 mL) and K2CO3 (151 mg, 1.09 mmol, 3.5 eq) was added followed by p-toluenesulfonyl chloride (60.7 mg, 0.312 mmol, 1 eq). The mixture was heated under reflux for 1h. Water was added and the mixture was extracted with DCM and separated through a separation cartridge. The solvent was removed under reduced pressure and the residue was purified by FC (Hept to Hep / EtOAc 6:4) to give the title compound (22.6 mg, 23%) as a white solid. LC-MS (2): tR= 0.84 min; [M+H]+: 311.11.

[0749] 3-Methyl-1-tosyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid: At rt, ethyl 3-methyl-1 -tosyl-4,5-dihydro-1 H- pyrazole-5-carboxylate (23 mg, 0.0741 mmol, 1 eq) was dissolved in THF (0.37 mL), then lithium hydroxide monohydrate (4.71 mg, 0.111 mmol, 1.5 eq) was added and the mixture was stirred at rt during 4h. The mixture was acidified with aq. 1 M HCI and extracted with DCM. The layers were separated with a phase separator. The solvent was removed under reduced pressure to give the title compound as a white solid which was used as such in the next step without further purification. LC-MS (2): tR= 0.66 min; [M+H]+: 283.13. rac-5-Methyl-2-(toluene-4-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(4- methyl-benzyl)-amide: Was synthesized using 3-methyl-1 -tosyl-4,5-dihydro-1 H-pyrazole-5-carboxylic acid and 4,4-difluoro-N-(4-methylbenzyl)cyclohexan-1-amine as described in Example 1.1 to give the title compound as a white solid. LC-MS(1): tR= 1.254 min; [M+H]+: 504.3.

[0750] Example 1.303 to Example 1.319 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.303 to Example 1.319 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0751] Example 1.320 (2S)-N-(3-Carbamoylcyclopentyl)-N-(4-chlorobenzyl)-1-tosylpyrrolidine-2-carboxamide: Methyl 3-((4-chlorobenzyl)amino)cyclopentane-1-carboxylate: Was synthesized as described in Example 1.1 using 4-chlorobenzylamine and methyl 3-oxocyclopentane-1 -carboxylate to give the title compound as a pale yellow oil. LC-MS (2): tR= 0.61 min; [M+H]+: 268.30.

[0752] 3-((4-Chlorobenzyl)amino)cyclopentane-1-carboxamide: Methyl 3-((4-chlorobenzyl)amino)cyclopentane-1- carboxylate (120 mg, 0.448 mmol) was dissolved in NH3 (7M in methanol, 2.1 mL, 15 mmol) and the reaction mixture was stirred at 85°C for 4 days. Fresh NH3 (7M in methanol, 4.2 mL, 30 mmol, 67 eq) was added and the reaction mixture was stirred at 85°C for 21 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by FC (DCM to DCM / (MeOH+3% Et3N) 9:1) to give the title compound (61.3 mg, 54%) as a beige sticky solid. LC-MS (2): tR= 0.49 and 0.52 min; [M+H]+: 253.35.

[0753] (2S)-N-(3-carbamoylcyclopentyl)-N-(4-chlorobenzyl)-1-tosylpyrrolidine-2-carboxamide: Was synthesized as described in Example 1.24 using tosyl-L-prolinoyl chloride and 3-((4-chlorobenzyl)amino)cyclopentane-1- carboxamide to give the title compound as a white solid. LC-MS (1): tR= 1.026 min; [M+H]+: 504.4.

[0754] Example 1.321 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4-cyano- bicyclo[2.2.2]oct-1-yl)-amide: Was synthesized as described in Example 1.320 using tosyl-L-prolinoyl chloride,

[0755] 4-aminobicyclo[2.2.2]octane-1 -carbonitrile hydrochloride and 4-chlorobenzaldehyde to give the title compound as a white solid. LC-MS (1): tR= 1.316 min; [M+H]+: 526.4.

[0756] Example 1.322 (2S)-N-((1R)-3-Carbamoyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1-tosylpyrrolidine-2- carboxamide:

[0757] Methyl (1S,3R)-3-(dibenzylamino)cyclopentane-1-carboxylate: Sodium carbonate (2.05 g, 18.9 mmol) was dissolved in H2O (5.7 mL) and DCM (11.4 mL) was added. Methyl (1 R,3R)-3-aminocyclopentane-1 -carboxylate hydrochloride (850 mg, 4.73 mmol) was added portionwise followed by benzyl bromide (1.18 mL, 9.7 mmol). The reaction mixture was stirred at 40°C for 22h. The reaction mixture was partitionned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 9: 1) to give the title compound (1.335 g, 87%) as a colourless oil. Rf(Hept / EtOAc 9:1)= 0.26. LC-MS (2): tR= 0.72 min; [M+H]+: 324.29.

[0758] Methyl (3R)-3-(dibenzylamino)-1-methylcyclopentane-1-carboxylate: Lithium diisopropylamide solution (1.0 M in THF / hexanes, 2.32 mL, 2.32 mmol) was stirred at -78°C. A soln, of methyl (1S,3R)-3- (dibenzylamino)cydopentane-l-carboxylate (250 mg, 0.773 mmol) in THF (7.7 mL) was added dropwise at -78°C and the reaction mixture was stirred at -78°C for 30 min. lodomethane (0.292 mL, 4.64 mmol) in THF (1 .5 mL) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was poured into sat. aq. NH4CI (50 ml) and extracted with EtOAc (75 ml). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 95:5) to give the title compound (214 mg; 82%) as a colourless oil. Rf(Hept / EtOAc 9:1)= 0.38. LC-MS (2): tR= 0.76 min; [M+H]+: 338.18.

[0759] (3R)-3-(Dibenzylamino)-1-methylcyclopentane-1-carboxylic acid: Methyl (3R)-3-(dibenzylamino)-1 - methylcyclopentane-1 -carboxylate (231 mg, 0.725 mmol) was dissolved in H2O (8 mL) and THF (2 mL) and lithium hydroxide monohydrate (134 mg, 3.17 mmol) was added at it The reaction mixture was stirred at rt for 14h then at 70°C for 5.5h. The reaction mixture was poured into cold aq. 1 M HCI and was extracted once with DCM and with DCM / MeOH 10% (3x50ml). The combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to give the title compound (293 mg, 100%) as a white solid. The compound was used as such in the next step without further purification. LC-MS (2): tR= 0.69; [M+H]+: 324.28.

[0760] (3R)-3-(Dibenzylamino)-1-methylcyclopentane-1-carboxamide: At rt, (3R)-3-(dibenzylamino)-1 - methylcyclopentane-1 -carboxylic acid (205 mg, 0.634 mmol) was dissolved in DMF (6 mL), then DIPEA (0.554 mL, 3.17 mmol) and HATU (497 mg, 1.27 mmol) were added. After stirring for 5 minutes, NH4CI (170 mg, 3.17 mmol) was added. The resulting solution was stirred at rt for 1h. The reaction mixture was filtered through a PTFE 0.45pim filter and purified by basic prep. HPLC to give the title compound (199 mg, 97%) as a pale orange sticky oil. LC- MS (2): tR= 0.62 and 0.64 min; [M+H]+: 323.33

[0761] (3R)-3-Amino-1-methylcyclopentane-1-carboxamide: (3R)-3-(Dibenzylamino)-1 -methylcyclopentane-1 - carboxamide (116 mg, 0.36 mmol) was dissolved in MeOH (3.6 mL) and Pd / C (10% Pd,~50% H2O 76.6 mg, 0.0719 mmol) was added. The reaction mixture was stirred at rt under a pressure of H2 (5 bars) for 18h.The reaction mixture was filtered through Celite® and the filtrate was concentrated to give the title compound (48 mg, 94%) as a colorless oil. The compound was used as such in the next step without further purification.

[0762] (3R)-3-((4-Chlorobenzyl)amino)-1-methylcyclopentane-1-carboxamide: Was synthesized as described in Example 1.1 using (3R)-3-amino-1 -methylcyclopentane-1 -carboxamide and 4-chlorobenzaldehyde (62 mg, 0.432 mmol) to give the title compound as a off-white solid. LC-MS (2): tR= 0.52 and 0.56 min; [M+H]+: 267.37.

[0763] (2S)-N-((1 R)-3-Carbamoyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1-tosylpyrrolidine-2-carboxamide: Was synthesized as described in Example 1.24 using (3R)-3-((4-chlorobenzyl)amino)-1 -methylcyclopentane-1 - carboxamide and tosyl-L-prolinoyl chloride to give the title compound as a white solid. LC-MS (1): tR= 1.088 min; [M+H]+: 518.4.

[0764] Example 1.323 (2S)-N-(4-chlorobenzyl)-N-((1 R)-3-cyano-3-methylcyclopentyl)-1-tosylpyrrolidine-2- carboxamide: (2S)-N-((1 R)-3-Carbamoyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1 -tosylpyrrolidine-2- carboxamide (30 mg, 0.0579 mmol) was dissolved in DCM (1 mL). Triethylamine (0.024 mL, 0.174 mmol) was added and the reaction mixture was stirred at 0°C. Trifluoroacetic anhydride (0.0179 mL, 0.127 mmol) was added and the resulting solution was stirred at 0°C for 1 h. Water was added and the reaction mixture was stirred for 10 min and filtered over phase separator. The organic phase was concentrated under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound (24 mg, 85%) as a white solid. LC-MS (1): IR= 1.259 min; [M+H]+: 500.4.

[0765] Example 1.324 (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5- ylmethyl-(4,4-difluoro-cyclohexyl)-amide: Was synthesized following the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde and the appropriate amino acid or aminoester and the appropriate sulfonyl chloride to give the title compound as a white solid. LC-MS (1): IR= 1 .203 min; [M+H]+: 552.4.

[0766] Example 1.325 and Example 1.326: (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1,1- difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N- ((3S,6r)-1,1-difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide: Were synthesized following the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde and (S)-methyl pyrrolidine-2-carboxylate hydrochloride to give (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(1 ,1- difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide as a 1 : 1 mixture of diastereomers. The diastereomeric mixture was separated by chiral SFC (SFC 5 method) to give (S)-N-(benzo[d]thiazol-5-ylmethyl)-N- ((3R,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide (first eluting diastereomer) and (S)-N- (benzo[d]thiazol-5-ylmethyl)-N-((3S,6r)-1,1-difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide (second eluting diastereomer) both as a white solids. Stereochemistry was arbitrarily assigned. (S)-N-(benzo[d]thiazol-5- ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2-carboxamide: LC-MS (1): IR= 1.241 min, [M+H]+: 560.5. (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,6r)-1,1-difluorospiro[2.5]octan-6-yl)-1-tosylpyrrolidine-2- carboxamide: LC-MS (1): IR= 1.243 min, [M+H]+: 560.4.

[0767] Example 1.327 and Example 1.328: (S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1,1- difluorospiro[2.3]hexan-5-yl)-1-tosylpyrrolidine-2-carboxamide and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N- ((3S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-1-tosylpyrrolidine-2-carboxamide: Were synthesized following the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde and tosyl-L-proline to give (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(1,1-difluorospiro[2.3]hexan-5-yl)-1- tosylpyrrolidine-2-carboxamide as a 1 :1 mixture of diastereomers. The diastereomeric mixture was separated by chiral SFC (SFC 6 method) to give (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 , 1 -difluorospiro[2.3]hexan-5-yl)- 1-tosylpyrrolidine-2-carboxamide (first eluting diastereomer) and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,5r)-1 , 1 - difluorospiro[2.3]hexan-5-yl)-1-tosylpyrrolidine-2-carboxamide (second eluting diastereomer) both as a white solids. Stereochemistry was arbitrarily assigned. (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1,1- difluorospiro[2.3]hexan-5-yl)-1 -tosylpyrrolidine-2-carboxamide: LC-MS (1): IR= 1.176 min, [M+H]+: 532.4. (S)-N- (benzo[d]thiazol-5-ylmethyl)-N-((3S,5r)-1 , 1-difluorospiro[2.3]hexan-5-yl)-1-tosylpyrrolidine-2-carboxamide: LC-MS (1): tR= 1.186 min, [M+H]+: 532.4. Example 1.329 to Example 1.332 were synthesized as described in Example 1.326 using the appropriate amine or amine salt derivative, the appropriate aldehyde, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.329 to Example 1.332 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0768] Example 1.333 to Example 1.334 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.333 to Example 1.334 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0769] Example 1.335 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)- (4,4-difluoro-cyclohexyl)-amide:

[0770] (2-Chlorobenzo[d]thiazol-5-yl)methanol: At 0°C under argon, UAIH4 (17.9 mg, 0.472 mmol) was added portionwise to a stirred solution of ethyl 2-chlorobenzo[d]thiazole-5-carboxylate (100 mg, 0.393 mmol) in THF (3.9 ml) (exothermic). The reaction was stirred for 10 minutes. Na2SO4 salt (1000 mg) was added (gas evolution) and the mixture was stirred vigorously for 3.5h . The suspension was filtered over Celite® and evaporated under reduced pressure to give the title compound (80 mg, 100%) as a yellow solid. LC-MS (2): IR= 0.70 min, [M+H]+: 200.19.

[0771] 2-Chlorobenzo[d]thiazole-5-carbaldehyde: A round bottom double neck flask charged with (2- chlorobenzo[d]thiazol-5-yl)methanol (80 mg, 0.401 mmol) was purged and refilled with argon three times. MnO2 activated (106 mg, 1.2 mmol) was added and the material diluted with DCM (4 mL, 62.6 mmol). The reaction mixture was stirred at rt overnight. MnC>2 activated (106 mg, 1 .2 mmol, 3 eq) was added again and the reaction mixture was stirred again for 24h. The reaction mixture was filtered through Celite® and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (52 mg, 66%) as a white solid. LC-MS (2): IR= 0.81 min, [M+H]+: not seen.

[0772] N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexan-1-amine: Was synthesized as described in Example 1.3 using 2-chlorobenzo[d]thiazole-5-carbaldehyde and 4,4-difluorocyclohexan-1-amine hydrochloride to give the title compound as a colorless oil. LC-MS (2): IR= 0.66 min, [M+H]+: 317.20.

[0773] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide: Was synthesized as described in Example 1.1 using N -((2-ch lorobenzo[d]th i azol-5-y IJmethyl)- 4,4-difluorocyclohexan-1-amine and tosyl-L-pyroline to give the title compound as a white solid. LC-MS (1): IR= 1.329 min, [M+H]+: 568.4.

[0774] Example 1.336 to Example 1.345 were synthesized according to the procedures described herein before using the appropriate amine, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.336 to Example 1.345 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0775] Example 1.346 and Example 1.347 (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide and (S)-1-(3-Fluoro-4-methyl- benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl- amide: Were obtained by chiral SFC separation (SFC 8 method) of (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N- (bicyclo[4.1.0]heptan-3-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidine-2-carboxamide, synthesized according to the procedures described herein before using benzozhiazole-5-carbaldehyde, L-proline, and 3-fluoro-4- methylbenzene sulfonyl chloride. (S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-( 1 R,3R,6R)-bicyclo[4.1 ,0]hept-3-yl-amide: LC-MS (1): tR= 1.292 min, [M+H]+: 527.17. (S)- 1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 S,3S,6S)- bicyclo[4.1.0]hept-3-yl-amide: LC-MS (1): tR= 1.288 min, [M+H]+: 527.17 .

[0776] Example 1.348 to Example 1.350 were obtained by chiral SFC separation (SFC 9 method) separation of (2S)-N- (benzo[d]th iazol-5-y I methy l)-N-(bicyclo[4.1 .0]heptan-3-y l)-1 -tosylpyrrolidine-2-carboxamide, synthesized according to the procedures described herein before using benzozhiazole-5-carbaldehyde, bicyclo[4.1 ,0]heptan-3- amine and N-p-tosyl-L-proline. LC-MS data of Example 1.348 to Example 1.350 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0777] Example 1.351 and Example 1.352 (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide and (S)-1-(4-methoxy-benzenesulfonyl)- pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide: Were obtained by chiral SFC separation (SFC 10 method) of (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N- (bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide, synthesized according to the procedure described in Example 1.96 using benzozhiazole-5-carbaldehyde, bicyclo[4.1.0]heptan-3-amine and lithium ((4-methoxyphenyl)sulfonyl)-L-prolinate. (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-( 1 R,3R,6R)-bicyclo[4.1 ,0]hept-3-yl-amide: LC-MS (1): tR= 1 ,209min, [M+H]+: 525.18. (S)- 1-(4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 S,3S,6S)- bicyclo[4.1.0]hept-3-yl-amide: LC-MS (1): tR= 1.205 min, [M+H]+: 525.18.

[0778] Example 1.353 (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4- difluoro-cyclohexyl)-amide:

[0779] N-(4-Chlorobenzyl)-4,4-difluorocyclohexan-1-amine: DIPEA (9.42 mL, 0.055 mol, 1.1 eq) was added to a solution of 4,4-difluorocyclohexan-1-amine hydrochloride (8.58 g, 0.05 mol, 1 eq) and 4-chlorobenzaldehyde (7.25 g, 0.05 mol, 1 eq) in MeOH (338 mL). The clear solution was stirred at rt overnight. NaBF (2.08 g, 0.055 mol, 1.1 eq) was added in portions and the mixture was stirred at rt for 45 min. The reaction mixture was quenched with aq. sat. NaHCOs. Most of the solvent was evaporated under reduced pressure and the residue was diluted with EtOAc. The layers were separated and the org. layer was washed with water and brine, dried with MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 1 :1) to give the title compound. tert-Butyl (S)-2-((4-chlorobenzyl)(4,4-difluorocyclohexyl)carbamoyl)pyrrolidine-1-carboxylate: To a solution of (tert-butoxycarbonyl)-L-proline (7 g, 0.0325 mol, 1 eq) and HATU (14.8 g, 0.039 mol, 1.2 eq) in DMF (110 mL) was added DIPEA (11.1 mL, 0.065 mol, 2 eq). The resulting solution was stirred at rt. After 10 min, a solution of N- (4-chlorobenzyl)-4,4-difluorocyclohexan-1-amine (9.52 g, 0.0356 mol, 1.093 eq) in DMF (20 mL) was added. The brown solution was stirred overnight. The reaction mixture was diluted with EtOAc and extracted with aq. 1 M HCI soln., aq. sat. NaHCOs, water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EA 6:4) to give the title compound.

[0780] (S)-N-(4-Chlorobenzyl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2-carboxamide: 4M HCL in dioxane (61.8 mL, 0.247 mol, 10 eq) was added dropwise to a solution tert-butyl (S)-2-((4-chlorobenzyl)(4,4- difluorocyclohexyl)carbamoyl)pyrrolidine-1-carboxylate (11.8 g, 0.0247 mol, 1 eq) in DCM (100 mL) at 0 °C. The reaction mixture was stirred allowed to reach rt overnight. The reaction mixture was cooled to 0 °C and quenched with aq. sat. NaHCOs. The layers were separated and the org. layer was washed with aq. sat. NaHCOs, water, and brine, dried with MgSCU, filtered, and concentrated under reduced pressure to give the title compound.

[0781] (S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro- cyclohexyl)-amide: 4-Methoxybenzenesulfonyl chloride (23 mg, 0.11 mmol, 1.1 eq), (S)-N-(4-chlorobenzyl)-N- (4,4-difluorocyclohexyl)pyrrolidine-2-carboxamide (37.6 mg, 0.1 mmol, 1 eq), and TEA (0.0696 mL, 0.5 mmol, 5 eq) were dissolved in ACN (1 mL). The reaction mixture was stirred rt overnight. The reaction mixture was purified by basic prep. HPLC to give the title compound.

[0782] Example 1.354 to Example 1.371 were synthesized according to the procedures described herein before using N- (4-chlorobenzyl)-4,4-difluorocyclohexan-1 -amine and the appropriate sulfonyl chloride. LC-MS data of Example 1.354 to Example 1.371 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0783] Example 1.372 to Example 1.378 were synthesized according to the procedure described in Example 1.33 using the appropriate aldehyde, the appropriate amine or amine salt, the appropriate amino acid and the appropriate sulfonyl chloride. LC-MS data of Example 1 .372 to Example 1.378 are listed in the table below.

[0784] Example 1.379 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)- (4,4-difluoro-cyclohexyl)-amide:

[0785] (2-Bromobenzo[d]thiazol-5-yl)methanol: At -78°C and under argon athmosphere, 1 M DIBAL soln, in DCM (13 mL, 13 mmol, 4 eq) was added dropwise to a stirred solution of ethyl 2-bromobenzo[d]thiazole-5-carboxylate (950 mg, 3.32 mmol, 1 eq) in THF (30 mL). The reaction was stirred for 30 min at -78°C, then allowed to warm up at 0°C and stirred at 0°C for 3h. The reaction mixture was diluted with water and the mixture was extracted with DCM twice. The combined organic layers were dried over MgSCU, filtered, and concentrated under reduced pressure. The crude was used as such in the next step without further purification. LC-MS (2): IR= 0.70 min; [M+H]+: 244.05.

[0786] 2-Bromobenzo[d]thiazole-5-carbaldehyde: In a round-bottom, double neck flask and under argon atmosphere, to a solution of (2-bromobenzo[d]thiazol-5-yl)methanol (750 mg, 3.08 mmol, 1 eq) in DCM (30.8 mL, 482 mmol, 156.3 eq) was added activated Manganese(IV) oxide (813 mg, 9.25 mmol, 3 eq) and the mixture was stirred at rt overnight. Activated Manganese(IV) oxide (813 mg, 9.25 mmol, 3 eq) was added again and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite® and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compond. LC-MS (2): IR= 0.77 min; [M+H]+: 241 .91.

[0787] N-((2-Bromobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using 2- bromobenzo[d]thiazole-5-carbaldehyde and 4,4-dimethylcyclohexan-1-amine and following the procedure described in Example 1.1 to give the title compound. LC-MS (2): IR = 0.67 min; [M+H]+: 361.05.

[0788] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide: Was synthesized using N-((2-bromobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocydohexan-1- amine and tosyl-L-proline and following the procedure described in Example 1.1 to give the title compound. LC-MS (1): tR= 1.336 min; [M+H]+: 611.07. Example 1.380 to Example 1.381 : were synthesized according to the procedure described in Example 1.96 using N-((2-bromobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocydohexan-1 -amine, L-proline methyl ester hydrochloride and the appropriate sulfonyl chloride. LC-MS data of Example 1 .380 to Example 1 .381 are listed in the table below.

[0789] Example 1.382 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2- methoxy-benzothiazol-5-ylmethyl)-amide:

[0790] (2-Chlorobenzo[d]thiazol-5-yl)methanol: At -78°C under argon, DIBAL (1.0 M in methylene chloride, 5.5 mL, 5.48 mmol, 4 eq) was added portionwise to a stirred solution of ethyl 2-chlorobenzo[d]thiazole-5-carboxylate (350 mg, 1 .38 mmol, 1 eq) in THF (12.5 mL). The reaction was stirred for 30 min at -78°C, then allowed to warm up to rt and stirred overnight. The reaction mixture was diluted with water. The mixture was extracted with DCM twice. The combined organic layers were dried with MgSCU, 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= 0.70 min; [M+H]+: 200.20.

[0791] 2-Chlorobenzo[d]thiazole-5-carbaldehyde: In a round-bottom, double-neck flask under N2 atmosphere, (2- chlorobenzo[d]thiazol-5-yl)methanol (277 mg, 1.39 mmol, 1 eq) was dissolved in DCM (14 mL) and manganese(IV) oxide (365 mg, 4.16 mmol, 3 eq) was added. The mixture was stirred at rt for 3h, filtered through Celite® and washed with DCM. The filtrate was concentrated under reduced pressure to giver the title compound which was used as such in the next step without further purification. LC-MS (2): IR= 0.82 min; [M+H]+: not seen.

[0792] N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexan-1-amine: Was synthesized using 2- chlorobenzo[d]thiazole-5-carbaldehyde and 4,4-dimethylcyclohexan-1-amine and following the procedure described in Example 1.1 to give the title compound. LC-MS (2): IR = 0.66 min; [M+H]+: 317.21.

[0793] 4,4-Difluoro-N-((2-methoxybenzo[d]thiazol-5-yl)methyl)cyclohexan-1-amine: In a sealed microwave tube, N- ((2-chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexan-1-amine (100 mg, 0.316 mmol, 1 eq) was treated with 0.5 M NaOMe in methanol (1.97 mL, 0.789 mmol, 2.5 eq) and heated to 50 °C with conventional heating (50°C) for 1 hour. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to DCM / MeOH 9.5:0.5) to give the title compound. LC-MS (2): IR= 0.65 min; [M+H]+: 313.26 . (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methoxy-benzothiazol- 5-ylmethyl)-amide: Was synthesized using 4,4-difluoro-N-((2-methoxybenzo[d]thiazol-5-yl)methyl)cyclohexan-1- amine and tosyl-L-proline and following the procedure described in Example 1.1 to give the title compound. LC-MS (1): tR= 1.285 min; [M+H]+: 563.17. Example 1.383 to Example 1.394: were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.383 to Example 1 .394 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.395 (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro- benzothiazol-5-ylmethyl)-amide:

[0794] N-((2-Fluoro-3-(hydroxymethyl)phenyl)carbamothioyl)benzamide: At rt, benzoyl isothiocyanate (0.194 mL, 1.41 mmol, 1.05 eq) was added to a solution of (3-amino-2-fluorophenyl)methanol (200 mg, 1.35 mmol, 1 eq) in MeCN (4 ml). The reaction was stirred at rt for 1h. The suspension was filtered and washed with MeCN. The solid was dried under reduced pressure to give the title compound. LC-MS (2): tR= 0.84 min; [M+H]+: 305.2.

[0795] 1-(3-Bromo-2-fluorophenyl)th iourea: N-((2-fluoro-3-(hydroxymethyl)phenyl)carbamothioyl)benzamide (3100 mg, 10.2 mmol, 1 eq) was treated with aq. 2M NaOH (25.4 mL, 50.8 mmol, 5 eq) and heated to 100°C for 1h. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated to give the title compound. LC-MS (2): tR= 0.65 min; [M+H]+: 249.03.

[0796] 5-Bromo-4-fluorobenzo[d]thiazol-2-amine: Bromine (0.922 mL, 17.8 mmol, 2 eq) was added to a stirred solution of 1-(3-bromo-2-fluorophenyl)thiourea (2220 mg, 8.91 mmol, 1 eq) in 1 ,2-dichloroethane (56.5 mL, 710 mmol, 79.62 eq) at rt. The mixture was stirred at 85° overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with aq. sat. NaHCOs. The organic layer was washed once with water, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to DCM / MeOH 9.5:0.5) to give the title compound. LC-MS (2): tR= 0.75 min; [M+H]+: 247.01.

[0797] 5-Bromo-4-fluorobenzo[d]thiazole: To a solution of 5-bromo-4-fluorobenzo[d]thiazol-2-amine (1190 mg, 4.82 mmol, 1 eq) in THF (7.9 ml) at rt, was added isopentyl nitrite (1.42 mL, 10.1 mmol, 2.1 eq) and the solution was refluxed for 2h. After cooling to rt, the solvent was evaporated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7.5:2.5) to give the title compound. LC-MS (2): tR= 0.84 min; [M+H]+: 274.94.

[0798] 4-Fluorobenzo[d]thiazole-5-carbonitrile: At rt and under N2 atmosphere, zinc cyanide (300 mg, 2.5 mmol, 0.7 eq), Zn (58.5 mg, 0.894 mmol, 0.25 eq), tris(dibenzylideneacetone)dipalladium(0) (164 mg, 0.179 mmol, 0.05003 eq) and 1,1'-bis(diphenylphosphino)ferrocene (158 mg, 0.277 mmol, 0.0775 eq) were added to a solution of 5- bromo-4-fluorobenzo[d]thiazole (830 mg, 3.58 mmol, 1 eq) in NMP (7.7 ml). The mixture was stirred at 110°C for 24h. After cooling to rt, the reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 1 :1) to give the tittle compound. LC-MS (2): tR= 0.73 min; [M+H]+: not seen.

[0799] 4-Fluorobenzo[d]thiazole-5-carbaldehyde: To a mixture of 4-fluorobenzo[d]thiazole-5-carbonitrile (220 mg, 1.23 mmol, 1 eq) in pyridine (2.7 mL), water (1 .3 mL), AcOH (1 .3 mL), under N2 atmosphere and at rt, was added sodium hypophosphite (530 mg, 6.17 mmol, 5 eq) and Raney nickel (85% in H20, 1245 mg, 12.3 mmol, 10 eq). The reaction was stirred at 50°C for 2h, diluted with EtOAc and filtered over a 0.45 pm PTFE syringe filter. The filtrate was extracted with aq. 1 M HCI soln., sat. NaHCOs and water. The organic layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (2): IR= 0.67 min; [M+H]+: not seen.

[0800] 4,4-Difluoro-N-((4-fluorobenzo[d]thiazol-5-yl)methyl)cyclohexan-1-amine: Was synthesized as described in Example 1.3 using 4-fluorobenzo[d]thiazole-5-carbaldehyde and 4,4-difluorocyclohexan-1-amine hydrochloride to give the title compound. LC-MS (2): IR= 0.56 min, [M+H]+: 301 .07.

[0801] (S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-benzothiazol-5- ylmethyl)-amide: Was sintesized using 4,4-difluoro-N-((4-fluorobenzo[d]thiazol-5-yl)methyl)cyclohexan-1-amine and tosyl-L-proline and following the procedure described in Example 1 .1 to give the title compound. LC-MS (1): IR = 1.189 min; [M+H]+: 551.15. Example 1.396 to Example 1.412 were synthesized according to the procedures described herein before using the appropriate amine or amine salt derivative, the appropriate aldehyde or ketone, the appropriate amino acid or aminoester and the appropriate sulfonyl chloride. LC-MS data of Example 1.396 to Example 1.412 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0802] Methods for the preparation of sulfoniminamides (SIA) compounds (Examples 2.x)

[0803] Example 2.1 (2S)-N-Benzyl-N-(4,4-dimethylcyclohexyl)-1-(4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide: tert-Butyl (p-tolylsulfinyl)carbamate: A soln, of 4-methyl-benzenesulfinamide (200 mg, 1 .22 mmol, 1 eq) in THF (5.5 mL, 1 .22 mmol, 1 eq) was cooled to 0°C under nitrogen atmosphere. Lithium bis(trimethylsilyl) amide solution (1.0 M in THF, 3.06 mL, 3.06 mmol, 2.5 eq) was added and the resulting orange soln, was stirred at 0°C for 30 minutes. Di-tert-butyl dicarbonate (0.426 mL, 1.84 mmol, 1.5 eq) was added dropwise and the reaction mixture stirred at 0°C for 2 hours. The reaction mixture was quenched with aq. sat. NaHCO3and extracted three times with EtOAc. The combined organic layers were dired with Na2SO4, filtered and concentrated under reduced pressure.

[0804] The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (mixture of 2 diasteromers, 108 mg, 34%) as a white solid. LC-MS (2): tR= 0.84 min; [M-CH3]+: 241.19. tert-Butyl (chloro(oxo)(p-tolyl)-X6-sulfaneylidene)carbamate: A soln, of tert-butyl (p-tolylsulfinyl)carbamate (388 mg, 1.45 mmol, 1 eq) and N-chlorosuccinimide (593 mg, 4.35 mmol, 3 eq) in MeCN (13.9 mL, 265 mmol, 182.8 eq) was stirred at rt overnight. The reaction mixture was quenched with water and extracted three times with

[0805] EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid (824 mg) that was used as a crude. LC-MS (2): tR= 1 .06 min; [M+H]+: 289.89. Methyl (N-(tert-butoxycarbonyl)-4-methylphenylsulfonimidoyl)-L-prolinate: A soln, of tert-butyl (chloro(oxo)(p- tolyl)-X6-sulfaneylidene)carbamate (824 mg, 1.42 mmol, 1 eq) and L-proline methyl ester hydrochloride (607 mg, 3.55 mmol, 2.5 eq) in a mixture MeCN (27.5 mL, 526 mmol, 369.9 eq) and DIPEA (0.73 mL, 4.27 mmol, 3 eq) was stirred at rt for 3 h. The reaction mixture was quenched with cold water and extracted three times with EtOAc. The combined organic layer was dired over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 7:3) to give the title compound (546 mg, quant.) as a yellow oil. LC-MS (2): tR= 0.95 min and 0.96 min; [M+H]+: 383.16.

[0806] Lithium (N-(tert-butoxycarbonyl)-4-methylphenylsulfonimidoyl)-L-prolinate: Aq. 1 M LiOH (0.324 mL, 0.324 mmol, 1 .25 eq) was added to a solution of methyl ( A / -(tert-butoxycarbony l)-4-methy I pheny Isulfoni m idoy l)-L-prol i nate (100 mg, 0.259 mmol, 1 eq) in THF (1.69 mL, 20.5 mmol, 79 eq) and the mixture was stirred at rt overnight. The reaction mixture was concentrated to give the title compound (104 mg, quant.) as white solid. LC-MS (2): tR= 0.85 min; [M+H]+: 369.20. tert-Butyl (((S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)pyrrolidin-1-yl)(oxo)(p-tolyl)-X6- sulfaneylidene)carbamate: A soln, of lithium (A / -(tert-butoxycarbonyl)-4-methylphenylsulfonimidoyl)-L-prolinate (20 mg, 0.0543 mmol, 1 eq) and HATU (21.7 mg, 0.057 mmol, 1.05 eq) in a mixture of DMF (0.2 mL) and DIPEA (0.0279 mL, 0.163 mmol, 3 eq) was stirred at rt for 1 h. A soln, of W-benzyl-4,4-dimethylcyclohexan-1-amine hydrochloride (13 mg, 0.0597 mmol, 1.1 eq) in DMF (0.2 mL) was then added and the resulting mixture stirred for an additional hour. The reaction mixture was acidified with formic acid and directly purified by basic prep. HPLC to give the title compound (18 mg, 58%) as a white solid. LC-MS (2): tR= 1.21 min and 1.22 min; [M+H]+: 569.31.

[0807] (2S)-A / -Benzyl-A / -(4,4-dimethylcyclohexyl)-1-(4-methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide: A soln. of tert-butyl (((S)-2-(benzy I (4, 4-d i methylcyclohexyl)carbamoyl) py rrol id in- 1 -yl) (oxo)(p-toly I )-6- sulfaneylidene)carbamate (15 mg, 0.0264 mmol, 1 eq) in a mixture of MeCN (0.2 mL, 3.83 mmol, 137.8 eq) and TFA (0.2 mL, 2.61 mmol, 93.9 eq) was stirred at 35°C for 2 h. The reaction mixture was diluted with DMF / NH3 (25% in water) and purified by basic prep. HPLC to give the title compound (6.6 mg, 57%) as an orange solid. LC-MS (1): tR= 1.341 min; [M+H]+: 468.3.

[0808] The same step can be achieved as follow: to a solution of Boc-protected compound (1 eq) in MeCN (0.13 M) at rt was added iodotrimethylsilane (2 eq). The resulting solution was stirred for 5 minutes before a few drops of NH4OH were added. The solution was evaporated under reduced pressure and the residue purified by FC or prep. HPLC.

[0809] Example 2.2 to Example 2.5 were synthesized as described in Example 2.1 using the appropriate amine or amine salt derivative and lithium (A / -(tert-butoxycarbonyl)-4-methylphenylsulfonimidoyl)-L-prolinate. LC-MS data of Example 2.2 to Example 2.5 are listed in the table below.

[0810] Example 2.6 (2S)-N-(Benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-1-(4- methoxyphenylsulfonimidoyl)pyrrolidine-2-carboxamide:

[0811] (Tritylimino)-X4-sulfanone: To a solution triphenylmethylamine (3000 mg, 11.5 mmol, 1 eq) in Et2<3 (90 mL) at rt were sussessively added dropwise Et3N (3.46 mL, 24 mmol, 2.1 eq) and thionyl chloride (0.844 mL, 11.5 mmol, 1 eq). The obtained light yellow suspension was stirred at rt for 2 h. The suspension was filtered over Celite®, washed with Et20 and the solvents evaporated under reduced pressure. The obtained light yellow solid (3.51 g, 100%) was used in the next step without further purification.

[0812] Methyl (4-methoxy-A / -tritylphenylsulfonimidoyl)-L-prolinate: 4-Methoxyphenylmagnesium bromide 0.5 M in THF (23.0 mL, 11.5 mmol, 1 eq) was added dropwise to a stirred soln, of (tritylimino)-X4-sulfanone (3513 mg, 11.5 mmol, 1 eq) in THF (71 ml) at 0°C under argon. The resulting yellow solution was stirred at 0°C for 5 minutes. tBuOCI (1457 mg, 12.1 mmol, 1.05 eq) was added dropwise (exothermic) at 0°C and the mixture was stirred for another 15 minutes before L-proline methyl ester hydrochloride (2062 mg, 12.1 mmol, 1 .05 eq) and Et3N (3.53 mL, 25.3 mmol, 2.2 eq) in THF (15 ml) were added. The resulting orange suspension was stirred overnight at rt. The pale yellow suspension was poured onto aq. sat. NaHCOs and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by FC (Hept to Hept / EtOAc 1 :1) to give the title compound (2.36 g, 38%) as a light yellow foam. LC-MS (2): tR= 1.12 min; [M+H]+: 541.2.

[0813] (4-Methoxy-A / -tritylphenylsulfonimidoyl)-L-proline: LiOH (1 M in H2O, 21.1 mL, 21.1 mmol, 5 eq) was added to a solution of methyl (4-methoxy-W-tritylphenylsulfonimidoyl)-L-prolinate (2286 mg, 4.23 mmol, 1 eq) in THF (21 mL) at rt and the resulting mixture was stirred overnight. The reaction mixture was diluted with water and the pH adjusted to 5 with aq. 1 M HCI. The product was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure ti give the title compound (1.917 g, 86%) as an orange foam. LC-MS (2): tR= 1.11 min; [M+H]+: 527.2. (2S)- / V-(Benzofuran-6-ylmethyl)- / V-(4,4-dimethylcyclohexyl)-1-(4-methoxyphenylsulfonimidoyl)pyrrolidine- 2-carboxamide: DIPEA (0.0223 mL, 0.13 mmol, 1.3 eq) was added to a soln, of (4-methoxy-A / - tritylphenylsulfonimidoyl)-L-proline (52.7 mg, 0.1 mmol, 1 eq), N-(benzofuran-6-ylmethyl)-4,4-dimethylcyclohexan- 1-amine (0.1 mmol, 1 eq) and HATU (45.6 mg, 0.12 mmol, 1.2 eq) in DMF (0.5 mL). The resulting mixture was strirred at 60°C for 1.5 h. The reaction mixture was acidified with HCI (4M in dioxane, 0.075 mL, 0.3 mmol, 3 eq), further stirred at rt for 30 minutes and purified by acidic prep. HPLC to give the title compound (13 mg, 25%) as a colorless oil. LC-MS (1): tR= 1.286 min; [M+H]+: 524.2.

[0814] Example 2.7 to Example 2.14 were synthesized as described in Example 2.6 using the appropriate amine or amine salt derivative and (4-methoxy-W-tritylphenylsulfonimidoyl)-L-proline. LC-MS data of Example 2.7 to Example 2.14 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0815] Example 2.15 to Example 2.22 were synthesized as described in Example 2.1 using the appropriate amine or amine salt derivative and lithium ( W-(tert-butoxycarbonyl)-4-methylpheny Isulfon i midoy l)-L-prolin ate followed by Boc deprotection using HCI (4M / in dioxane). LC-MS data of Example 2.15 to Example 2.22 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0816] Example 2.23 to Example 2.24 were synthesized as described in Example 2.6 using the appropriate amine or amine salt derivative and (4-methoxy-W-tritylphenylsulfonimidoyl)-L-proline. LC-MS data of Example 2.23 to Example 2.24 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0817] Examples 2.25 to Example 2.26 were synthesized as described for Example 2.1 using the appropriate amine or amine salt derivative and lithium (W-(tert-butoxycarbonyl)-4-methylpheny Isulfon i midoy l)-L-prolin ate followed by Boc deprotection using HCI (4M in dioxane). LC-MS data of Example 2.25 to Example 2.26 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0818] Example 2.27 (2S)-N-(4,4-Difluorocyclohexyl)-1-(N-ethyl-4-methylphenylsulfonimidoyl)-N-(4- methylbenzyl)pyrrolidine-2-carboxamide: NaH (60% in mineral oil, 4.49 mg, 0.112 mmol, 2 eq) was added to a stirred soln, of (2S)-W-(4,4-difluorocyclohexyl)-W-(4-methylbenzyl)-1 -(4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide (27.5 mg, 0.0562 mmol, 1 eq) in DMF (1 mL) at rt and the resulting mixture was stirred for 15 minutes. lodoethane (6.8 iL, 0.0842 mmol, 1 .5 eq) was added dropwise and the mixture was stirred for another 30 minutes. The reaction is quenched with a few drops of water, filtered and purified by basic prep. HPLC to give the title compound (20.2 g, 69%) as a white solid. LC-MS (2): tR= 0.96 min; [M+H]+: 518.3.

[0819] Example 2.28 (2S)-N-(4,4-Difluorocyclohexyl)-1-(N,4-dimethylphenylsulfonimidoyl)-N-(4- methylbenzyl)pyrrolidine-2-carboxamide: NaH (60% in mineral oil, 4.49 mg, 0.112 mmol, 2 eq) was added to a stirred solution of (2S)-A / -(4,4-difluorocyclohexyl)- / V-(4-methylbenzyl)-1-(4-methylphenylsulfonimidoyl)pyrrolidine- 2-carboxamide (27.5 mg, 0.0562 mmol, 1 eq) in DMF (1 mL) at rt and the resulting mixture was stirred for 15 minutes. Mel (0.00531 mL, 0.0842 mmol, 1.5 eq) was added dropwise and the mixture was stirred for another 30 minutes. The reaction is quenched with a few drops of water, filtered and purified by basic prep. HPLC to give the title compound (20 g, 71 %) as a white solid. LC-MS (2): tR= 0.95 min; [M+H]+: 504.3.

[0820] Example 2.29 to Example 2.46 were synthesized as described in Example 2.27 using the appropriate (4- methoxyphenylsulfonimidoyl)pyrrolidine-2-carboxamide and the appropriate alkylating agent. LC-MS data of Example 2.29 to Example 2.46 are listed in the table below. The LC-MS conditions used were LC-MS (1).

[0821] Example 2.47 (S)-N-(Benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4- methoxyphenylsulfonimidoyl)pyrrolidine-2-carboxamide and Example 2.48 (S)-A / -(benzofuran-6-ylmethyl)- N-(4,4-difluorocyclohexyl)-1-(( / ?)-4-methoxyphenylsulfonimidoyl)pyrrolidine-2-carboxamide: Methyl 4-methoxybenzenesulfinate: At 0°C under argon, W-bromosuccinimide (3700 mg, 20.8 mmol, 2 eq) was added in one portion to a solution of 4-methoxythiophenol (1.30 mL, 10.4 mmol, 1 eq) in CH2CI2 (52 mL) and MeOH (52 mL). The ice bath was removed and the reaction was stirred at rt for 1 h. The reaction mixture was poured onto aq. sat. NaHCOs and extracted with CH2CI2. The combined organic layers were dried over MgSCU, filtered and evaporated under reduced pressure. The residue was purified by FC (CH2CI2 to Cf Cfe / MeOH 95:5) to give the title compound (1.93 g, 100%) as a light pink liquid. LC-MS (2): IR = 0.73 min; [M+H]+: 182.2.

[0822] 4-Methoxybenzenesulfinamide: Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15.5 mL, 15.5 mmol, 1.498 eq) was added dropwise to a stirred soln, of methyl 4-methoxybenzenesulfinate (1928 mg, 10.4 mmol, 1 eq) in THF (15.5 mL) at -78°C under argon. The mixture was stirred at -78°C for 10 min, then the cooling bath was removed and the reaction was allowed to warm up to rt while stirring for another 1 .5 h. Aq. sat. NH4CI (40 mL) was added to quench the reaction and the mixture was stirred at rt for 30 minutes. The reaction mixture was poured o...

Claims

Claims1. A compound of Formula (I)Formula (I) whereinRing B is a 6-membered aromatic ring, wherein:• X1represents N or CRB2, wherein RB2represents hydrogen, halogen, (Ci_3)alkyl, or (Ci-3)alkoxy; and• RB1represents independently hydrogen, (Ci-4)alkyl, (Ci-3)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl;X2represents 0 or NR4, wherein R4represents hydrogen, (Ci-3)alkyl, monocyclic (Cs-ejcycloalkyl or phenyl;X3represents CH or N such that:• when X3represents CH, Ring A represents a monocyclic (Cs-ejcycloalkan-diyl or a monocyclic 5- or 6- membered heterocycloalkan-diyl comprising one ring 0 atom; or• when X3represents N, Ring A represents:• a 4- to 6-membered saturated monocyclic heterocycloalkan-diyl comprising X3and zero or one ring 0 atom; 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, hydroxy, and (Ci-3)alkylidene;• a 4- to 6-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and zero or one additional ring N atom; wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3); wherein said mono-unsaturated heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-s)alkyl; or• a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3;R1represents:• 3-cyano-3,3-dimethylpropyl or 4-cyanobutyl;• a saturated monocyclic (C^cycloalkyl; wherein said (C^cycloalkyl is unsubstituted, or mono- or disubstituted; wherein the substituents are independently selected from the group consisting of: (Ci_3)alkyl, halogen, (Ci_3)fluoroalkyl, (Ci-3)alkoxy, carbamoyl, hydroxy, and cyano;• a mono-unsaturated monocyclic (Csejcycloalkyl; wherein the double bond of said mono-unsaturated (Csejcycloalkyl does not contain the carbon atom attached to the group -N(CO)CH(R2)(R3);• a saturated bicyclic (Ce-sjspirocycloalkyl; wherein said (Ce-sjspirocycloalkyl is unsubstituted, or mono- or disubstituted; wherein the substituents are independently halogen;• a saturated fused or bridged bicyclic (Ce-sjcycloalkyl; wherein said (Ce-sjcydoalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano and carbamoyl; or• a 5- or 6-membered saturated monocyclic heterocycloalkyl comprising one ring heteroatomic group selected from 0, S, or SO2; wherein said heterocycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl, halogen, and (Ci-3)fluoroalkyl;R2represents hydrogen or methyl;R3represents:• an 8- to 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, or S; wherein said 8- to 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 8- to 10-membered ring system is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-s)alkyl, halogen and oxo;• naphthyl or an 8- to 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S; wherein said 8- to 10-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl and halogen; 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-, di- or tri-substituted, wherein the substituents are independently selected from the group consistingof: (Ci-s)alkyl, halogen, (Ci-3)alkoxy, (Ci-3)fluoroalkoxy, monocyclic (Cs-ejcycloalkyl, (Ci-3)alkylthio, (Ci-3)fluoroalkyl, cyano, NRN1RN2, wherein RN1and RN2independently represent hydrogen or (Ci-4)alkyl; or a pharmaceutically acceptable salt thereof; with the exception of the following compounds:• W-benzyl-W-(1 ,1-dioxidotetrahydrothiophen-3-yl)-1-tosylpyrrolidine-2-carboxamide;• (R)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;• (S)-A / -benzyl-A / -((R)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;• (S)-A / -benzyl-A / -((S)-1 , 1-dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;• (R)-A / -benzyl-A / -((S)-1 ,1 -dioxidotetrahydrothiophen-3-yl)-1 -tosylpyrrolidine-2-carboxamide;• N-(1 , 1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide;• (2 R)- A / -( 1 , 1 -d ioxidotetrahydrothiophen-3-yl )- / -(f uran-2-yl methyl)- 1 -tosylpyrrolidine-2-carboxamide;• (2S)-A / -(1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide;• (S)-A / -((R)-1,1-dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1-tosylpyrrolidine-2-carboxamide;• (S)-A / -((S)-1 , 1 -dioxidotetrahydrothiophen-3-yl)-A / -(furan-2-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide; and• W-[(2-Methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-W-[(tetrahydro-2-thienyl)methyl]-2- pyrrolidinecarboxamide.

2. A compound of Formula (I) according to claim 1, wherein RB1represents independently (Ci-4)alkyl, (Ci-3)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C-i)fluoroalkyl; or a pharmaceutically acceptable salt thereof.

3. A compound of Formula (I) according to claim 1 or 2, wherein X3represents CH or N such that:• when X3represents CH, Ring A represents a monocyclic (Cs-ejcycloalkan-diyl or a monocyclic 5- or 6- membered heterocycloalkan-diyl comprising one ring 0 atom; or• when X3represents N, Ring A represents:• a 4- or 5-membered saturated monocyclic heterocycloalkan-diyl comprising X3and zero ring 0 atoms; 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, hydroxy, and (Ci-s)alkylidene;• an unsubstituted 5- or 6-membered saturated monocyclic heterocycloalkan-diyl comprising X3and one ring 0 atom;• a 5-membered mono-unsaturated monocyclic heterocycloal kan-d iy I comprising X3and zero additional ring N atoms; wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3);• a 5-membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X3and one additional ring N atom; wherein the double bond of said mono-unsaturated heterocycloalkan-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3); wherein said heterocycloalkan-diyl is unsubstituted or mono-substituted with (Ci-s)alkyl; or• a 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3; or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (I) according to any one of claims 1 to 3, wherein X3represents CH and Ring A is:wherein the asterisks indicate the point of attachment of the substituent -C(=O)NR1-CH2(R2)(R3); or a pharmaceutically acceptable salt thereof.

5. A compound of Formula (I) according to any one of claims 1 to 3, wherein X3represents N and Ring A represents:• pyrrolidin-diyl; wherein said pyrrolidin-diyl is unsubstituted, or mono-substituted with (Ci-s)alkyl, halogen, (Ci-3)alkoxy, hydroxy, or (Ci_3)alkylidene; or di-substituted with (Ci-s)alkyl or halogen;• oxazolidin-diyl;• dihydro-1 / 7-pyrrol-diyl; wherein the double bond of said dihydro-1 H-pyrrol-diyl does not contain X3or the carbon atom attached to the group -CO-N(R1)CH(R2)(R3); or• a 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X3; or a pharmaceutically acceptable salt thereof.

6. A compound of Formula (I) according to any one of claims 1 to 5, wherein R1represents:• 3-cyano-3-methylbutyl;• a saturated monocyclic (Cs-ejcycloalkyl; wherein said (Cs-ejcycloalkyl is mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: methyl, fluoro, hydroxy, and cyano;• cyclohex-3-en-1-yl;• a saturated bicyclic (Ce-sjspirocycloalkyl;• a saturated fused or bridged bicyclic (Ce-sjcycloalkyl; wherein said (Ce-sjcydoalkyl is unsubstituted or disubstituted with fluoro; or• tetrahyd ro-2H-thiopyran- 1 , 1 -dioxide• or 1 ,1-dioxidotetrahydro-2 / 7-thiopyran-3-yl; or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (I) according to any one of claims 1 to 6, wherein R3represents:• a 9- or 10-membered partially aromatic fused bicyclic ring system comprising a total of zero to three ring heteroatoms independently selected from N, 0, and S; wherein said 9- or 10-membered ring system is linked to the rest of the molecule at the aromatic ring moiety; wherein said 9- or 10-membered ring system is unsubstituted, or mono-substituted with halogen;• a 9- or 10-membered heteroaryl comprising a total of one to three ring heteroatoms independently selected from N, 0, and S ; wherein said 9- or 10-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci.3)alkyl and halogen: or• phenyl; wherein said phenyl is 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)alkylthio; or a pharmaceutically acceptable salt thereof.

8. A compound of Formula (I) according to any one of claims 1 to 7, which are also compounds of the Formula (IV):Formula (IV);or a pharmaceutically acceptable salt thereof.

9. A compound of Formula (I) according to claim 1 , selected from the group consisting of:(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-6-ylmethyl-(4,4-difluoro-cydohexyl)- amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-dimethyl-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(1, 1-dioxo-hexahydro-X6- thiopyran-4-yl)-amide;(1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1.0]hexane-2- carboxamide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4-fluoro-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[b]thiophen-5-ylmethyl-(4-hydroxy-cyclohexyl)- amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)- amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;(2S)-N-(benzofuran-6-ylmethyl)-N-(cyclohex-3-en-1-yl)-1-tosylpyrrolidine-2-carboxamide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzooxazol-5-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzooxazol-6-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzooxazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(1 R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(2S,4S)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzooxazol-6-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(2S)-N-(benzo[b]thiophen-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6- ylmethyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4-dimethyl- cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(1,1-dioxo- hexahydro-1X6-thiopyran-4-yl)-amide;(1 R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,3S,4S)-2-(Toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4- dimethyl-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzofuran-6-ylmethyl-(4-hydroxy-cyclohexyl)-amide;(2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;(2S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;(2S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;(2S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-tosylpyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4-hydroxy- cyclohexyl)-amide;(1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R*,5S*)-(2RS)-N-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-(benzo[d]oxazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R*,5S*)-(2RS)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-tosyl-3-azabicydo[3.1 ,0]hexane-2- carboxamide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-dimethyl- cyclohexyl)-amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4- dimethyl-cyclohexyl)-amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-tosylpyrrolidine-2-carboxamide;(25.45)-4-Fluoro-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(S)-N-(4,4-Difluorocydohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-1 -tosylpyrrolidine-2-carboxamide;(25.45)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1 ,0]heptan-3-yl)-4-fluoro-1 -tosylpyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(5-fluoro-2,3-dihydro-benzofuran- 6-ylmethyl)-amide;(1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;(25.45)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-4-fluoro-1-tosylpyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(4-fluoro-2,3-dihydro-benzofuran- 6-ylmethyl)-amide;(2S)-N-(benzo[d]oxazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;(2S)-N-(benzo[d]oxazol-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;(2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2- carboxamide;(2S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide;(S)-4-Methylene-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(2S,4S)-4-Fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1 R,3R,6R)-bicyclo[4.1 ,0]hept-3-yl-(2,3-dihydro-benzofuran-6-ylmethyl)-amide;(S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(S)-N-(4,4-difluorocyclohexyl)-N-(furo[3,2-c]pyridin-6-ylmethyl)-1 -tosylpyrrolidine-2-carboxamide;(1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)- (2,3-dihydro-benzofuran-6-ylmethyl)-amide;(1 R*,5S*)-(2RS)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5- ylmethyl-(4,4-difluoro-cyclohexyl)-amide;(1 S,2S,5R)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;(1 R,2S,5S)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;(1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid benzothiazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;(1 R,3S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-tosyl-2-azabicyclo[3.1 ,0]hexane-3- carboxamide;(1 R,3S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-((4-methoxyphenyl)sulfonyl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide;(1 R,3S,5R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-tosyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide;(1 R,3S,5R)-N-(bicyclo[4.1 .0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((4-methoxyphenyl)sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide;(1 R,3S,5R)-2-(4-Methoxy-benzenesulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid benzooxazol-5-ylmethyl- (4,4-difluoro-cydohexyl)-amide;(1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;(1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicydo[3.1 ,0]hexane-3-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cydohexyl)-amide;(1 R,2S,5S)-3-(Toluene-4-sulfonyl)-3-azabicydo[3.1.0]hexane-2-carboxylic add (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;(1S,2S,5R)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic add (4,4-difluoro-cyclohexyl)-(2,3- dihydro-benzofuran-6-ylmethyl)-amide;(1 R,2S,5S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-tosyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;(1S,2S,5R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-tosyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;(S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methoxyphenylsulfonimidoyl)pyrrolidine-2- carboxamide ;(S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxyphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(1 R*,5S*)-(2RS)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-d ifluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide;(1 S,2S,5R)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4 ,4-dif I uoro-cyclohexy I)- (2,3-dihydro-benzofuran-6-ylmethyl)-amide;(1 R,2S,5S)-3-(4-Methoxy-benzenesulfonyl)-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)- (2,3-dihydro-benzofuran-6-ylmethyl)-amide;(1R* 5S*)-(2RS)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;(1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicydo[4.1 .0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;(1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicydo[4.1 .0]heptan-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicyclo[3.1 ,0]hexane-2-carboxamide;(1 R*,5S*)-(2RS)-N-(bicyclo[4.1 ,0]heptan-3-y l)-N-((2, 3-di hyd robenzofu ran-6-yl) methy l)-3-((4- methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;(1S,2S,5R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicydo[3.1 ,0]hexane-2-carboxamide;(1 R,2S,5S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3- azabicydo[3.1 ,0]hexane-2-carboxamide;(2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-1-(N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide;(1 R,3S,5R)-2-(Toluene-4-sulfonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro- 2,3-dihydro-benzofuran-6-ylmethyl)-amide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(S)-1-(3-Fluoro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(S)-1-(4-Chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran- 6-ylmethyl)-amide;(S)-1-(4-Cyclopropyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(2S,5R)-5-Methyl-1 -(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(2S)-N-(4,4-difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1 -tosylpyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-2,3-dihydro-1 H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro- benzofuran-6-ylmethyl)-amide;(1 R,3S,4S)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((6-methylpyridin-3- yl)sulfonyl)-2-azabicydo[2.2.1 ]heptane-3-carboxamide;(1 R,3S,4S)-2-(6-Methyl-pyridine-3-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (4,4-difluoro- cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(2S)-N-(benzo[d][1 , 3]dioxol-5-y I methy l)-N -(bicyclo[4.1 ,0]heptan-3-yl)-1 -tosylpyrrolidine-2-carboxamide;(2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;(2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-(3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(benzo[d][1 ,3]dioxol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-(methylthio)benzyl)pyrrolidine-2- carboxamide;(2S)-N-(benzofuran-6-ylmethyl)-1 -(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;(2S)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4-difluorocyclohexyl)-N-((2,3- dihydrobenzofuran-6-yl)methyl)pyrrolidine-2-carboxamide;(2S)-N-(benzo[d]thiazol-5-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;(1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methoxyphenylsulfonimidoyl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide;(2S)-N-(4-chlorobenzyl)-1-(N-cyclopropyl-4-methylphenylsulfonimidoyl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2- carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(1 R*,2S*)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(2S)-N-(4-chlorobenzyl)-N-(4,4-dimethylcyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(2S)-N-(4-chlorobenzyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-((4-ethynyl-2-hydroxycyclopentyl)pyrrolidine-2-carboxamide;(2S)-N-(4-chlorobenzyl)-N-(1 , 1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide;(2S)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzooxazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(2S)-N-((3S,5R)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4- methylbenzyl)pyrrolidine-2-carboxamide;(2S)-N-(4-chlorobenzyl)-N-((3S,5R)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(4-chlorobenzyl)-N-(1 , 1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(2S)-N-(4-chlorobenzyl)-N-((3S,6R)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(1S,2R)-N-(bicyclo[4.1.0]heptan-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-tosylcyclopentane-1- carboxamide;(1S,2R)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-2-tosylcyclopentane-1 -carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(4,4-difluoro-cyclohexyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct-6-yl)- amide;(2S)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;(2S)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(4-Chlorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(2S)-N-(4-Chloro-2-fluorobenzyl)-N-((3S,5r)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-(4-Chloro-2-fluorobenzyl)-N-((3S,6r)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(2S)-N-((3S,6r)-1 , 1 -D if I uorospiro[2.5]octan-6-y I)- 1 -(( R)-N , 4-d i methy Iphenylsu Ifon i midoy l)-N -(4- methylbenzyl)pyrrolidine-2-carboxamide;(1S,2R)-N-(4-chlorobenzyl)-N-((1S*,3R*)-3-cyanocyclopentyl)-2-tosylcyclopentane-1-carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct-6-yl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methoxy-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(4-cyano-cyclohexyl)-amide;(2S)-N-(4-Chlorobenzyl)-N-((1 R*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(25.45)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- methylpyrrolidine-2-carboxamide;(25.45)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- methylpyrrolidine-2-carboxamide;(25.45)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-(N,4-dimethylphenylsulfonimidoyl)-4-methylpyrrolidine-2- carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzooxazol-5-ylmethyl-(1 ,1-difluoro-spiro[2.5]oct-6- yl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methyl-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-(4-methylsulfanyl- benzyl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(1 ,1-difluoro-spiro[2.5]oct- 6-yl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1 ,3]dioxol-5-ylmethyl-(1 ,1-difluoro- spiro[2.5]oct-6-yl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(2-fluoro-4-methyl-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(4-cyano-cyclohexyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(2,4-difluoro-benzyl)-amide;(1S,2R)-N-(4-Cyanocyclohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1 -carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methylsulfanyl-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methyl-benzyl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-bromo-benzyl)-(4-cyano-cyclohexyl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-fluoro-benzyl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(3-cyano-3,3-dimethyl-propyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (7,7-difluoro-bicyclo[4.1.0]hept-3-yl)-(4-methyl- benzyl)-amide;(25.45)-N-(4-chlorobenzyl)-N-(1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4- fluoropyrrolidine-2-carboxamide;(25.45)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)- 4-methylpyrrolidine-2-carboxamide;(S)-N-((1 R*,3S*)-3-cyanocyclopentyl)-N-(4-methylbenzyl)-1-tosylpyrrolidine-2-carboxamide;(S)-N-(4-chlorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-1-tosylpyrrolidine-2-carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1S*,3R*)-3-cyano-cyclopentyl)-(4-methyl-benzyl)- amide;(25.45)-N-(4-Chlorobenzyl)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-(R)-(N,4-dimethylphenylsulfonimidoyl)- 4-methylpyrrolidine-2-carboxamide;(2RS)-N-((1 R*,3S*)-3-Cyanocydopentyl)-N-(4-methylbenzyl)-3-tosyloxazolidine-2-carboxamide;(2RS)-N-((1 R*,3S*)-3-Cyanocydopentyl)-N-(4-chlorobenzyl)-3-tosyloxazolidine-2-carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-(4-methyl-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-indan-5-ylmethyl- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (4-chloro-2-fluoro-benzyl)-(3-cyano-3,3-dimethyl- propyl)-amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-bromo-benzyl)-(3-cyano-3,3-dimethyl-propyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1 R*,3R*)-3-cyano-cyclohexyl)-(4-methyl-benzyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-((1 R,3S)-3-cyano-cyclopentyl)- amide;(1S,2R)-N-((1 R*,3S*)-3-Cyanocyclopentyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;(1S,2R)-N-(7,7-Difluorobicyclo[4.1 ,0]heptan-3-yl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;(1S,2R)-N-((1 R*,3R*)-3-Cyanocydohexyl)-N-((2,3-dihydro-1 H-inden-5-yl)methyl)-2-tosylcyclopentane-1- carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid ((1 R*,3S*)-3-cyano-cyclopentyl)-(3-fluoro-4-methyl- benzyl)-amide;(25.45)-N-(4-chloro-2-fluorobenzyl)-N-(1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)- 4-fluoropyrrolidine-2-carboxamide;(25.45)-N-(4,4-difluorocydohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-4-methyl-N-(4-methylbenzyl) pyrrolidine-2-carboxamide;(1S,2R)-N-((1r,4S)-4-cyanocyclohexyl)-N-(4-(methyl-d3)benzyl)-2-tosylcydopentane-1-carboxamide;(1S,2R)-N-(4-Chloro-2-fluorobenzyl)-N-((1 R*,3S*)-3-cyanocyclopentyl)-2-tosylcyclopentane-1-carboxamide;(1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid benzooxazol-6-ylmethyl-(4,4-difluoro-cydohexyl)- amide;(1S,2R)-2-(Toluene-4-sulfonyl)-cydopentanecarboxylic acid (4,4-difluoro-cyclohexyl)-(6-fluoro-benzooxazol-5- ylmethyl)-amide;(1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-2-((R)-4-methylphenylsulfonimidoyl) cyclopentane-1 -carboxamide;(1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-2-((S)-4-methylphenylsulfonimidoyl) cyclopentane-1 -carboxamide;(2S)-N-(4-chlorobenzyl)-N-((1 R)-3-cyano-3-methylcyclopentyl)-1-tosylpyrrolidine-2-carboxamide;(1S,2R)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocyclopentyl)-2-((R)-4-methylphenylsulfonimidoyl)cyclopentane-1- carboxamide;(1S,2R)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocyclopentyl)-2-((S)-4-methylphenylsulfonimidoyl)cyclopentane-1- carboxamide;(1S,2R)-N-(4-chlorobenzyl)-N-((1 R)-3-cyano-3-methylcyclopentyl)-2-tosylcyclopentane-1 -carboxamide;(S)-N-((3R,5s)-1,1-difluorospiro[2.3]hexan-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonimidoyl) pyrrolidine-2-carboxamide;(S)-N-((3S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonimidoyl) pyrrolidine-2-carboxamide;(S)-N-((1S*,3R*)-3-Cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;(S)-N-((1S*,3S*)-3-Cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;(S)-N-(4-chlorobenzyl)-N-((1 R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(S)-N-((1 R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)-N-(4-methylbenzyl)pyrrolidine-2- carboxamide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)-1 -tosylpyrrolidine-2-carboxamide;(S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 , 1 -dif I uorospi ro[2.3]hexan-5-yl)-1 -tosylpyrrolidine-2-carboxamide;(S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((3-fluoro-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;(S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 , 1 -dif I uorospi ro[2.3]hexan-5-yl)-1 -((3-fluoro-4- methylphenyl)sulfonyl)pyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methyl-benzothiazol-5- ylmethyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4- difluoro-cyclohexyl)-amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;(S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide;(S)-N-(benzo[d]th i azol-5-y I methy l)-N -((3R, 5s)- 1 , 1 -dif I uorospi ro[2 ,3]hexan-5-y l)-1 -((4- methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide;(1 R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-tosyl-3-azabicyclo[3.1 ,0]hexane-2- carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonimidoyl)pyrrolidine-2- carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonimidoyl)pyrrolidine- 2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1 S,3S,6S)- bicyclo[4.1 ,0]hept-3-yl-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1 ,0]hept-3- yl-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3R,6S)-bicyclo[4.1.0]hept-3- yl-amide;(S)-1-(4-Methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)- bicydo[4.1.0]hept-3-yl-amide;(S)-1-(4-lodo-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cydohexyl)-amide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro- cyclohexyl)-amide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1 ,1-difluorospiro[2.3]hexan-5-yl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1 ,1-difluorospiro[2.5]octan-6-yl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-1-(4-Ethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicydo[4.1.0]heptan-3-yl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl-(1 ,1- difluoro-spiro[2.5]oct-6-yl)-amide;(1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl-(1 ,1- difluoro-spiro[2.3]hex-5-yl)-amide;(1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cydohexyl)-(2- methyl-benzothiazol-5-ylmethyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4-difluoro- cyclohexyl)-amide;(S)-1-(3-Fluoro-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4- difluoro-cydohexyl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(3-methoxy-cydohexyl)-amide;(S)-1-(3-Fluoro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro- cyclohexyl)-amide;(S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-((2-Bromobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-3-fluoro-N,4- dimethylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-N-((2-Chlorobenzo[d]thiazol-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxy-N- methylphenylsulfonimidoyl)pyrrolidine-2-carboxamide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(6-methyl-1 ,1 -dioxo-hexahydro-1 X6- thiopyran-3-yl)-amide;(S)-1-(Toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4-chloro-benzyl)-(1 ,1-dioxo-hexahydro-1X6-thiopyran-3- yl)-amide;(1S*,2S*,5R*)-3-(Toluene-4-sulfonyl)-3-azabicydo[3.2.0]heptane-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(1 R*,2S*,5S*)-3-(Toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4- difluoro-cyclohexyl)-amide;(1 R*,2S*,5S*)-N-Benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptan-3-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-2- carboxamide; and(1 R,2S,5S)-N-(Benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-((R)-N,4-dimethylphenylsulfonimidoyl)-3- azabicyclo[3.1 ,0]hexane-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.

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