Aryl sulfone and sulfone ketone derivatives as orexin receptor modulators

Abstract

This invention relates to novel aryl sulfones and sulfone ketone derivatives of formula (I), wherein R 1 R 2 R 3 R B1 X 1 X 2 X 3 Rings A and B are as described in this specification; regarding their pharmaceutically acceptable salts and their use as pharmaceuticals. This invention also relates to related aspects including methods for preparing such compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as agonists of orexin-2 receptors (hereinafter also referred to as OX2R), and particularly as agonists of human orexin-2 receptors (hereinafter also referred to as hOX2R).

Description

[Technical Field] This invention relates to novel aryl sulfones and sulfone derivatives of formula (I) and their use as pharmaceuticals. The invention also relates to methods for preparing such compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as agonists of orexin-2 receptors (hereinafter also referred to as OX2R), and particularly as agonists of human orexin-2 receptors (hereinafter also referred to as hOX2R). [Background Technology] The orexin system (also known as the hypothalamus-secretin system) was discovered in 1998 by two independent research groups and consists of two neuropeptides and two receptors (de Lecea L et al.; The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity; Proc Natl Acad Sci US 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 after 696). Orexin A (OX-A) and orexin B (OX-B) are neuropeptides specifically expressed in a small group of neurons in the lateral, dorsomedial, and periforaminal regions of the hypothalamus. They are derived from a single precursor proorexin peptide via proteolytic processes. Orexin A is a 33-amino acid peptide, and orexin B is a 28-amino acid peptide. Orexin binds to two G protein-coupled receptors (orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R)) that are widely expressed throughout the brain. OX-A binds to both receptors with similar affinity, while OX-B preferentially binds to OX2R. The widespread distribution of orexin fibers and receptors in many brain regions suggests that orexin has multiple functions.

[0003] The orexin system is considered crucial for the stability of wakefulness and the regulation of insomnia according to various physiological processes (de Lecea L; Hypocretins and the neurobiology of sleep-wake mechanisms; ProgBrain 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 mainly 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). It sends excitatory projections to arousal-promoting neuronal groups, such as histaminergic neurons in the tuberomammillary nucleus, noradrenergic neurons in the locus coeruleus, serotonin-excited neurons in the dorsal raphe, dopamine-excited neurons in the ventral tegmentum, and cholinergic neurons in the basal forebrain, pons, and dorsolateral tegmental nuclei. Different arousal-promoting brain regions primarily exhibit OX1R or OX1R, or both (see Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat RevNeurosci. 2007, 8(3):171-81)). The levels of OX-A in the extracellular space and cerebrospinal fluid (CSF) follow a diurnal rhythm: they increase during wakefulness and decrease rapidly during sleep.Elevated orexin levels are necessary to cope with increased sleep pressure during prolonged wakefulness in order to prevent 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 aprimate model: implications for the consolidation of wakefulness; J Neurosci.2003, 23(8):3555-60).

[0004] Furthermore, orexin neurons integrate multiple signals related to internal or external environments (e.g., mood, day / night cycle, sleep stress, energy balance) and send information to various neuronal systems to regulate arousal levels to the levels required for appropriate behavioral responses (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 not only follow activation patterns associated with circadian rhythms but also with behaviorally relevant bursts of firing, and are particularly active, for example, during periods of high 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).

[0005] Evidence from human and animal studies has shown that narcolepsy type 1 (a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, and cataplexy (a loss of muscle tone in a state of full consciousness, usually triggered by positive emotions) is associated with a deficiency in the orexinknockout system (Chemelli RM et al.; Narcolepsy in orexinknockout 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 humans, 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 onsetnarcolepsy and a generalized absence of hypocretin peptides in humannarcoleptic brains; Nat Med. 2000, 6(9):991-7), and low OX-A levels in CSF can be used as a specific biometric for diagnosis (Dauvilliers Y et al.; Narcolepsy and Other Central Hypersomnias; Continuum (Minneap Minn). 2017, 23(4, Sleep Neurology):989-1004).Several gene-based animal models (in mice and dogs) have shown that disruption of orexin signaling leads to a narcolepsy phenotype accompanied by excessive daytime sleepiness (fragmented awakenings) 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 sleepregulatory processes; Neuron. 2003, 38(5):715-30). Central administration of OX-A or ectopic expression of proorexin transgenes can reverse the narcolepsy phenotype in mice with depleted orexin neurons (Mieda M et al.; Orexin peptides prevent cataplexy and improve wakefulness in an orexinneuron-ablated model of narcolepsy in mice; Proc Natl Acad Sci US A. 2004, 101(13):4649-54). Their data suggest that orexin receptor agonists are an appropriate treatment for patients with narcolepsy.

[0006] In addition, intraventricular injection of OX-A in rats or mice significantly increased wakefulness and reduced both non-rapid eye movement (NREM) sleep 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 US A. 2001, 98(17):9965-70). Furthermore, optogenetic or chemogenetic studies have shown that stimulation of orexin neurons reduces the waiting time between sleep and wakefulness in both NREM and REM sleep, and induces wakefulness with a very short waiting time (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; PLoSOne. 2011, 6(5):e20360).

[0007] In summary, this suggests that activation of the orexin receptor is a promising treatment for the following patient complaints related to difficulty maintaining wakefulness: feelings of excessive sleepiness; episodes of involuntary sleep onset, including sleep attacks (sleep attacks without aura symptoms); long-term primary sleep attacks of fatigue; recurrent naps on the same day; or sleep inertia (long-term difficulty in waking up, accompanied by irritability, automatisms, or confusion).

[0008] Such conditions can be seen in sleep disorders such as hypersomnia. Based on the International Classification of Sleep Disorders, 3rd Edition (ICSD-3) (Sateia MJ; International classification of sleep disorders-thirdedition: highlights and modifications; Chest. 2014, 146(5):1387-1394), central disorders of hypersomnia include narcolepsy (including narcolepsy type 1 and narcolepsy type 2), idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to medical conditions, hypersomnia due to drugs or substances, hypersomnia associated with mental illness, and sleep deprivation syndrome.

[0009] Narcolepsy is thought to be the result of an autoimmune disorder that specifically destroys neurons that produce orexin. However, symptoms of narcolepsy (or secondary narcolepsy) can occur during other neurological processes and are caused by underlying conditions such as genetic disorders (such as Prader-Willi syndrome, Niemann-Pick C disease, or myotonic dystrophy), tumors, or head trauma (especially when the hypothalamic region 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). Decreased orexin levels in CSF are commonly seen in cases of symptomatic narcolepsy and EDS.

[0010] Other immune-mediated disorders can show disruptions in orexin neurotransmission, with symptoms reminiscent of narcolepsy (Fronczek R et al.; The orexin / hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms; Handb ClinNeurol. 2021, 180:343-358). In some of these cases, the destruction of partial orexin neurons, among other cell types, has been confirmed. For example, orexin deficiency and narcolepsy-like symptoms in CSF have been observed in patients with the following conditions: 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-Barré syndrome (Nishino S et al.; CSF hypocretin levels in Guillain-Barré 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-Ma2associated encephalitis; Neurology. 2004, 62(1):138-40).

[0011] EDS and other sleep disorders are frequently reported in neurodegenerative diseases. The loss of orexin neurons has been described in several neurodegenerative diseases and is shown to contribute to EDS and sleep disorders, including Alzheimer's disease (Fronczek R et al.; Hypocretin (orexin) loss in Alzheimer's disease; Neurobiol Aging. 2012, 33(8):1642-50), Parkinson's disease (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 disorders in Parkinson's Disease; Brain. 2008, 131(Pt 1):e88), and Lewy body dementia (Kasanuki K et al.; Neuropathological investigation). (References include: of hypocretin expression in brains of dementia with Lewy bodies; Neurosci Lett. 2014, 569:68-73), Perry syndrome (Mishima T et al.; Reduced orexin immuneoreactivity in Perry syndrome and multiple system atrophy; ParkinsonismRelat 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 disease (Petersen A et al.; Orexin loss in Huntington's disease; Hum Mol Genet. 2005, 14(1):39-47).

[0012] Excessive Daytime Sleepiness (EDS) can also be observed in circadian sleep-wake disorders, such as sleep-wake phase delay disorder, shift work disorder, or jet lag, and is caused by a mismatch between the biological clock and social demands (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). This is especially true when patients need to remain awake, but their alertness levels are low due to their internal biological clock.

[0013] Similarly, EDS is associated with conditions such as obesity, diabetes, depression, and objective sleep disorders, such as sleep apnea (Fernandez-Mendoza J et al.; Natural history of excessive daytimesleepiness: role of obesity, weight loss, depression, and sleep propensity; Sleep. 2015, 38(3):351-60). Obstructive sleep apnea (OSA) is a particularly notable example, suggesting that dysregulation of the orexin system may play a role in the pathogenesis of this condition (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 have been reported in patients with OSA (Busquets X et al.; Decreased plasma levels of orexin-A in sleep apnea; Respiration. 2004, 71(6):575-9). In addition, the frequency of spontaneous sleep apnea increased in the orexin knockout narcolepsy mouse model (Nakamura A et al.; Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleepapnea in orexin knockout mice; J Appl Physiol (1985). 2007, 102(1):241-8).

[0014] Unlike EDS, fatigue is characterized by a lack of energy (“feelings of exhaustion and despair are dominant”) and a diminished ability to perform previously easily accomplished physical activities. It may be accompanied by mental fatigue with poor concentration and memory, but it is not usually associated with inappropriate daytime sleep episodes. It has been observed in a variety of conditions, including infections, chronic inflammatory diseases, cancer, and neurodegeneration. This suggests that dysregulation of the orexin system can cause fatigue. In rodents, lipopolysaccharide-induced fatigue (or disease behavior) is associated with decreased orexin neuronal activity and reduced OX-A in the CSF (Grossberg AJ et al.; Inflammation-induced lethargy is mediated by suppression of orexinneuron activity; J Neurosci. 2011, 31(31):11376-86). Intraventricular injection of OX-A in lipopolysaccharide-treated rats restored normal cage-exploration behavior. Similar findings were retrieved in tumor-bearing rats, suggesting that reduced orexin signaling may play a role in chronic diseases.

[0015] In humans, 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 patients with primary Sjogren's syndrome had reduced levels of OX-A in their CSF, a chronic autoimmune disease characterized by inflammation of exocrine glands, with fatigue being a key 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).

[0016] This typically indicates that dysfunction of the orexin system can contribute to fatigue, and that orexin receptor agonists can help patients with chronic diseases who experience fatigue, thereby improving their quality of life.

[0017] Traumatic brain injury (TBI) can induce disorders of consciousness (DOC), such as coma syndrome, 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 that includes wakefulness and perception, and the ascending reticular activating system (ARAS) is known to play a fundamental 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 brainstem reticular formations (such as the nuclei of serotonin-, norepinephrine-, dopamine-, choline-, and glutamic neurons) to nonspecific thalamic nuclei, the basal forebrain, the hypothalamus, and the cerebral cortex. ARAS damage can lead to loss of consciousness following traumatic brain injury (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 JPhys Med Rehabil. 2019, 98(12):1067-1071). Monoaminergic drugs that work by increasing levels of, for example, dopamine, norepinephrine, and acetylcholine may have some beneficial effects on DOC. Given its transmission to the arousal system and its role in stabilizing the state of wakefulness / awakening, the orexin system is well-positioned to support and regulate consciousness. Interestingly, abnormally low levels of OX-A have been reported in the CSF in a large number of patients with moderate to severe TBI (Baumann CR et al.; Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury; Neurology. 2005, 65(1):147-9).Preclinical studies in a TBI mouse model showed that electromagnetically controlled cortical impacts in both the hypothalamus and hippocampus reduced orexin levels and decreased diurnal orexin variability (Willie JT et al.; Controlled cortical impact traumatic brain injury acutely disrupts swakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice; J Neurotrauma. 2012, 29(10):1908-21). Their data suggest that the orexin system is dysregulated after TBI and that orexin receptor agonists may be a suitable treatment option.

[0018] Furthermore, in a rat model of unconsciousness induced by acute alcohol poisoning, icv administration of OX-A or OX-B reduced the duration of right reflex loss, shortened coma time, and decreased EEG differential signal (JiaX et al.; Arousal effects of orexin A on acute alcohol intoxication-induced coma rats; Neuropharmacology. 2012, 62(2):775-83). This indicates that orexin receptor agonists may have a pro-awakening effect in coma induced by acute alcohol poisoning. Furthermore, intranasal or ICV administration of OX-A contributes to arousal recovery in rat models of cardiac arrest-induced coma (Koenig MA et al.; Intraventricular orexin-A improves arousal and early EEG entropy in rats after cardiac arrest; BrainRes. 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). Following cardiac failure, orexin agonists may subsequently provide beneficial effects.

[0019] Furthermore, in this model of cardiac arrest, OX-A not only accelerated arousal and recovery of movement, but also exhibited some anti-inflammatory effects. Other studies have enhanced the potential role of the orexin system in regulating inflammation. For example, Ogawa et al. (Ogawa Y et al.; Peripherally administered orexin improves survival of mice with endotoxin shock; Elife. 2016, 5) showed that in a mouse model of septic shock, administration of OX-A contributed to survival and recovery and inhibited excessive cytokine production. In a mouse model of intracerebral hemorrhage, OX-A improved neurological outcomes and alleviated cerebral 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). This suggests that OX-A is beneficial due to its anti-inflammatory effects.

[0020] Furthermore, it also indicates that orexin promotes unconscious awakening induced by anesthetics, where intraperitoneal or gas anesthesia and inhibition of orexin signaling delay awakening (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 generalanesthesia; Proc Natl Acad Sci US A. 2008, 105(4):1309-14; Zhang LN et al.; Orexin-A facilitates emergence of the rat from isoflurane anesthesia viamediation of the basal forebrain; Neuropeptides. 2016, 58:7-14; Kushikata T et al.; Orexinergic neurons and barbiturate anesthesia; Neuroscience. 2003, 121(4):855-63).

[0021] In addition to stabilizing wakefulness, the orexin system appears to play a role in many other functions, such as energy homeostasis, learning and memory, stress / emotion, reward and pain regulation.

[0022] The orexin system is involved in the regulation of feeding behavior and energy homeostasis. Orexin neurons are sensitive to glucose, leptin, and ghrelin. High concentrations of glucose and leptin inhibit orexin neurons, while low concentrations of glucose and ghrelin stimulate orexin neurons (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 suggests that behavioral / wake responses can be coordinated with energy requirements (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, narcolepsy mice exhibit energy homeostasis. Despite significantly lower calorie expenditure, these mice still exhibited obesity, which could be partly explained by their lower energy expenditure (Zhang S et al.; Sleep / wakefragmentation 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 patients with narcolepsy (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 have shown that central OX-A involvement is associated with the prevention of 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 JPhysiol Endocrinol Metab. 2012, 303(7):E865-74).

[0023] In summary, this suggests that orexin receptor agonists may be a promising treatment option for diseases associated with eating behavior or energy homeostasis.

[0024] The orexin system appears to play a role in learning and memory. On the one hand, given its recognized role in maintaining wakefulness and regulating sleep-wake mechanisms according to 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.; NeuralCircuitry of Wakefulness and Sleep; Neuron. 2017, 93(4):747-765), it would contribute to a stable level of wakefulness necessary for learning. On the other hand, orexin neurons also project to regions involved in learning and memory processes, such as the hippocampus (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23):9996-10015), suggesting a potential direct role. Preclinical data have shown that activation of the orexin system can benefit learning and memory. For example, mouse data show that OX-A can promote increased hippocampal plasticity associated with realization 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 sleep-deprived rhesus monkeys' performance on short-term memory tasks altered by sleep loss, 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). Furthermore, ICV injection of OX-A in wild-type mice improved memory processing in two different avoidance tasks and also improved memory performance in the accelerated aging mouse strain (SAMP8), demonstrating age-related learning and memory deficits (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 age-related dementia. Age also affects the orexin system. In fact, loss of orexin neurons has been reported in both humans and animals (see Nixon JP et al.; Sleep disorders, obesity, and aging: the role of orexin; Ageing ResRev. 2015, 20:63-73) for a review). Interestingly, intranasal administration of OX-A improved age-related impairment of attention performance in rats (Calva CB et al.; Intranasal administration of orexinpeptides: Mechanisms and therapeutic potential for age-related cognitivedysfunction; 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), demonstrating the therapeutic benefit of orexin receptor agonists for age-related cognitive disorders.

[0026] Furthermore, local intracerebral infusion of OX-A can reduce distraction-induced decrease in attentional 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) This suggests that orexin receptor agonists may be suitable for treating conditions accompanied by attention deficit.

[0027] The orexin system plays a role in motivating behaviors (Mahler SV et al.; Motivationalactivation: a unifying hypothesis of orexin / hypocretin function; NatNeurosci. 2014, 17(10):1298-303). Motivation (the psychological drive under goal-oriented behavior) is crucial to the psychological and physiological processes that organize adaptive behaviors. Motivated behaviors support the development of behaviors such as foraging, coordinating stress responses, and coping strategies. Dysregulation of these processes can lead to neuropsychiatric disorders, in which orexin receptor agonists can provide beneficial effects.

[0028] For example, OX2R stimulation in mice during social stress promotes a positive response in a decision-making test (in this test, it promotes escape behavior) (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). OX2R stimulation also increases resilience to social stress (i.e., social novelty preference) (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, a key symptom of depression, can be described as the inability to experience pleasure or seek satisfaction, and encompasses reward-related disorders such as impaired decision-making and motivational drives. Anhedonia symptoms cause dysregulation of the brain's reward processing, in which alterations in the function of the orexin system can 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 demonstrated a link between orexin system dysregulation 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 exhibiting depressive-like behaviors, compared with Wistar rats, OX-A immunoreactivity and preproorexin mRNA levels were reduced in the hypothalamus (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 long-term, unavoidable stressors (such as long-term stress in the social defeat model), decreased orexin neurotransmission has been 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), low levels of OX-A in the cerebrospinal fluid have been 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 a sharp diurnal variation in orexin levels in the cerebrospinal fluid (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, low levels of OX-A in CSF were associated with psychiatric symptoms of depression in suicide attempters, such as fatigue, slow movement, and a higher overall grade of 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 numerous brain regions involved in pain regulation, including the dorsal horn of the spinal cord, the periventrolateral aqueductal gray matter, the ventromedial cephalic medulla oblongata, and the caudate nucleus of the trigeminal nerve (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23): 9996-10015). Administration of orexin to the spinal cord or to brain regions associated with descending pain regulation circuits reduces nociceptive responses in animal models of inflammatory pain and chronic neuropathic pain. Therefore, intrathecal or local injection of orexin receptor antagonists into pain-regulating brain regions modulates pain responses (see commentary: (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)). Furthermore, orexin knockout mice exhibited lower pain thresholds following peripheral local inflammation (Watanabe S et al.; Persistent pain and stress activate pain-inhibitory orexin pathways; Neuroreport. 2005, 16(1):5-8). Interestingly, patients with cluster headaches reported lower CSF orexin levels (Barloese M et al.; Reduced CSF hypocretin-1 levels are associated with cluster headache; Cephalalgia. 2015, 35(10):869-76), and the prevalence of migraines was increased in patients with narcoleptic disease (Dahmen N et al.; Increased frequency of migraine in narcoleptic patients: a confirmatory study; Cephalalgia. 2003, 23(1):14-9).

[0032] Overall, this suggests that orexin receptor agonists may have a beneficial role in the treatment of pain.

[0033] Numerous documents document appetite hormone receptor antagonists, such as WO 2010 / 131192.

[0034] US 2014 / 0051700 discloses cyclic guanidine OX2R agonists for enhanced arousal or increased resistance to diet-induced fat accumulation, or simply for recovery from general anesthesia or jet lag. WO 2014 / 198880 discloses 2-(2-aminophenoxy)-3-chloronaphthyl-1,4-dione compounds with orexin 2 receptor agonist activity, and their use as therapeutically active substances for the treatment of symptoms mediated by orexin 2 receptor agonists. WO 2017 / 135306 discloses substituted piperidine compounds with orexin type 2 receptor agonist activity, and their use as preventative or therapeutic agents for narcolepsy. WO 2018 / 164191 (English family member US 2021 / 0385345) discloses substituted pyrrolidine compounds with orexin type 2 receptor agonist activity. WO 2019 / 117148 (English family patent US 2021 / 0078955) discloses sulfonamide derivatives with orexin receptor agonist activity. WO 2019 / 027003, WO 2019 / 027058, WO 2020 / 004537 / US2021 / 198240, WO 2020 / 122092 and WO 2020 / 122093 disclose heterocyclic compounds with orexin type 2 receptor agonist activity. Macrocyclic orexin receptor agonists have been 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.Appetite receptors are highly active in relation to each other. 2015 / 152367, WO 2016 / 133160, WO 2016 / 199906, WO 2018 / 164192, WO 2019 / 112007, WO 2019 / 191327, WO 2020 / 004536, WO 2020 / 158958, WO 2020 / 167701, WO 2020 / 167706, WO 2021 / 026047, WO 2021 / 048821, WO 2021 / 048822, WO 2021 / 107023, WO 2021 / 065893, WO 2021 / 106975, WO 2022 / 014680, WO 2022 / 040058, WO 2022 / 040070, WO 2022 / 051596, WO 2022 / 119888, WO 2022 / 132696, WO 2022 / 140317, WO 2022 / 187231, WO 2022 / 207935, WO 2022 / 233872, WO 2022 / 250108, WO 2022 / 269049, WO2023017180, WO2023167865, WO2023167925, WO2023199091 and WO2023204308.

[0035] The preparation of N-toluenesulfonylproline amide was reported by Walther K. et al. (J. Prakt. Chem, 1987, 329(5), 859-870). Selected N-sulfonylindoline derivatives with affinity for vasopressin and oxytocin receptors are described in US 5,338,755, US 5,397,801, US 5,481,005 and EP 0 469 984. The selected pyrrole sulfone derivatives are described as non-nucleoside reverse transcriptase inhibitors (Silvestri R. et al., Il Farmaco, 2004, 59, 201-210; WO 2008 / 054605) and indoline sulfone as a regulator of the G protein-coupled receptor GPR119 (WO 2009 / 105722). This study reveals that certain thiazoline sulfonamides act as prostaglandin F receptor modulators (US 2008 / 255094). WO 2016 / 004180 reveals quinoline and quinazoline sulfonamides as O-GlcNAc transferase inhibitors. Some N-cyclic sulfonamide derivatives have been reported as inhibitors / antagonists for the following: 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), TRPA1 (Chen H. et al., J. Med. Chem., 2018, 61, 3641-3659; WO 2013 / 108857 (US 2014 / 0329796; EP2805718); WO 2016 / 128529), CCR-9 (WO 2004 / 073634; US 2004 / 180892; US 2005 / 49286; US 2007 / 293503), γ-secretase (WO 2005 / 113542), or bradykinin B2 (US 6,071,917), or as a binding VLA-4 (US 6,583,139 B1). Selected aziridine sulfonamides have been further reported as STAT3 inhibitors (Brotherton-Pleiss C. et al., J. Med. Chem., 2021, 64, 695-710; WO 2021 / 016333). WO 2018 / 015411 reveals certain sulfonylcycloalkyl compounds as TRPA1 regulators. Selected thiol pyrrolidine derivatives have been reported as metalloproteinase inhibitors in US 2002 / 049243. The following compounds are known as library compounds: • N -benzyl- N-(1,1-dioxo-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide (CAS 1101176-47-9), • (R)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PubChem CID (PID) 25620704); • (S)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PID 25620707); • (S)-N-benzyl-N-((S)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PID 51731021); • (R)-N-benzyl-N-((S)-1,1-dioxotetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PID 124809066); • N -(1,1-dioxo-tetrahydrothiophene-3-yl)- N -(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide (CAS 1100238-77-4); • (2R)- N -(1,1-dioxo-tetrahydrothiophene-3-yl)- N -(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide (CAS 2180106-48-1); • (2S)- N -(1,1-dioxo-tetrahydrothiophene-3-yl)- N -(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide (CAS 956630-44-7); • (S)-N-((R)-1,1-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PID 26716027); • (S)-N-((S)-1,1-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide (PID 26716029); and • N-[(2-methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-N-[(tetrahydro-2-thienyl)methyl]-2-pyrrolidinecarboxamide (CAS 2716353-53-4). [Summary of the Invention] 1) The first aspect of the present invention relates to compounds of formula (I). Formula (I) in Ring B is a 6-member aromatic ring, in which: •X 1 Indicates N or CR B2 , where R B2 Indicates hydrogen, halogens (especially fluorine), (C 1-3 )alkyl (especially methyl) or (C 1-3 )alkoxy groups (especially methoxy groups); (especially X groups) 1 (Indicates CH, CF, or N); and •R B1 Independently representing hydrogen, (C 1-4 )alkyl (especially methyl or ethyl), (C 1-3 Alkyl groups (especially methoxy groups), halogens (especially fluorine, chlorine, or iodine), monocyclic compounds (C... 3-4 )cycloalkyl (especially cyclopropyl) or (C1) fluoroalkyl (especially trifluoromethyl); [especially R B1 Independently representing hydrogen, (C 1-3 )alkyl (especially methyl or ethyl), (C 1-3 Alkyl groups (especially methoxy groups), halogens (especially fluorine, chlorine, or iodine), or monocyclic compounds (C) 3-4 )cycloalkyl (especially cyclopropyl); especially R B1 [Indicates methyl, ethyl, methoxy, chlorine, iodine, or cyclopropyl]; [Specific 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 alternatively 4-ethylphenyl, 4-iodophenyl, 4-isopropylphenyl, 4-propylphenyl,] 4-(tert-butyl)phenyl, 4-(tert-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-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 other 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; 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 other 4-ethylphenyl or 4-iodophenyl]; X 2 Indicates O or NR 4 , where R 4 Indicates hydrogen, (C 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), monocyclic (C 3-6 )cycloalkyl or phenyl; [especially X 2 [Indicates O, N-methyl, NH or N-cyclopropyl]; X 3 Represent CH or N such that: • When X 3 When CH is represented, ring A indicates a monocyclic ring (C 5-6 ) cycloalkane-diyl or monocyclic 5- or 6-membered heterocyclic alkane-diyl containing one ring O atom (especially tetrahydrofuran-diyl or tetrahydro-2H-piperan-diyl); [specifically, such ring A represents cyclopentane-1,2-diyl]; or • When X 3 When N is represented, ring A represents: • Contains X 3and 4- to 6-membered saturated monocyclic heterocyclic alkyl-diyl groups (particularly aziridine-diyl, pyrrolidine-diyl, aziridine-diyl, or oxaziridine-diyl) with zero or one ring O atom; wherein the heterocyclic alkyl-diyl group is unsubstituted or monosubstituted or disubstituted (particularly unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine), (C 1-3 )alkoxy (especially methoxy or ethoxy), hydroxy and (C 1-3 )alkylene (especially H2C=); [such ring A particularly represents pyrrolidone-1,2-diyl, 4-methylpyrrolidone-1,2-diyl, 4-fluoropyrrolidone-1,2-diyl, 3-methylenepyrrolidone-1,2-diyl, 5-methylpyrrolidone-1,2-diyl, acezolidinone-2,3-diyl, aziridine-1,2-diyl, 4-methylacetidine-1,2-diyl, 3-fluoropyrrolidone-1,2-diyl, 4-hydroxypyrrolidone-1,2-diyl, 4-methoxy Pyrrolidine-1,2-diyl, 4-ethoxypyrrolidine-1,2-diyl, 4,4-dimethylpyrrolidine-1,2-diyl, acezolidin-3,4-diyl, or 1,3-oxazolidin-2,3-diyl; specifically, ring A represents pyrrolidine-1,2-diyl, 4-methylpyrrolidine-1,2-diyl, 4-fluoropyrrolidine-1,2-diyl, 3-methylenepyrrolidine-1,2-diyl, 5-methylpyrrolidine-1,2-diyl, or acezolidin-2,3-diyl; • Contains X 3 and 4- to 6-membered (especially 5-membered) monounsaturated monocyclic heterocyclic alkyl-diyl groups (especially dihydro-1H-pyrrole-diyl or dihydro-1H-pyrazole-diyl) with zero or one additional ring nitrogen atom; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X atoms. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of ) ; wherein the monounsaturated heterocyclic alkane-diyl group is unsubstituted or monosubstituted or disubstituted (specifically unsubstituted); wherein the substituents are independently (C 1-3 )alkyl (especially methyl); [such ring A particularly represents 2,3-dihydro-1H-pyrrole-1,2-diyl, 4,5-dihydro-1H-pyrazole-1,5-diyl or 3-methyl-4,5-dihydro-1H-pyrazole-1,5-diyl; specifically such ring A represents 2,3-dihydro-1H-pyrrole-1,2-diyl]; or • Contains X 3A 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl group; wherein the bicyclic heterocyclic alkyl-diyl group is unsubstituted or disubstituted (especially unsubstituted); wherein the substituents are independently (C 1-3 Alkyl (especially methyl); (such ring A particularly represents azabicyclo[2.2.1]hept-diyl, azabicyclo[3.1.0]hex-diyl or azaspiro[2.4]hept-diyl, or other azabicyclo[3.2.0]hept-diyl or 6,6-dimethyl-3-azabicyclo[3.1.0]hex-diyl; such ring A particularly represents 2-azabicyclo[2.2.1]hept-1,2-diyl, 2-azabicyclo[3.1.0]hex-2,3-diyl, 3-azabicyclo[3.1.0]hex-2,3- Diyl or 5-azaspiro[2.4]hept-4,5-diyl, or another 3-azabicyclo[3.2.0]hept-2,3-diyl or 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2,3-diyl); [specifically, such ring A represents 2-azabicyclo[2.2.1]hept-1,2-diyl, 2-azabicyclo[3.1.0]hex-2,3-diyl or 3-azabicyclo[3.1.0]hex-2,3-diyl, or another 3-azabicyclo[3.2.0]hept-2,3-diyl]; R 1 express: • 3-Cyano-3,3-dimethylpropyl or 4-cyanobutyl [specifically 3-cyano-3,3-dimethylpropyl]; •Saturated monocyclic (C 4-6 ) cycloalkyl (especially cyclopentyl or cyclohexyl); wherein the (C 4-6 ) cycloalkyl groups are unsubstituted or monosubstituted or disubstituted (especially monosubstituted or disubstituted); wherein the substituents are independently selected from the group consisting of: (C 1-3 Alkyl groups (especially methyl or isopropyl), halogens (especially fluorine), (C 1-3 ) fluoroalkyl groups (especially difluoromethyl or trifluoromethyl), (C 1-3 )alkoxy (especially methoxy), carbamoyl, hydroxyl and cyano; [this type of R 1Specifically, 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-aminoformylcyclopentyl, 3-aminoformyl-3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 4-Cyano-2-methoxycyclopentyl, cyclohexyl, 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, or another 2-methoxycyclopentyl or 3-hydroxycyclopentyl; specifically, such R 1 [Represents 3-cyanocyclopentyl, 3-cyano-3-methylcyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-2-hydroxycyclopentyl, or 4-fluorocyclohexyl]; • Monounsaturated monocyclic (C 5-6 ) cycloalkyl (especially cyclohexenyl); wherein the monounsaturated (C 5-6 The double bond of the cycloalkyl group does not contain the group -N(CO)CH(R) 2 (R) 3 The carbon atom of ); [specifically, this type of R 1 [Represents cyclohexyl-3-en-1-yl]; •Saturated bicyclic (C 6-8 Spirocycloalkyl (particularly spiro[2.3]hexyl, spiro[3.3]heptyl, spiro[2.4]heptyl or spiro[2.5]octyl); wherein the (C 6-8 Spirocycloalkyl groups are unsubstituted or monosubstituted or disubstituted (especially disubstituted); wherein such substituents are independently halogens (especially fluorine); [such R 1 Specifically, this refers to 1,1-difluorospiro[2.3]hexane-5-yl, 1,1-difluorospiro[2.5]octane-6-yl, spiro[3.3]heptane-2-yl, 6,6-difluorospiro[3.3]heptane-2-yl, 1,1-difluorospiro[2.4]heptane-5-yl or spiro[2.5]octane-6-yl; specifically, such R 1 It represents 1,1-difluorospiro[2.3]hexane-5-yl or 1,1-difluorospiro[2.5]octane-6-yl; • Saturated fused or bridged double rings (C 6-8)cycloalkyl (particularly bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl or bicyclo[2.2.2]octyl); wherein the (C 6-8 ) cycloalkyl groups are unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: halogens (especially fluorine), cyano and carbamoyl; [such R 1 Specifically, this refers to bicyclo[4.1.0]heptane-3-yl, 7,7-difluorobicyclo[4.1.0]heptane-3-yl, 4-aminoformylbicyclo[2.1.1]hexane-2-yl, or 4-cyanobicyclo[2.2.2]octane-1-yl; specifically, such R 1 This indicates bicyclo[4.1.0]heptane-3-yl or 7,7-difluorobicyclo[4.1.0]heptane-3-yl]; or • A 5- or 6-membered saturated monocyclic heterocyclic alkyl group comprising a cyclic heteroatom group selected from O, S, or SO2 (the monocyclic heteroatom group is particularly selected from O or SO2; the heterocyclic alkyl group is particularly tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-piperan, tetrahydro-2H-thiopiperan, tetrahydro-2H-thiopiperan-1,1-dioxide); wherein the heterocyclic alkyl group is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine) and (C 1-3 )fluoroalkyl (trifluoromethyl); [such R 1 Specifically, it refers to 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, 1,1-dioxo-tetrahydrothiophene-3-yl, tetrahydro-2H-piperan-4-yl, 3-fluorotetrahydro-2H-piperan-4-yl, 2-methyltetrahydro-2H-piperan-4-yl, 2-(trifluoromethyl)tetrahydro-2H-piperan-4-yl, 2,2-dimethyltetrahydro-2H-piperan-4-yl, tetrahydro-2H-thiopiperan-4-yl, or... Tetrahydro-2H-piperan-3-yl, or other 6-methyltetrahydro-2H-piperan-3-yl, 6,6-dimethyltetrahydro-2H-piperan-3-yl, 3-methyltetrahydro-2H-piperan-4-yl, 2,6-dimethyltetrahydro-2H-piperan-4-yl, 1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl, or 6-methyl-1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl; specifically such R 1 [Represents 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, or another 1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl or 6-methyl-1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl]; R 2 Indicates hydrogen or methyl (especially hydrogen); R 3 express: • An 8- to 10-membered partially aromatic fused bicyclic system comprising a total of zero to three cyclic heteroatoms independently selected from N, O, or S (particularly 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]m-dioxacyclopentenyl, 6,7-dihydro-5H-cyclopentadienyl, 2,3-dihydrofuran[3,2]pyridyl, chromium, isochromium, or 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl); wherein the 8- to 10-membered ring system is bonded in the aromatic ring portion to the remainder of the molecule; wherein the 8- to 10-membered ring system is unsubstituted or monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine) and syl group; [such R 3 Specifically, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, 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-sideoxy-2,3-dihydrobenzofuran-6-yl, and benzo[d][1,3]dioxacyclopenten-5-yl are mentioned. Cyclopenten-4-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl, 6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenten[c]pyridin-3-yl, 2,3-dihydrofuran[3,2-b]pyridin-6-yl, 2,3-dihydrofuran[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]dioxacyclohexen-6-yl; specifically, such R 3 It represents 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl or 4-fluoro-2,3-dihydrobenzofuran-6-yl; • Naphthyl or an 8- to 10-membered heteroaryl group comprising a total of one to three independently selected cyclic heteroatoms from N, O, and S (particularly benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, furanopyridyl, benzodiazolyl, thiophenepyridyl, 1H-indolyl, quinolinyl, or isoquinolinyl); wherein the 8- to 10-membered heteroaryl group is unsubstituted or monosubstituted or disubstituted (especially unsubstituted or monosubstituted), wherein such substituents are independently selected from the group consisting of: (C 1-3 [alkyl groups (especially methyl groups) and halogens (especially fluorine or chlorine)]; [such R groups]3 Specifically, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophene-5-yl, benzo[b]thiaphene-6-yl, furano[3,2-c]pyridin-6-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]furan-2-yl, benzo[d]furan-5-yl, 2-methylbenzo[6-yl]furan-6-yl, benzo[d]thiazol-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-2-yl, benzo[b]thiaphene-2-yl 2-Methylbenzo[b]thiophene-5-yl, furano[3,2-b]pyridin-6-yl, furano[2,3-b]pyridin-6-yl, benzo[d]carbazo-2-yl, benzo[c][1,2,5]carbazodiazole-5-yl, thiophene[2,3-b], pyridin-2-yl, 1H-indol-6-yl, naphth-2-yl, quinolin-7-yl, isoquinolin-3-yl or isoquinolin-7-yl, or additionally 2-bromobenzo[d]thiazo-5-yl, 4-fluorobenzo[d]thiazo-5-yl or 2-methoxybenzo[d]thiazo-5-yl; specifically such R 3 This indicates benzofuran-6-yl, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophene-5-yl, benzo[b]thiaphene-6-yl, furano[3,2-c]pyridin-6-yl or 2-methylbenzo[d]thiazol-5-yl, or additionally 2-bromobenzo[d]thiazol-5-yl; or • A phenyl group or a 5- or 6-membered heteroaryl group comprising one to three independently selected cyclic heteroatoms from N, O, and S (particularly pyridinyl, thiophene, acezol, thiazol, isothiazolyl, or isoacezolyl); wherein the phenyl group or the 5- or 6-membered heteroaryl group is independently unsubstituted or monosubstituted, disubstituted, or trisubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), halogens (especially fluorine, chlorine, or bromine), (C 1-3 )alkoxy (especially methoxy), (C 1-3 ) fluoroalkoxy (especially difluoromethoxy), monocyclic (C 3-6 )cycloalkyl (especially cyclopropyl), (C 1-3 ) alkylthio (especially methylthio), (C 1-3 )Fluoroalkyl (especially trifluoromethyl), cyano, NR N1 R N2 , where R N1 and R N2 Independently representing hydrogen or (C1-4 )alkyl (especially NR) N1 R N2 (representing dimethylamino) and 4 to 6-membered monocyclic heterocyclic alkyl groups (especially aziridine or glycidyl); wherein the heterocyclic alkyl group is unsubstituted or monosubstituted with a halogen (especially fluorine); [such R 3 Specifically, 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-(azacyclobut-1-yl)phenyl, 3-(3-) -Fluoroxycyclobut-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, 2,4-difluoro-5-methylphenyl, 5-chloropyridin-2-yl, 2-methylthiophen-3-yl, 5-methylthiophen-2-yl 5-chlorothiophene-2-yl, 3-methylthiophene-2-yl, 5-isopropylisothiazolinone-2-yl, 5-chlorothiazolinone-2-yl, 5-bromothiazolinone-2-yl, 5-isopropylthiazolinone-2-yl, 2-isopropylthiazolinone-5-yl, 5-methylisothiazolinone-4-yl, 5-methylisothiazolinone-4-yl, 4-ethyl-5-methylisothiazolinone-3-yl, 5-cyclopropylisothiazolinone-3-yl, or 5-cyclopropyl-4-ethylisothiazolinone-3-yl; specifically, this type of R 3 [Represents 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]; The following compounds are excluded: •N-Benzyl-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; • (R)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; • (S)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; • (S)-N-benzyl-N-((S)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; • (R)-N-benzyl-N-((S)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; •N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; •(2R)-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; •(2S)-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; • (S)-N-((R)-1,1-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide; • (S)-N-((S)-1,1-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide; and • N-[(2-methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-N-[(tetrahydro-2-thienyl)methyl]-2-pyrrolidinecarboxamide.

[0037] Compounds of formula (I) may contain one or more stereosymmetric or asymmetric centers, such as one or more asymmetric carbon atoms, which may exist in (R)-configuration or (S)-configuration. Compounds of formula (I) may further encompass compounds having one or more double bonds, which may exist in Z-configuration or E-configuration; and / or compounds having substituents at the ring system, which may exist in cis-configuration or trans-configuration relative to each other. Therefore, compounds of formula (I) may exist as mixtures of stereoisomers, or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated in ways known to those skilled in the art.

[0038] When a particular compound (or general structure) is referred to as a (R)- or (S)- mirror isomer, such names should be understood to refer to the corresponding compound (or general structure) in an enriched, especially essentially pure, mirror isomer form. Similarly, when a particular asymmetry center in a compound is indicated as an (R)- or (S)- configuration or a relative configuration, such names should be understood to refer to the compound in an enriched, especially essentially pure, configuration with respect to that asymmetry center. Likewise, cis or trans names should be understood to refer to the corresponding stereoisomer in an enriched, especially essentially pure, relative configuration. In the case where a particular compound (or general structure) contains one or more stereosymmetric centers or asymmetric centers (such as one or more asymmetric carbon atoms), it may exist in (R)-configuration or (S)-configuration. However, if one (or more) of such stereosymmetric centers or asymmetric centers is not explicitly specified as (R)- or (S)-configuration, it should be understood that the stereosymmetric center or asymmetric center may be in (R)-configuration or (S)-configuration. Such compound names or general structures should be understood to cover compounds / general structures in which such centers are in (R)-configuration or (S)-configuration, or any mixture of epimers with respect to such centers. Similarly, where such stereosymmetric centers or asymmetric centers are specified as being in (RS)-configuration, this means that such stereosymmetric centers or asymmetric centers in such compounds may exist in (R)-configuration, (S)-configuration, or any mixture of epimers with respect to such centers. In the case where two or more such stereosymmetric centers or asymmetric centers (in unspecified or specified as (RS)-configuration) exist in a molecule, it should be understood that the order of absolute configurations does not indicate any defined relative configuration with respect to the two or more centers.

[0039] In the presence of any defined relative configuration of two or more centers, such centers are named using the (R*,R*) or (R*,S*) nomenclature, indicating that in the first case the corresponding center is (R,R) or (S,S), and in the second case the corresponding center is (R,S) or (S,R), covering any mixture of such stereoisomers, including racemic mixtures. It should be understood that explicitly designated (R)-configuration or (S)-configuration, undesignated or designated (RS)-configuration, and relative (R*,R*)-configuration or (R*,S*)-configuration can coexist in the same molecule and should be interpreted accordingly. For example, the compound (1R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide encompasses the mirror-isomer-enriched (1R,2R,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, and (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. (1S,2R,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or any mixture of such stereoisomers of the compound. Similarly, the compound (1R*,5S*)-(2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide encompasses the mirror-isomerically enriched (1S,2S,5R)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, the mirror-isomerically enriched (1R,2S,5S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or any mixture thereof.

[0040] In cases where a particular compound (or general structure) is designated as a Z- or E-stereoisomer (or where a particular double bond in a compound is designated as having a Z- or E-configuration), such designation shall be understood to refer to the corresponding compound (or general structure) in an enriched, especially substantially pure, stereoisomeric form (or to the compound in an enriched, especially substantially pure form relative to the individual configuration of the double bond).

[0041] In the context of this invention, when used in the context of stereoisomers, it should be understood that the term “enrichment” means that, relative to the individual stereoisomers / all of the individual stereoisomers, the individual stereoisomers are present in a ratio of at least 70:30, especially at least 90:10 (i.e., a purity of at least 70% by weight, especially at least 90% by weight).

[0042] In the context of this invention, when used in the context of stereoisomers, it should be understood that the term "substantially pure" means that, relative to the individual stereoisomers / all of the individual stereoisomers, the individual stereoisomers exist with a purity of at least 95% by weight, and especially at least 99% by weight.

[0043] This invention also includes isotopically labeled, particularly 2H (deuterium) labeled compounds of formula (I) according to embodiments 1) to 24), which are identical to compounds of formula (I) except that one or more atoms have undergone atomic substitutions having the same number of atoms but with atomic masses different from those normally found in nature. Isotopically labeled, particularly 2H (deuterium) labeled compounds of formula (I) and their salts are within the scope of this invention. Replacing hydrogen with the heavier isotope 2H (deuterium) can produce greater metabolic stability, resulting in, for example, an extended in vivo half-life or reduced dosage requirements, or can cause reduced inhibition of cytochrome P450 enzymes, producing, for example, an improved safety profile. In one embodiment of the invention, the compound of formula (I) is unlabeled, or is labeled with only one or more deuterium atoms. In a sub-embodiment, the compound of formula (I) is completely unlabeled. Isotopically labeled compounds of formula (I) can be prepared similarly to the methods described below, but using appropriate isotopic variants suitable for the reagents or starting materials.

[0044] In this patent application, the bonds plotted as dashed lines indicate the connection points of the plotted groups. For example, a free radical is plotted as follows: It is 2,3-dihydro-1 H -indole-5-yl.

[0045] In some cases, compounds of formula (I) may contain tautomer forms. Such tautomer forms are covered within the scope of this invention. Where a tautomer form is present for a particular residue and only one form of such residue is disclosed or defined, it should be understood that other tautomer forms are covered within such disclosed residues. For example, the group 3-sideoxy-2,3-dihydrobenzofuran-6-yl should be understood to also include its tautomer form 3-hydroxy-benzofuran-6-yl.

[0046] When compounds, salts, pharmaceutical compositions, diseases and their analogues are used in the plural form, this is also intended to refer to a single compound, salt or its analogue.

[0047] Where appropriate and advantageous, any reference to compounds of formula (I) according to embodiments 1) to 24) shall be understood to also refer to salts of such compounds (and especially pharmaceutically acceptable salts).

[0048] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds of the present invention and exhibits minimal undesirable toxicological effects. Depending on the presence of basic and / or acidic groups in the compounds of the present invention, such salts include inorganic or organic acid and / or base addition salts. 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 Quéré (eds.), RSC Publishing, 2012.

[0049] The definitions provided herein are intended to apply uniformly to compounds of formula (I) as defined in any of embodiments 1) through 24), and, with necessary adjustments to the details, will be provided with broader or narrower definitions throughout the specification and claims unless otherwise expressly stated. It should be fully understood that any definition or preferred definition of a term is independent of (and in combination with) any or all other definitions herein and may supersede the respective terms.

[0050] Whenever a substituent is indicated as optional, it should be understood that such a substituent may not be present. In this case, all positions with free valence (such as the positions to which such optional substituents may be attached, such as in an aromatic ring, a carbocyclic atom with free valence and / or a cyclic nitrogen atom) are substituted with hydrogen where appropriate.

[0051] The term "halogen" means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.

[0052] The term "alkyl" used alone or in combination, unless explicitly defined in a broader or narrower manner, refers to a saturated straight-chain or branched hydrocarbon group containing one to six carbon atoms. The term "(C... x-y Alkyl group (where x and y are integers) refers to an alkyl group containing x to y carbon atoms as previously defined. For example, (C 1-6 Alkyl groups contain one to six carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, and 3,3-dimethyl-butyl. For the avoidance of ambiguity, if a group is referred to as, for example, propyl or butyl, it means n-propyl and n-butyl, respectively. Methyl and ethyl are preferred. Methyl is the most desirable. B1 The embodiment is shown in (C) 1-4 )alkyl, especially (C 1-3 )alkyl groups, such as methyl or ethyl, especially methyl. When X 1 Indicates CR B2 When, it means (C) 1-3 )alkyl R B2 The example is methyl. (C) 1-3 An example of an alkyl group as a substituent for ring A is methyl. (C) 1-3 )Alkyl group as R 1 Examples of substituents include methyl and isopropyl (especially methyl). (C) 1-3 )Alkyl group as R 3 Examples of substituents include methyl, ethyl, and isopropyl (especially methyl). When X 2 For NR 4 When, it means (C) 1-3 )alkyl R 4 Examples of these compounds include methyl, ethyl, and isopropyl (especially methyl).

[0053] The term "alkoxy" used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to an alkyl-O- group, wherein the alkyl group is as previously defined. The term "(C... x-y )alkoxy group (where x and y are integers) refers to an alkoxy group containing x to y carbon atoms as previously defined. For example, (C 1-4 )alkoxy predicate (C 1-4 )alkyl-O-group, wherein the term "(C 1-4 "Alkoxy" has the meaning previously given. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Methoxy is preferred. (C) 1-3 )alkoxy RB1 The example is methoxylated. When X 1 Indicates CR B2 When, it means (C) 1-3 )alkoxy R B2 The example is methoxylated. (C) 1-3 Examples of alkoxy groups used as substituents for ring A include methoxy or ethoxy. (C) 1-3 )alkoxy group as R 1 An example of a substituent for the group is a methoxy group. (C) 1-3 )alkoxy group as R 3 An example of a substituent for the group is a methoxy group.

[0054] The term "fluoroalkyl" used alone or in combination, unless explicitly defined in a broader or narrower manner, refers to an alkyl group containing one to three carbon atoms as previously defined, wherein one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term "(C... x-y ()Fluoroalkyl (where x and y are integers) refers to a fluoroalkyl group containing x to y carbon atoms as previously defined. For example, (C 1-3 fluoroalkyl groups contain one to three carbon atoms, of which one to seven hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl; especially trifluoromethyl. Preferably, (C...) 1-3 )Fluoroalkyl groups, such as trifluoromethyl. R represents a (C1) fluoroalkyl group. B1 The example is trifluoromethyl. (C) 1-3 ) Fluoroalkyl groups as R 1 Examples of substituents include difluoromethyl and trifluoromethyl. (C) 1-3 ) Fluoroalkyl groups as R 3 An example of a substituent is trifluoromethyl.

[0055] The term "fluoroalkoxy" used alone or in combination, unless explicitly defined in a broader or narrower manner, refers to an alkoxy group containing one to three carbon atoms as previously defined, wherein one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term "(C... x-y ()Fluoroalkoxy group (where x and y are integers) refers to a fluoroalkoxy group containing x to y carbon atoms, as previously defined. For example, (C 1-3 The fluoroalkoxy group contains one to three carbon atoms, of which one to seven hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Preferably, it is a (C1) fluoroalkoxy group, such as trifluoromethoxy and difluoromethoxy, and 2,2,2-trifluoroethoxy. (C1) 1-3)Fluoroalkoxy as a group R 3 An example of a substituent is difluoromethoxy.

[0056] The term "cyano" refers to the -CN group. It indicates a saturated monocyclic ring (C) with a cyano substituent. 4-6 ) cycloalkyl R 1 A specific embodiment is 3-cyanocyclopentyl; specifically, R represents 3-cyanocyclopentyl. 1 Such cyano substituents are in a relatively cis configuration relative to the bond (from the carbon ring at position 1 of the 3-cyanocyclopentyl group), and R 1 Bonded to the remainder of formula (I) [representing 3-cyanocyclopentyl of this type R] 1 Specifically (1R,3S)-3-cyanocyclopentyl).

[0057] The term "side oxygen group" refers to the =O group, which is preferably attached to the sulfur atom in the A chain or carbide ring or, for example, carbonyl-(CO)- or sulfonyl-(SO2)-.

[0058] The term "(C)" can be used alone or in combination. x-y ()alkylene (where x and y are integers), and unless otherwise defined in a broader or narrower manner, refers to an alkyl group containing x to y carbon atoms as previously defined, wherein the alkyl group is bonded to the remainder of the molecule by double bonds. (C 1-3 Examples of alkylene groups include methylene (also known as methylene) H2C= group.

[0059] The term "cycloalkyl" used alone or in combination, unless explicitly defined in a broader or narrower manner, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms. The term "(C... x-y (Cycloalkyl) (where x and y are integers) refers to a cycloalkyl group containing x to y carbon atoms. For example, (C 3-6 Cycloalkyl groups contain three to six carbon atoms.

[0060] The term "single ring (C)" x-y )cycloalkyl" or "saturated monocyclic (C x-y "Cycloalkyl" refers to a saturated monocyclic cycloalkyl group containing x to y carbon atoms as previously defined. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The monocyclic (C) group indicates a monocyclic cycloalkyl group. 3-4 ) cycloalkyl R B1 The embodiment is cyclopropyl. It represents a saturated monocyclic (C) 4-6 ) cycloalkyl R 1 Preferred embodiments are cyclopentyl and cyclohexyl; wherein these groups are unsubstituted or substituted as expressly defined. When X 2 For NR4 When, it indicates a single ring (C 3-6 ) cycloalkyl R 4 A preferred embodiment is cyclopropyl. (C) 3-6 ) Cycloalkyl groups as R 3 An example of a substituent is cyclopropyl.

[0061] The term "(C)" can be used alone or in combination. x-y )cycloalkane-diyl" or "monocyclic (C x-y "(cycloalkyl-diyl)" (where x and y are integers), and unless explicitly defined in a broader or narrower manner, refers to a divalent cycloalkyl group containing x to y carbon atoms as previously defined. 3 It represents CH and ring A represents a monocyclic ring (C 5-6 When cycloalkane-diyl, the (C) in formula (I) 5-6 The cycloalkane-diyl linkage point is at X 3 Above and in the vicinity of X 3 On the carbon atom; examples are cyclopentane-1,2-diyl and cyclohexane-1,2-diyl (especially cyclopentane-1,2-diyl).

[0062] The term "saturated bicyclic (C)" can be used alone or in combination. x-y "(spirocycloalkyl)" (where x and y are integers) and, unless otherwise defined in a broader or narrower manner, refers to a saturated spiro-bicyclic hydrocarbon ring containing x to y carbon atoms as previously defined. A saturated bicyclic (C 6-8 )spirocycloalkyl R 1 Examples include spiro[2.3]hexyl, spiro[3.3]heptyl, spiro[2.4]heptyl, and spiro[2.5]octyl (especially spiro[2.3]hexyl and spiro[2.5]octyl); such saturated bicyclic (C 6-8 Spirocycloalkyl groups are either unsubstituted or substituted as defined. This indicates a saturated bicyclo(C) ring. 6-8 ) Spirocycloalkyl of this type of R 1 Specific embodiments are 1,1-difluorospiro[2.3]hexane-5-yl, 1,1-difluorospiro[2.5]octane-6-yl, spiro[3.3]heptane-2-yl, 6,6-difluorospiro[3.3]heptane-2-yl, and 1,1-difluorospiro[2.4]heptane-5-yl, and spiro[2.5]octane-6-yl (especially 1,1-difluorospiro[2.3]hexane-5-yl and 1,1-difluorospiro[2.5]octane-6-yl).

[0063] The term "saturated fused or bridged double ring" (C) is used alone or in combination. x-y "Cycloalkyl" (where x and y are integers) and, unless explicitly defined in a broader or narrower manner, refers to a saturated fused or bridged bicyclic hydrocarbon ring containing x to y carbon atoms. A saturated bridged bicyclic (C...)6-8 ) cycloalkyl R 1 Examples of such formulations include bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, and bicyclo[2.2.2]octyl (especially bicyclo[4.1.0]heptyl); such R 1 Unsubstituted or substituted as explicitly defined. Indicates a saturated fused bicyclic (C... 6-8 ) cycloalkyl-type R 1 Specific embodiments are bicyclo[4.1.0]heptane-3-yl, 7,7-difluorobicyclo[4.1.0]heptane-3-yl, 4-aminoformyl[2.1.1]hex-2-yl, and 4-cyanobicyclo[2.2.2]oct-1-yl (especially bicyclo[4.1.0]heptane-3-yl and 7,7-difluorobicyclo[4.1.0]heptane-3-yl). In one embodiment, when R 1 When representing a bicyclic [4.1.0]heptyl group, the fused cyclopropyl ring of such a bicyclic [4.1.0]heptyl group is configured such that the two bonds of the bridgehead ring carbon atom to the fused cyclohexane ring of such a bicyclic [4.1.0]heptyl group are in particular (1S,6S)-bicyclic [4.1.0]heptyl groups. R represents a bicyclic [4.1.0]heptane-3-yl group. 1 A specific embodiment is (1S,3S,6S)-bicyclo[4.1.0]heptane-3-yl; such R 1 Not replaced or replaced as explicitly defined.

[0064] The term "monounsaturated monocyclic" (C) can be used alone or in combination. x-y "(cycloalkyl)" (where x and y are integers) and, unless explicitly defined in a broader or narrower manner, refers to a monounsaturated monocyclic hydrocarbon ring containing x to y carbon atoms (i.e., the ring contains monounsaturated (double) bonds and additionally saturated bonds). In one embodiment, when R 1 For monounsaturated monocyclic (C 5-6 When cycloalkyl is used, this type of (C 5-6 The unsaturated (double) bonds of cycloalkyl groups do not contain groups connected to -N(CO)CH(R) 2 (R) 3 Carbon atoms of this type; R 1 Unsubstituted or substituted as expressly defined. This type of R 1 Examples of the cyclohexenyl group, particularly cyclohex-3-en-1-yl.

[0065] The terms "heterocyclic," "heterocyclic alkyl," or "saturated monocyclic heterocyclic alkyl," used alone or in combination, and unless explicitly defined in a broader or narrower manner, refer to a saturated monocyclic hydrocarbon ring containing one or two independent cyclic heteroatoms or heteroatom groups selected from N, O, S, and SO2; wherein, in each case, it should be understood that the number and nature of the cyclic heteroatoms or heteroatom groups are explicitly defined, or may be more precisely defined (i.e., such a ring contains / contains the defined cyclic heteroatoms or heteroatom groups, and has no other cyclic heteroatoms or heteroatom groups). The terms "x-membered to y-membered heterocyclic alkyl" or "x-membered to y-membered saturated monocyclic heterocyclic alkyl" (where x and y are each integers) refer to such a heterocycle containing x to y ring atoms. Such a heterocycle is unsubstituted or, if explicitly defined, substituted. When R 1 When it is a 5- or 6-membered saturated monocyclic heterocyclic alkyl group, this type of R 1 It may be unsubstituted or, as explicitly defined, substituted; such R 1 Examples include tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-piperanone, and tetrahydro-2H-thiopiperanone-1,1-dioxide (of this type R). 1 Specific embodiments include 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, 1,1-dioxo-tetrahydrothiophene-3-yl, tetrahydro-2H-piperan-4-yl, 3-fluorotetrahydro-2H-piperan-4-yl, 2-methyltetrahydro-2H-piperan-4-yl, 2-(trifluoromethyl)tetrahydro-2H-piperan-4-yl, 2,2-dimethyltetrahydro-2H-piperan-4-yl, tetrahydro-2H-thiopiperan-4-yl, and tetrahydro-2H-piperan-3-yl; and other than those listed above: 6-methyltetrahydro-2H-piperan-3-yl, 6,6-dimethyltetrahydro-2H-piperan-3-yl, 3-methyltetrahydro-2H-piperan-4-yl, 2,6-dimethyltetrahydro-2H-piperan-3-yl, and 2,6-dimethyltetrahydro-2H-piperan-4-yl. H-piperan-4-yl, 1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl and 6-methyl-1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl; especially 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, 1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl and 6-methyl-1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl). The group R representing a phenyl group... 3 Examples of 4- to 6-membered monocyclic heterocyclic alkyl groups of the substituent are particularly 4-membered monocyclic heterocyclic alkyl groups (especially aziridine or oxobutidine); wherein such heterocyclic alkyl groups are unsubstituted or monosubstituted with halogen (especially fluorine); specific examples are aziridine-1-yl and 3-fluorooxobutidine-3-yl.

[0066] The terms "x- to y-membered heterocyclic alkyl diester" or "monocyclic x- to y-membered heterocyclic alkyl diester" (where x and y are each integers) used alone or in combination, and unless explicitly defined in a broader or narrower manner, refer to a divalent heterocyclic alkyl group as previously defined; wherein, in each case, the number and nature of the cyclic heteroatom or heteroatom group are explicitly defined. When X 3 When CH represents a monocyclic 5- or 6-membered heterocyclic alkane-diyl group containing one ring O atom, the connection point of the heterocyclic alkane-diyl group in formula (I) is at X. 3 and linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 On the carbon atom of ); examples are tetrahydrofuran-2,3-diyl and tetrahydro-2H-piperan-3,4-diyl. When X 3 Let N represent the ring and let A represent the ring containing X. 3 When a 4- or 6-membered saturated monocyclic heterocyclic alkyl-diyl group has zero or one ring O atom, the connection point of the heterocyclic alkyl-diyl group in formula (I) is at X. 3 and linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 On the carbon atom of ), examples are aziridine-diyl, pyrrolidine-diyl, aziridine-diyl (particularly aziridine-2,3-diyl or aziridine-3,4-diyl) and oxaziridine-diyl (particularly 1,3-oxaziridine-2,3-diyl); such ring A may be unsubstituted or substituted as explicitly defined. In a particular embodiment, it is attached to the group -CO-N(R 1 )CH(R 2 (R) 3 The carbon atoms of ring A are not further substituted.

[0067] The term "x to y monounsaturated monocyclic heterocyclic alkane-diyl" (where x and y are each integers), used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to a divalent monocyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S, and wherein the ring contains a monounsaturated (double) bond and otherwise contains a saturated bond. When X 3 Let N represent the ring and let A represent the ring containing X. 3 When a 4- to 6-membered (especially 5-membered) monounsaturated monocyclic heterocyclic alkyl-diyl group with zero or one additional ring N atom and no other ring heteroatoms (especially 5-membered monounsaturated monocyclic heterocyclic alkyl-diyl groups; particularly dihydro-1H-pyrrole-diyl or dihydro-1H-pyrazole-diyl groups), the connection point of the monounsaturated heterocyclic alkyl-diyl group in formula (I) is located at X. 3 The upper part and the group -CO-N(R) are attached to it. 1)CH(R 2 (R) 3 On the carbon atoms of the monounsaturated heterocyclic alkyl-diyl group, for example, arranged in a 1,2 configuration, and the unsaturated (double) bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of the ring A. Such ring A may be unsubstituted or substituted as explicitly defined; specific examples are 2,3-dihydro-1H-pyrrole-1,2-diyl, 4,5-dihydro-1H-pyrazole-1,5-diyl, and 3-methyl-4,5-dihydro-1H-pyrazole-1,5-diyl (especially 2,3-dihydro-1H-pyrrole-1,2-diyl). In one specific embodiment, it is attached to the group -CO-N(R 1 )CH(R 2 (R) 3 The carbon atoms of ring A are not further substituted.

[0068] The term "x- to y-member saturated spiro, fused, or bridged bicyclic heterocyclic alkyl" refers to a saturated spiro, fused, or bridged bicyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S. The term "x- to y-member saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl" refers to a saturated spiro, fused, or bridged bicyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S, wherein the saturated spiro, fused, or bridged bicyclic hydrocarbon ring is divalent. Such saturated spiro, fused, or bridged bicyclic heterocyclic alkyl or heterocyclic alkyl-diyl is unsubstituted or, as explicitly defined, substituted. When ring A is an X representing N... 3 When the 6- to 8-member saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl group is used, the connection point of the heterocyclic alkyl-diyl group in formula (I) is at X. 3 And on the group -CO-N(R) 1 )CH(R 2 (R) 3On the carbon atoms of ), for example, arranged in a 1,2 configuration. Therefore, the term “x- to y-member saturated spirocyclic bicyclic heterocyclic alkyl” (where x and y are each integers) used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to a saturated spirocyclic bicyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S (especially N). Similarly, the term “x- to y-member saturated spirocyclic bicyclic heterocyclic alkyl-diyl” refers to a divalently bonded x- to y-member saturated spirocyclic bicyclic heterocyclic alkyl as previously defined. An example of such ring A representing a 6- to 8-member saturated spirocyclic bicyclic heterocyclic alkyl-diyl is azaspiro[2.4]heptane-diyl (especially 5-azaspiro[2.4]heptane-4,5-diyl). Therefore, the term "x-to-y-member saturated fused bicyclic heterocyclic alkyl" (where x and y are each integers), used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to a saturated fused-bicyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S (especially N). Similarly, the term "x-to-y-member saturated fused bicyclic heterocyclic alkyl-diyl" refers to a divalently bonded x-to-y-member saturated fused bicyclic heterocyclic alkyl as previously defined. When ring A is containing X representing N... 3 When 6- to 8-membered saturated fused bicyclic heterocyclic alkyl-diyl groups are attached to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atoms of ring A are not shared between the two cycles of this type of bicyclic ring. An example of such ring A representing a 6- to 8-member saturated fused bicyclic heterocyclic alkyl-diyl is azabicyclo[3.1.0]hex-diyl (especially 2-azabicyclo[3.1.0]hex-2,3-diyl or 3-azabicyclo[3.1.0]hex-2,3-diyl); an additional example of such ring A representing a 6- to 8-member saturated fused bicyclic heterocyclic alkyl-diyl is azabicyclo[3.2.0]heptane-diyl (especially 3-azabicyclo[3.2.0]heptane-2,3-diyl). Therefore, the term "x-to-y-member saturated bridged bicyclic heterocyclic alkyl" (where x and y are each integers), used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to a saturated bridged bicyclic hydrocarbon ring containing x to y ring atoms, wherein one or two (especially one) ring atoms are heteroatoms independently selected from N, O, and S (especially N). Similarly, the term "x-to-y-member saturated bridged bicyclic heterocyclic alkyl-diyl" refers to a divalently bonded x-to-y-member saturated bridged bicyclic heterocyclic alkyl as previously defined. When ring A contains X representing N... 3 When a 6- to 8-membered bridging saturated bicyclic heterocyclic alkyl-diyl group is attached to a -CO-N(R) group, it is linked to the 6- to 8-membered bridging group. 1 )CH(R 2 (R) 3The carbon atom of ring A is not a bridgehead atom. An example of such ring A representing a 6- to 8-membered bridged saturated bicyclic heterocyclic alkyl-diyl group is azabicyclo[2.2.1]heptane-diyl (especially 2-azabicyclo[2.2.1]heptane-1,2-diyl). In the presence of X representing N... 3 In certain cases of 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl groups, the group contains 6 to 8 ring atoms, including X representing nitrogen. 3 And there are no other heteroatoms.

[0069] The term "aryl" used alone or in combination means phenyl or naphthyl, especially phenyl. The aryl groups mentioned above are either unsubstituted or substituted as explicitly defined.

[0070] When R 3 When representing a phenyl group, such phenyl groups may be unsubstituted or substituted as explicitly defined. Whenever R... 3 When representing a phenyl group, it is particularly indicated that such a phenyl group is monosubstituted, disubstituted, or trisubstituted, wherein one of these substituents is connected to the linking site of the rest of the molecule in a para or meta position (especially para). In R 3 In one embodiment representing a phenyl group, the phenyl group is monosubstituted at the para position relative to the connection point of the rest of the molecule, or disubstituted independently at the para and a meta position or at the para and an ortho position relative to the connection point of the rest of the molecule. In particular, the substituent at the para position is (C... 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), halogens (especially fluorine, chlorine, or bromine), (C 1-3 )alkoxy (especially methoxy), (C 1-3 ) fluoroalkoxy (especially difluoromethoxy), (C 1-3 ) alkylthio (especially methylthio), (C 1-3 ) fluoroalkyl (especially trifluoromethyl) or NR N1 R N2 , where R N1 and R N2 The vertical representation indicates hydrogen or (C) 1-4 )alkyl(NR) N1 R N2 In particular, the dimethylamino group is indicated. The remaining substituents (if present) are selected independently, especially from (C... 1-3 Alkyl (especially methyl), halogen (especially fluorine or chlorine), and cyano groups. The R group represents a phenyl group. 3Specific embodiments include 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-(azacyclobutane-1-yl)phenyl, 3-(3-fluorooxocyclobutane-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. R represents a para-substituted phenyl group of this type. 3 Examples of the formulations include 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 3-fluoro-4-methylphenyl, and excluding those listed above: 3-fluoro-4-methoxyphenyl).

[0071] The term "heteroaryl," used alone or in combination, refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to at most four heteroatoms (especially one to at most three), each heteroatom being independently selected from N, O, and S. Examples of such heteroaryls include 5-membered heteroaryls such as furanyl, acezolyl, isoacezolyl, acediazolyl, thiophene, thiazolyl, isothiazolyl, thiadiazolyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryls such as pyridyl, pyrimidinyl, pyridyl, and pyridyl; and 8- to 10-membered bicyclic heteroaryls such as indolyl, isoyindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, furanylpyridyl, and pyridylpyridyl. The following are aryl groups: pyridyl, indazole, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxahiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienenopyridyl, quinolinyl, isoquinolinyl, pyridyl, pyrinyl, quinazolinyl, pyrrolidine, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidine, pyrrolopyridyl, imidazopyridyl, imidazopyridyl, and imidazothiazolyl. The heteroaryl groups mentioned above are either unsubstituted or substituted as explicitly defined.

[0072] When R 3 When representing 5- or 6-membered heteroaryl groups, it is used for R 3 The heteroaryl group comprises one to three independent cyclic heteroatoms selected from N, O, and S, wherein such heteroaryl groups are particularly connected to the rest of the molecule via cyclic carbon atoms. This type of R... 3 In particular, pyridyl, thiophenyl, acezolyl, thiazolyl, isothiazolyl, or isoacezolyl; such 5- or 6-membered heteroaryl groups are unsubstituted or, especially as explicitly defined, substituted. Such R 3 Examples include 5-chloropyridin-2-yl, 2-methylthiophen-3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5-isopropylisothiazol-2-yl, 5-chlorothiazol-2-yl, 5-bromothiazol-2-yl, 5-isopropylthiazol-2-yl, 2-isopropylthiazol-5-yl, 5-methylisothiazol-4-yl, 5-methylisothiazol-4-yl, 4-ethyl-5-methylisothiazol-3-yl. 5-Cyclopropylisothiazolin-3-yl and 5-Cyclopropyl-4-ethylisothiazolin-3-yl (especially 5-chloropyridin-2-yl, 2-methylthiophene-3-yl, 5-methylthiophene-2-yl, 5-chlorothiophene-2-yl, 3-methylthiophene-2-yl, 5-isopropylisothiazolin-2-yl, 5-chlorothiazolin-2-yl, 5-bromothiazolin-2-yl, 5-isopropylthiazolin-2-yl, 2-isopropylthiazolin-5-yl, 5-methylisothiazolin-4-yl, 5-methylisothiazolin-4-yl and 4-ethyl-5-methylisothiazolin-3-yl).

[0073] The term "8- to 10-membered heteroaryl" refers to a bicyclic heteroaryl group as previously defined, wherein the 8- to 10-membered heteroaryl group particularly comprises a total of one to at most three (especially one or two) heteroatoms independently selected from N, O, and S. In particular, such terms refer to 9- or 10-membered heteroaryl groups, such as, in particular, indazole, benzimidazolyl, indolyl, benzotriazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinolinyl, pyrrolopyridyl, and imidazopyridyl. These groups are unsubstituted or, as explicitly defined, substituted. The R symbol representing an 8- to 10-membered heteroaryl group... 3 Examples of such heteroaryl groups include benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, furanopyridyl, benzodiazolyl, thiophenepyridyl, 1H-indolyl, quinolinyl, and isoquinolinyl (especially benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, and furanothiophene); wherein such 8- to 10-membered heteroaryl groups are unsubstituted or substituted as defined. Such R 3 Specific embodiments include benzo[d] acezolidinyl, benzo[d] acezolidinyl, 6-fluorobenzo[d] acezolidinyl, benzo[d] acezolidinyl, benzo[d] thiazolidinyl, 2-chlorobenzo[d] thiazolidinyl, benzo[b] thiophene-5-yl, benzo[b] thiaphene-6-yl, furano[3,2-c]pyridin-6-yl, 2-methylbenzo[d] thiazolidinyl, and benzofuran. -2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[d]thiazol-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-2-yl, benzo[b]thiophene-2-yl, 2-methylbenzo[b]thiophene-5-yl, furano[3,2-b]pyridin-6-yl, furano[2,3-b]pyridin-6-yl, benzo[d] phosphatidyl-2-yl Benz[c][1,2,5]diazol-5-yl, thien[2,3-b], pyridin-2-yl, 1H-indol-6-yl, quinolin-7-yl, isoquinolin-3-yl and isoquinolin-7-yl; and other than those listed above: 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl and 2-methoxybenzo[d]thiazol-5-yl (especially benzofuran-6-yl, benzo[d] [5-yl benzo[d]benzo[d]benzo[6-yl benzo[d]benzo[d]benzo[6-yl benzo[d]thiazol-5-yl , 2-chlorobenzo[d]thiazol-5-yl , benzo[b]thiophene-5-yl , benzo[b]thiophene-6-yl , furano[3,2-c]pyridin-6-yl and 2-methylbenzo[d]thiazol-5-yl ; and other than those listed above: 2-bromobenzo[d]thiazol-5-yl .

[0074] The term "8- to 10-member partially aromatic fused bicyclic system" refers to a 5- or 6-member aromatic ring (especially a 6-member aromatic ring), which, as previously defined (C... 5-6) Cycloalkyl or 5- or 6-membered heterocyclic fusion, wherein the fused ring system contains a total of zero to at most three heteroatoms independently selected from N, O, and S. When R 3 When representing an 8- to 10-membered partially aromatic fused bicyclic system, such a ring system is bonded at the aromatic ring moiety (especially at the aromatic ring carbon) to the rest of the molecule; such 8- to 10-membered partially aromatic fused bicyclic systems are unsubstituted or, if explicitly defined, substituted; it should be understood that any side oxygen substituent is attached to a non-aromatic ring of such a ring system. R represents an 8- to 10-membered partially aromatic fused bicyclic system. 3 Examples of phenyl or pyridine are used, which, when combined with (C) as previously defined 5-6 Cycloalkyl or 5- or 6-membered heterocyclic alkyl ring fusion (where it should be understood that the total number of heteroatoms contained in such bicyclic systems is zero to three); in particular, R represents an 8- to 10-membered partially aromatic fused bicyclic system. 3 Examples of such ring systems include 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]m-dioxacyclopentenyl, 6,7-dihydro-5H-cyclopentadienyl, 2,3-dihydrofuran[3,2]pyridyl, chromium, isochromium, and 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl); wherein such ring systems are bonded in the aromatic ring moiety to the remainder of the molecule; wherein such ring systems are unsubstituted or substituted as explicitly defined. R represents an 8- to 10-membered partially aromatic fused bicyclic system of this type. 3 Examples include 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, 4-fluoro-2,3-dihydrobenzofuran-6-yl, 7-fluoro-2,3-dihydrobenzofuran-6-yl, 3-methyl-2,3-dihydrobenzofuran-6-yl, and 2-methyl-2,3-dihydrobenzofuran-6-yl. 3-Side-oxy-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-4-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl, 6,7-dihydro-5H-cyclopentan[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl, 2,3-dihydrofuran[3,2-b]pyridin-6-yl, 2,3-dihydrofuran[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]dioxacyclohexen-6-yl; this class of R 3Specific examples are 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, and 4-fluoro-2,3-dihydrobenzofuran-6-yl. For the avoidance of doubt, certain groups having tautomer forms that are primarily considered non-aromatic (such as 3-sideoxy-2,3-dihydrobenzofuran-6-yl) are defined herein as 8- to 10-membered partially aromatic fused bicyclic heterocyclic groups, even though the corresponding tautomer form (3-hydroxy-benzofuran-6-yl) may in some cases be considered as 8- to 10-membered heteroaryl groups; such tautomer forms are covered within this scope.

[0075] When using the term "between" to describe a range of values, it should be understood that the endpoints of the indicated range are explicitly included within the range. For example, if a temperature range is described as being between 40°C and 80°C, this means that the endpoints 40°C and 80°C are included within the range; or if a variable is defined as an integer between 1 and 4, this means that the variable is an integer 1, 2, 3, or 4.

[0076] Unless used for temperature, the term "about" preceding a numerical value "X" in this application refers to the range from X minus (10% of X) to X plus (10% of X), and preferably to the range from X minus (5% of X) to X plus (5% of X). Similarly, the term "about" preceding a numerical range "X to Y" in this application refers to the range from X minus (10% of X) to X plus (10% of X), and preferably to the range from X minus (5% of X) to X plus (5% of X). In the specific case of temperature, the term "about" preceding a temperature "Y" in this application refers to the range from temperature Y minus 10°C to Y plus 10°C, and preferably to the range from Y minus 5°C to Y plus 5°C. Furthermore, the term "room temperature" as used herein refers to a temperature of approximately 25°C.

[0077] Other embodiments of the present invention are presented below: 2) Another embodiment relates to a compound as in embodiment 1), wherein X 1 Indicates CH, CF, or N (specifically, X) 1 (Indicates CH or CF).

[0078] 3) Another embodiment relates to compounds as in embodiment 1) or 2), wherein R B1 Independent representation (C) 1-3 )alkyl, (C 1-3 )alkoxy, halogen or monocyclic (C 3-4 )cycloalkyl; [R B1Specifically, R can independently represent methyl, ethyl, methoxy, chlorine, iodine, or cyclopropyl; specifically, R B1 Independently representing methyl or methoxy].

[0079] 4) Another embodiment relates to the compound as in embodiment 1), wherein Cycle 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 alternatively 4-ethylphenyl, 4-isopropylphenyl, 4-propylphenyl, 4-(tert-butyl)phenyl, 4-(tert-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 [especially 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; in particular, 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 alternatively 4-ethylphenyl or 4-iodophenyl; specifically ring B represents p-tolyl, 3-fluoro-4-methylphenyl or 4-methoxyphenyl).

[0080] 5) Another embodiment relates to a compound as described in any one of embodiments 1) to 4), wherein X 2 Indicates O or NR 4 , where R 4 Indicates hydrogen, methyl, or cyclopropyl [specifically, X]. 2 Indicates O or NR 4 , where R 4 [Indicates hydrogen or methyl].

[0081] 6) Another embodiment relates to a compound as described in any one of embodiments 1) to 4), wherein X 2 It represents O.

[0082] 7) Another embodiment relates to a compound as described in any one of embodiments 1) to 6), wherein X 3 Represent CH or N such that: • When X 3 When CH is represented, ring A indicates a monocyclic ring (C 5-6 ) cycloalkane-diyl or monocyclic 5- or 6-membered heterocyclic alkane-diyl containing one ring O atom (especially tetrahydrofuran-diyl or tetrahydro-2H-piperan-diyl); [specifically; such ring A represents cyclopentane-1,2-diyl]; or • When X 3 When N is represented, ring A represents: • Contains X 3 and 4- to 6-membered saturated monocyclic heterocyclic alkyl-diyl groups (particularly aziridine-diyl or pyrrolidine-diyl) with zero ring O atoms; wherein the heterocyclic alkyl-diyl group is unsubstituted or monosubstituted or disubstituted (particularly unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine), (C 1-3 )alkoxy (especially methoxy or ethoxy), hydroxy and (C 1-3 ) alkylene (especially H2C=); [such ring A particularly represents pyrrolidone-1,2-diyl, 4-methylpyrrolidone-1,2-diyl, 4-fluoropyrrolidone-1,2-diyl, 3-methylenepyrrolidone-1,2-diyl, 5-methylpyrrolidone-1,2-diyl, aziridine-1,2-diyl, 4-methylacetidine-1,2-diyl, 3-fluoropyrrolidone-1,2-diyl, 4-hydroxypyridine Pyrrolidine-1,2-diyl, 4-methoxypyrrolidine-1,2-diyl, 4-ethoxypyrrolidine-1,2-diyl or 4,4-dimethylpyrrolidine-1,2-diyl; specifically, ring A represents pyrrolidine-1,2-diyl, 4-methylpyrrolidine-1,2-diyl, 4-fluoropyrrolidine-1,2-diyl, 3-methylenepyrrolidine-1,2-diyl or 5-methylpyrrolidine-1,2-diyl; • Contains X 3 And an unsubstituted 5- or 6-membered saturated monocyclic heterocyclic alkyl-diyl (particularly azolidinyl-diyl or oxazolidinyl-diyl, especially azolidinyl-diyl) with one ring O atom; [such ring A particularly represents azolidinyl-2,3-diyl, azolidinyl-3,4-diyl or 1,3-oxazolidinyl-2,3-diyl; specifically, such ring A represents azolidinyl-2,3-diyl]; • Contains X 3 and 5-membered monounsaturated monocyclic heterocyclic alkyl-diyl groups (particularly dihydro-1H-pyrrole-diyl groups) with zero extra ring nitrogen atoms; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X atoms. 3 Or linked to the group -CO-N(R)1 )CH(R 2 (R) 3 The carbon atom of ); [specifically, such ring A represents 2,3-dihydro-1H-pyrrole-1,2-diyl]; • Contains X 3 and a 5-membered monounsaturated monocyclic heterocyclic alkyl-diyl (especially dihydro-1H-pyrrole-diyl) with an additional ring N atom; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of the heterocyclic alkyl-diyl group; wherein the heterocyclic alkyl-diyl group is unsubstituted or substituted with (C) 1-3 )alkyl (especially methyl) monosubstituted; [specifically, such ring A represents 4,5-dihydro-1H-pyrazole-1,5-diyl or 3-methyl-4,5-dihydro-1H-pyrazole-1,5-diyl]; or • Contains X 3 A 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl group; wherein the bicyclic heterocyclic alkyl-diyl group is unsubstituted or disubstituted (specifically unsubstituted); wherein the substituents are independently (C 1-3 Alkyl (especially methyl); (such ring A particularly represents azabicyclo[2.2.1]heptane-diyl, azabicyclo[3.1.0]hexane-diyl or azaspiro[2.4]heptane-diyl, or other azabicyclo[3.2.0]heptane-diyl; especially such ring A represents 2-azabicyclo[2.2.1]heptane-1,2-diyl, 2-azabicyclo[3.1.0]hexane-2,3-diyl, 3-azabicyclo[3.1.0]hexane-2,3-diyl or 5-azaspiro[2.4]heptane -4,5-diyl, or alternatively, 3-azabicyclo[3.2.0]heptane-2,3-diyl or 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2,3-diyl); [specifically, such ring A represents 2-azabicyclo[2.2.1]heptane-1,2-diyl, 2-azabicyclo[3.1.0]hex-2,3-diyl or 3-azabicyclo[3.1.0]hex-2,3-diyl, or alternatively, 3-azabicyclo[3.2.0]heptane-2,3-diyl].

[0083] 8) Another embodiment relates to a compound as described in any one of embodiments 1) to 7), wherein X 3 It represents CH.

[0084] 9) Another embodiment relates to the compound as in embodiment 8), wherein ring A is: • ;or • ; (Specifically, ring A is) ); The asterisk indicates the substituent -C(=O)NR. 1 -CH2(R 2 (R) 3 ( ) connection points.

[0085] 10) Another embodiment relates to compounds as in embodiment 8) or 9), wherein the substituents -S(=O)(=X) 2 -(ring B) and -C(=O)NR of ring A 1 -CH2(R 2 (R) 3 It exhibits a relatively inverse configuration.

[0086] When X 3 When CH is represented, the compound of formula (I) contains at least two stereosymmetry centers located at two carbon atoms of ring A, which are bonded to ring A to -S(=O)(=X). 2 )-(loop B) and bonding to -C(=O)NR 1 -CH2(R 2 (R) 3 Therefore, according to this embodiment, compound (I) represents compound (II) or compound (III) or any mixture thereof (especially compound (II) enriched by mirror isomerism): Equation (II) Equation (III).

[0087] In this case, the relative configurations of stereoisomers in this application are thus represented as follows: For example, the compound (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1,1-difluoro-spiro[2.5]octyl-6-yl)-amide having the relative configuration (1R*,2S*) refers to the compound (1R,2S)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1,1-difluoro-spiro[2.5]octyl-6-yl)-amide. [2.5]oct-6-yl)-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 such stereoisomers, including racemic mixtures (named rac-(1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-(1,1-difluoro-spiro[2.5]oct-6-yl)-amide).

[0088] 11) Another embodiment relates to a compound as described in any one of embodiments 1) to 7), wherein X3 N represents N.

[0089] 12) Another embodiment relates to a compound as in embodiment 11), wherein ring A represents: • Pyrrolidine-diyl; wherein the pyrrolidine-diyl is unsubstituted or via (C) 1-3 )alkyl (especially methyl), halogen (especially fluorine), (C 1-3 )alkoxy (especially methoxy or ethoxy), hydroxy or (C 1-3 )alkylene (especially H2C=) monosubstituted; or via (C 1-3 Alkyl (especially methyl) or halogen (especially fluorine) disubstituted; [such ring A particularly represents pyrrolidone-1,2-diyl, 4-methylpyrrolidone-1,2-diyl, 4-fluoropyrrolidone-1,2-diyl, 3-methylenepyrrolidone-1,2-diyl, 5-methylpyrrolidone-1,2-diyl, 4,4-dimethylpyrrolidone-1,2-diyl, 3-fluoropyrrolidone-1,2-diyl, 4-hydroxypyrrolidone-1,2-diyl, 4-methoxypyrrolidone-1,2-diyl or 4-ethoxypyrrolidone-1,2-diyl; specifically, such ring A represents pyrrolidone-1,2-diyl, 4-methylpyrrolidone-1,2-diyl, 4-fluoropyrrolidone-1,2-diyl, 3-methylenepyrrolidone-1,2-diyl, or 5-methylpyrrolidone-1,2-diyl; • Acazolidine-diyl; [specifically, ring A of this type represents acazolidine-2,3-diyl]; • Dihydro-1H-pyrrole-diyl; wherein the double bond of the dihydro-1H-pyrrole-diyl group does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of ); [specifically, such ring A represents 2,3-dihydro-1H-pyrrole-1,2-diyl]; or • Contains X 3 A 6- to 7-membered saturated spiro, fused, or bridged bicyclic heterocyclic alkyl-diyl group; wherein the bicyclic heterocyclic alkyl-diyl group is unsubstituted or disubstituted (specifically unsubstituted); wherein the substituents are independently (C 1-3Alkyl (especially methyl); (such ring A particularly represents azabicyclo[2.2.1]heptane-diyl, azabicyclo[3.1.0]hexane-diyl or azaspiro[2.4]heptane-diyl, or additionally, azabicyclo[3.2.0]heptane-diyl; especially such ring A represents 2-azabicyclo[2.2.1]heptane-1,2-diyl, 2-azabicyclo[3.1.0]hexane-2,3-diyl, 3-azabicyclo[3.1.0]hexane-2,3-diyl or 5-azaspiro[2.4] Heptane-4,5-diyl. Or alternatively, 3-azabicyclo[3.2.0]heptane-2,3-diyl or 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-diyl); [specifically, such ring A represents 2-azabicyclo[2.2.1]heptane-1,2-diyl, 2-azabicyclo[3.1.0]hexane-2,3-diyl or 3-azabicyclo[3.1.0]hexane-2,3-diyl, or alternatively 3-azabicyclo[3.2.0]heptane-2,3-diyl].

[0090] 13) Another embodiment relates to a compound as in embodiment 11), wherein ring A represents pyrrolidone-1,2-diyl, 4-methylpyrrolidone-1,2-diyl, 4-fluoropyrrolidone-1,2-diyl, 3-methylenepyrrolidone-1,2-diyl, 2,3-dihydro-1H-pyrrole-1,2-diyl, 2-azabicyclo[2.2.1]heptane-1,2-diyl, 2-azabicyclo[3.1.0]hex-2,3-diyl or 3-azabicyclo[3.1.0]hex-2,3-diyl, or another 3-azabicyclo[3.2.0]heptane-2,3-diyl.

[0091] 14) Another embodiment relates to a compound as described in any one of embodiments 1) to 13), wherein R 1 express: • 3-Cyano-3,3-dimethylpropyl or 4-cyanobutyl (especially 3-cyano-3,3-dimethylpropyl); •Saturated monocyclic (C 4-6 )cycloalkyl; wherein the (C 4-6 ) cycloalkyl groups are monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: (C 1-3 Alkyl groups (especially methyl or isopropyl), halogens (especially fluorine), (C 1-3 ) fluoroalkyl groups (especially difluoromethyl or trifluoromethyl), (C 1-3 )alkoxy (especially methoxy), carbamoyl, hydroxyl and cyano; • Monounsaturated monocyclic (C 5-6 ) cycloalkyl (especially cyclohexenyl); wherein the monounsaturated (C 5-6The double bond of the cycloalkyl group does not contain the group -N(CO)CH(R) 2 (R) 3 The carbon atom of ); [specifically, such R 1 [Represents cyclohexyl-3-en-1-yl]; •Saturated bicyclic (C 6-8 Spirocycloalkyl (particularly spiro[2.3]hexyl, spiro[3.3]heptyl, spiro[2.4]heptyl or spiro[2.5]octyl); wherein the (C 6-8 Spirocycloalkyl groups are either unsubstituted or difluorinated; [specifically, such R...] 1 This indicates 1,1-difluorospiro[2.3]hexane-5-yl, 1,1-difluorospiro[2.5]octane-6-yl, spiro[3.3]heptane-2-yl, 6,6-difluorospiro[3.3]heptane-2-yl, 1,1-difluorospiro[2.4]heptane-5-yl or spiro[2.5]octane-6-yl; • Saturated fused or bridged double rings (C 6-8 )cycloalkyl (particularly bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl or bicyclo[2.2.2]octyl); wherein the (C 6-8 ) cycloalkyl groups are either unsubstituted or difluorinated; [specifically, such R 1 This indicates bicyclo[4.1.0]heptane-3-yl, 7,7-difluorobicyclo[4.1.0]heptane-3-yl]; or • A 6-membered saturated monocyclic heterocyclic alkyl group comprising a cyclic heteroatom group selected from O, S, and SO2 (the heterocyclic alkyl group is particularly tetrahydro-2H-piperan, tetrahydro-2H-thiopiperan, or tetrahydro-2H-thiopiperan-1,1-dioxide); wherein the heterocyclic alkyl group is unsubstituted, or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine) and (C 1-3 ) fluoroalkyl groups (especially trifluoromethyl); specifically, such R 1 It represents 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, tetrahydro-2H-piperan-4-yl, 3-fluorotetrahydro-2H-piperan-4-yl, 2-methyltetrahydro-2H-piperan-4-yl, 2-(trifluoromethyl)tetrahydro-2H-piperan-4-yl, 2,2-dimethyltetrahydro-2H-piperan-4-yl or tetrahydro-2H-piperan-3-yl, or other 3-methyltetrahydro-2H-piperan-4-yl, 6-methyltetrahydro-2H-piperan-3-yl, 6,6-dimethyltetrahydro-2H-piperan-3-yl, 2,6-dimethyltetrahydro-2H-piperan-4-yl or 1,1-dioxo-tetrahydro-2H-thiopiperan-3-yl).

[0092] 15) Another embodiment relates to a compound as described in any one of embodiments 1) to 13), wherein R 1 express: • 3-Cyano-3,3-dimethylpropyl or 4-cyanobutyl (especially 3-cyano-3,3-dimethylpropyl); • Cyclobutyl; wherein the cyclobutyl group is monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine), (C 1-3 ) fluoroalkyl (especially trifluoromethyl), hydroxyl and cyano groups; specifically, such R 1 [Represents 3-cyanocyclobutyl, 3-(trifluoromethyl)cyclobutyl or 3-hydroxy-3-(trifluoromethyl)cyclobutyl] cyclobutyl • Cyclopentyl; wherein the (C 4-6 The cycloalkyl group is monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine), (C 1-3 ) fluoroalkyl (especially trifluoromethyl), (C 1-3 )alkoxy (especially methoxy), carbamoyl, hydroxyl and cyano; [such R 1 In particular, it refers to 3-cyanocyclopentyl, 3-cyano-3-methylcyclopentyl, 4-cyano-2-hydroxycyclopentyl, 3-fluorocyclopentyl, 3-methoxycyclopentyl, 3-(difluoromethyl)cyclopentyl, 3-aminoformylcyclopentyl, 3-aminoformyl-3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3,3-difluorocyclopentyl, or 4-cyano-2-methoxycyclopentyl, or another 2-methoxycyclopentyl or 3-hydroxycyclopentyl; specifically, such R 1 [Represents 3-cyanocyclopentyl, 3-cyano-3-methylcyclopentyl, or 4-cyano-2-hydroxycyclopentyl]; • Cyclohexyl; wherein (C 4-6 The cycloalkyl group is monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: (C 1-3 Alkyl groups (especially methyl or isopropyl), halogens (especially fluorine), (C 1-3 )alkoxy (especially methoxy), carbamoyl, hydroxyl and cyano; [such R 1In particular, it refers to 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 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; specifically, such R 1 [Represents 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl or 4-fluorocyclohexyl]; • Cyclohexenyl group; wherein the double bond of the cyclohexenyl group does not contain a bond connected to -N(CO)CH(R) 2 (R) 3 The carbon atom of the group; [specifically, such R 1 [Represents cyclohexyl-3-en-1-yl]; •Saturated bicyclic (C 6-8 Spirocycloalkyl (particularly spiro[2.3]hexyl, spiro[3.3]heptyl, spiro[2.4]heptyl or spiro[2.5]octyl); wherein the (C 6-8 Spirocycloalkyl groups are either unsubstituted or difluorinated; [specifically, such R...] 1 This indicates 1,1-difluorospiro[2.3]hexane-5-yl, 1,1-difluorospiro[2.5]octane-6-yl, spiro[3.3]heptane-2-yl, 6,6-difluorospiro[3.3]heptane-2-yl, 1,1-difluorospiro[2.4]heptane-5-yl or spiro[2.5]octane-6-yl; • Saturated fused or bridged double rings (C 6-8 )cycloalkyl (particularly bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl or bicyclo[2.2.2]octyl); wherein the (C 6-8 ) cycloalkyl groups are either unsubstituted or difluorinated; [specifically, such R 1 This indicates bicyclo[4.1.0]heptane-3-yl, 7,7-difluorobicyclo[4.1.0]heptane-3-yl]; or • A 5- or 6-membered (preferably 6-membered) saturated monocyclic heterocyclic alkyl group comprising a cyclic heteroatom group selected from O, S, or SO2 (the heterocyclic alkyl group is particularly tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-piperan, tetrahydro-2H-thiopiperan, or tetrahydro-2H-thiopiperan-1,1-dioxide); wherein the heterocyclic alkyl group is unsubstituted, or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine) and (C 1-3 ) fluoroalkyl (especially trifluoromethyl); [specifically, such R1 It represents 1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl, 1,1-dioxo-tetrahydrothiophen-3-yl, tetrahydro-2H-piperan-4-yl, 3-fluorotetrahydro-2H-piperan-4-yl, 2-methyltetrahydro-2H-piperan-4-yl, 2-(trifluoromethyl)tetrahydro-2H-piperan-4-yl, 2,2-dimethyltetrahydro-2H-piperan-4-yl or tetrahydro-2H-piperan-3-yl, or another 3-methyltetrahydro-2H-piperan-4-yl, 6-methyltetrahydro-2H-piperan-3-yl, 6,6-dimethyltetrahydro-2H-piperan-3-yl, 2,6-dimethyltetrahydro-2H-piperan-4-yl, or 1,1-dioxo-tetrahydro-2H-thiophen-3-yl).

[0093] 16) Another embodiment relates to a compound as described in any one of embodiments 1) to 13), wherein R 1 express: •3-Cyano-3-methylbutyl; •Saturated monocyclic (C 5-6 )cycloalkyl; wherein the (C 5-6 ) Cycloalkyl groups are monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: methyl, fluorine, hydroxyl, and cyano; [especially such R 1 [Represents 3-cyanocyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-2-hydroxycyclopentyl, or 4-fluorocyclohexyl]; • Cyclohex-3-en-1-yl; •Saturated bicyclic (C 6-8 )spirocycloalkyl (particularly spiro[2.3]hexyl or spiro[2.5]octyl); wherein the (C 6-8 Spirocycloalkyl groups are disubstituted with fluorine; [such R 1 Specifically, 1,1-difluorospiro[2.3]hexyl-5-yl and 1,1-difluorospiro[2.5]octyl-6-yl; • Saturated fused or bridged double rings (C 6-8 )cycloalkyl (particularly bicyclo[4.1.0]heptyl); wherein the (C 6-8 ) Cycloalkyl groups are either unsubstituted or difluorinated; [such R 1 Specifically, it refers to bicyclo[4.1.0]heptane-3-yl, 7,7-difluorobicyclo[4.1.0]heptane-3-yl]; or •Tetrahydro-2H-thiopiperan-1,1-dioxide

[0094] 17) Another embodiment relates to a compound as described in any one of embodiments 1) to 13), wherein R 1 express: •Saturated monocyclic (C 5-6 )cycloalkyl; wherein the (C 5-6 ) Cycloalkyl groups are monosubstituted with cyano or hydroxyl groups; or disubstituted with methyl or fluorine groups; [specifically, such R 1 [Represents 3-cyanocyclopentyl, 3-cyanocyclohexyl, 4-hydroxycyclohexyl, 4-cyanocyclohexyl, 4,4-dimethylcyclohexyl, or 4,4-difluorocyclohexyl]; •Saturated bicyclic (C 6-8 )spirocycloalkyl (particularly spiro[2.3]hexyl or spiro[2.5]octyl); wherein the (C 6-8 Spirocycloalkyl groups are disubstituted with fluorine; [specifically, such R...] 1 Represents 1,1-difluorospiro[2.3]hexyl-5-yl, 1,1-difluorospiro[2.5]octyl-6-yl; or • Bicyclo[4.1.0]heptane-3-yl; • Or another 1,1-dioxane-tetrahydro-2H-thiopiperan-3-yl.

[0095] 18) Another embodiment relates to a compound according to any one of embodiments 1) to 17), wherein R 3 express: • A 9- or 10-membered partially aromatic fused bicyclic system comprising a total of zero to three independently selected cyclic heteroatoms from N, O, and S (particularly 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]m-dioxacyclopentenyl, 6,7-dihydro-5H-cyclopentadienyl, 2,3-dihydrofuran[3,2]pyridyl, chromium, isochromium, or 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl); wherein the 9- or 10-membered ring system is bonded in the aromatic ring portion to the remainder of the molecule; wherein the 9- or 10-membered ring system is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of halogens (especially fluorine) and lateral oxygen groups; [specifically, such R 3This refers to 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, 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-sideoxy-2,3-dihydrobenzofuran-6-yl, and benzo[d][1,3]dioxacyclopenten-5-yl. Heterocyclopenten-4-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl, 6,7-dihydro-5H-cyclopenten[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenten[c]pyridin-3-yl, 2,3-dihydrofuran[3,2-b]pyridin-6-yl, 2,3-dihydrofuran[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]dioxacyclohexen-6-yl; • Naphthyl or 8- to 10-membered heteroaryl groups comprising a total of one to three independently selected cyclic heteroatoms from N, O, and S (such R groups) 3 Specifically, it refers to 9- or 10-membered heteroaryl groups; especially benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiophene, furan-pyridyl, benzodiazolyl, thiophene-pyridyl, 1H-indolyl, quinolinyl, or isoquinolinyl); wherein the naphthyl or 8- to 10-membered heteroaryl group is independently unsubstituted or monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: (C 1-3 ) alkyl (especially methyl) and halogens (especially fluorine or chlorine); [specifically, such R 3This refers to benzofuran-6-yl, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophene-5-yl, benzo[b]thiaphene-6-yl, furano[3,2-c]pyridin-6-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[b]thiaphene-2-yl, 2-methylbenzo[b]thiaphene-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[d]thiazol-2-yl, benzene [d] benzo[d] 2-yl, thien[2,3-b]pyridin-2-yl, 1H-indol-6-yl, furano[3,2-b]pyridin-6-yl, furano[2,3-b]pyridin-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[c][1,2,5] benzo[c] diazol-5-yl, naphthyl-2-yl, quinoline-7-yl, isoquinoline-3-yl, or isoquinoline-7-yl, or additionally 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, or 2-methoxybenzo[d]thiazol-5-yl; • Phenyl; wherein the phenyl group is monosubstituted, disubstituted, or trisubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), halogens (especially fluorine, chlorine, or bromine), (C 1-3 )alkoxy (especially methoxy), (C 1-3 ) fluoroalkoxy (especially difluoromethoxy), monocyclic 4- to 6-membered heterocyclic alkyl (especially azahexacyclic butyl or oxohexacyclic butyl); wherein the heterocyclic alkyl is unsubstituted or monosubstituted with halogen (especially fluorine), monocyclic (C 3-6 )cycloalkyl (especially cyclopropyl), (C 1-3 ) alkylthio (especially methylthio), (C 1-3 )Fluoroalkyl (especially trifluoromethyl), cyano and NR N1 R N2 , where R N1 and R N2 Independently representing hydrogen or (C 1-4 )alkyl(NR) N1 R N2 In particular, it indicates dimethylamino); [specifically, this type of R 3This indicates 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-(azacyclobutane-1-yl)phenyl, 3-(3-fluorooxocyclobutane-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, 4-fluoro-4-methoxyphenyl, 2,3-difluoro-4-methylphenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-2,6-difluorophenyl, or 2,4-difluoro-5-methylphenyl]; or • Contains a total of one to three 5- or 6-membered heteroaryl groups (particularly pyridinyl, thiophene, acezol, thiazol, or isoacezol) independently selected from N, O, and S; wherein the 5- or 6-membered heteroaryl group is independently monosubstituted or disubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), halogens (especially fluorine, chlorine, or bromine), (C 1-3 )alkoxy (especially methoxy), (C 1-3 ) fluoroalkoxy (especially difluoromethoxy), monocyclic (C 3-6 )cycloalkyl (especially cyclopropyl), (C 1-3 ) alkylthio (especially methylthio), (C 1-3 )Fluoroalkyl (especially trifluoromethyl), cyano, NR N1 R N2 , where R N1 and R N2 Independently representing hydrogen or (C 1-4 )alkyl(NR) N1 R N2 In particular, it represents a dimethylamino group, and a 4- to 6-membered monocyclic heterocyclic alkyl group (especially an azahexacyclic or oxohexacyclic); wherein the heterocyclic alkyl group is unsubstituted or monosubstituted with a halogen (especially fluorine); [specifically, such R 3It represents 5-chloropyridin-2-yl, 2-methylthiophen-3-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-2-yl, 3-methylthiophen-2-yl, 5-isopropylthiozol-2-yl, 5-chlorothiazol-2-yl, or 5-bromothiazol-2-yl.

[0096] 19) Another embodiment relates to a compound according to any one of embodiments 1) to 17), wherein R 3 express: • A 9- or 10-membered aromatic fused bicyclic system comprising a total of zero to three independently selected cyclic heteroatoms from N, O, and S (particularly 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, benzo[d][1,3]dioxacyclopenten-4-yl, 6,7-dihydro-5H-cyclopentan[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl, 2,3-dihydrofuran[3,2-b]pyridin- 6-yl, 2,3-dihydrofurano[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]dioxane-6-yl); wherein the 9- or 10-membered ring system is bonded to the remainder of the molecule at the aromatic ring moiety; wherein the 9- or 10-membered ring system is unsubstituted, or monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of halogens (especially fluorine) and lateral oxygen groups; [specifically, such R 3 This refers to 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, 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-sideoxy-2,3-dihydrobenzofuran-6-yl, and benzo[d][1,3]dioxacyclopenten-5-yl. Heterocyclopenten-4-yl, 2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl, 6,7-dihydro-5H-cyclopentan[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopentan[c]pyridin, -3-yl2,3-dihydrofuran[3,2-b]pyridin-6-yl, 2,3-dihydrofuran[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]dioxacyclohexen-6-yl; • Containing a total of one to three independent cyclic heteroatoms selected from N, O, and S, consisting of 9- or 10-membered heteroaryl groups (particularly benzofuran-2-yl, benzofuran-5-yl, benzofuran-6-yl, benzo[d]carbazo-5-yl, benzo[d]carbazo-6-yl, benzo[d]carbazo-2-yl, benzo[d]thiazo-5-yl, benzo[d]thiazo-6-yl, benzo[d]thiazo-2-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-5-yl, benzo[ [b] Thiophene-6-yl, furano[3,2-c]pyridin-6-yl, furano[3,2-b]pyridin-6-yl, benzo[c][1,2,5]diazol-5-yl, thienano[2,3-b], pyridin-2-yl, 1H-indol-6-yl, quinolin-7-yl, isoquinolin-3-yl, or isoquinolin-7-yl); wherein the 9- or 10-membered heteroaryl group is unsubstituted or monosubstituted or disubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 ) alkyl (especially methyl) and halogens (especially fluorine or chlorine); [specifically, such R 3 This refers to benzofuran-6-yl, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophene-5-yl, benzo[b]thiaphene-6-yl, furano[3,2-c]pyridin-6-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[b]thiaphene-2-yl, 2-methylbenzo[b]thiaphene-5-yl, benzofuran-2-yl, benzofuran-5-yl, 2-methylbenzofuran-6-yl, benzo[d]thiazol-2-yl , benzo[d]pyridin-2-yl, thien[2,3-b]pyridin-2-yl, 1H-indol-6-yl, furano[3,2-b]pyridin-6-yl, furano[2,3-b]pyridin-6-yl, 6-fluoro-2-methylbenzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[c][1,2,5]diazol-5-yl, quinoline-7-yl, isoquinoline-3-yl, or isoquinoline-7-yl], or additionally 2-bromobenzo[d]thiazol-5-yl, 4-fluorobenzo[d]thiazol-5-yl, or 2-methoxybenzo[d]thiazol-5-yl; • Phenyl; wherein the phenyl group is monosubstituted, disubstituted, or trisubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 alkyl groups (especially methyl, ethyl, or isopropyl), halogens (especially fluorine, chlorine, or bromine), (C 1-3 )alkoxy (especially methoxy), (C 1-3 ) fluoroalkoxy (especially difluoromethoxy), (C 1-3 ) alkylthio (especially methylthio), (C 1-3) fluoroalkyl (especially trifluoromethyl), cyano, and NR N1 R N2 , where R N1 and R N2 Independently representing hydrogen or (C 1-4 )alkyl(NR) N1 R N2 In particular, it indicates dimethylamino); [specifically, this type of R 3 This indicates 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, 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 2,4-difluoro-5-methylphenyl]; or • Containing one to three 5-membered heteroaryl groups (particularly thien-3-yl, thien-2-yl, chloro-2-yl, thiazo-2-yl, thiazo-5-yl, isothiazol-4-yl, isochloro-3-yl, or isochloro-4-yl) independently selected from N, O, and S; wherein the 5-membered heteroaryl group is independently monosubstituted or disubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl, ethyl or isopropyl) and halogens (especially chlorine or bromine); [specifically, such R 3 [Represents 2-methylthiophene-3-yl, 5-methylthiophene-2-yl, 5-chlorothiophene-2-yl, 3-methylthiophene-2-yl, 5-isopropylthiozol-2-yl, 5-chlorothiozol-2-yl, 5-bromothiozol-2-yl, 5-isopropylthiozol-2-yl, 2-isopropylthiozol-5-yl, 5-methylisothiozol-4-yl, 4-ethyl-5-methylisothiozol-3-yl, or 5-methylisothiozol-4-yl]; or • Pyridyl (especially pyridin-2-yl); wherein the pyridyl group is monosubstituted with a halogen (especially chlorine); [specifically, such R 3 (Represents 5-chloropyridin-2-yl).

[0097] 20) Another embodiment relates to a compound according to any one of embodiments 1) to 17), wherein R 3 express: • A 9- or 10-membered partially aromatic fused bicyclic system comprising a total of zero to three independently selected cyclic heteroatoms from N, O, and S (particularly 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, or benzo[d][1,3]dioxacyclopenten-5-yl); wherein the 9- or 10-membered ring system is bonded in the aromatic ring moiety to the remainder of the molecule; wherein the 9- or 10-membered ring system is unsubstituted or monosubstituted with a halogen (especially fluorine); [specifically, such R 3 It represents 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, benzo[d][1,3]dioxacyclopenten-5-yl, or 4-fluoro-2,3-dihydrobenzofuran-6-yl; • Containing a total of one to three 9- or 10-membered heteroaryl groups independently selected from N, O, and S (particularly benzofuran-6-yl, benzo[d]carbazo-5-yl, benzo[d]carbazo-6-yl, benzo[d]thiophen-5-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, furano[3,2-c]pyridin-6-yl); wherein the 9- or 10-membered heteroaryl group is unsubstituted or monosubstituted or disubstituted, wherein such substituents are independently selected from the group consisting of: (C 1-3 ) alkyl (especially methyl) and halogen (especially chlorine); [specifically, such R 3 This indicates benzofuran-6-yl, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, 2-chlorobenzo[d]thiazol-5-yl, benzo[b]thiophene-5-yl, benzo[b]thiaphene-6-yl, furano[3,2-c]pyridin-6-yl, or 2-methylbenzo[d]thiazol-5-yl, or another 2-bromobenzo[d]thiazol-5-yl; or • Phenyl; wherein the phenyl group is monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine, chlorine or bromine), (C 1-3 )alkoxy (especially methoxy) and (C 1-3 ) alkylthio (especially methylthio); [specifically, such R 3It represents 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 another 3-fluoro-4-methoxyphenyl.

[0098] 21) Another embodiment relates to a compound according to any one of embodiments 1) to 17), wherein R 3 express: • A 9- or 10-membered partially aromatic fused bicyclic system selected from 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, and benzo[d][1,3]dioxacyclopenten-5-yl; wherein the 9- or 10-membered ring system is bonded in the aromatic ring moiety to the remainder of the molecule; wherein the 9- or 10-membered ring system is unsubstituted or monosubstituted with a halogen (especially fluorine); [specifically, such R 3 It represents 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, 5-fluoro-2,3-dihydrobenzofuran-6-yl, or benzo[d][1,3]m-dioxacyclopenten-5-yl; • A 9- or 10-membered heteroaryl group selected from benzofuran-6-yl, benzo[d]carbazo-5-yl, benzo[d]carbazo-6-yl, and benzo[d]thiazo-5-yl; wherein the 9- or 10-membered heteroaryl group is unsubstituted or monosubstituted with a halogen (fluorine or chlorine); [specifically, such R 3 [Represents benzofuran-6-yl, benzo[d]carbazol-5-yl, 6-fluorobenzo[d]carbazol-5-yl, benzo[d]carbazol-6-yl, benzo[d]thiazol-5-yl, or 2-chlorobenzo[d]thiazol-5-yl]; or • Phenyl; wherein the phenyl group is monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine, chlorine or bromine), (C 1-3 )alkoxy (especially methoxy) and (C 1-3 ) alkylthio (especially methylthio); (wherein such substituents are selected, in particular, independently from the group consisting of: (C 1-3 )alkyl (especially methyl), halogen (especially fluorine, chlorine or bromine) and (C 1-3 )alkylthio (especially methylthio)); [specifically, such R 3 It represents p-tolyl, 4-chlorophenyl, 4-bromophenyl, 4-(methylthio)phenyl, or 4-chloro-2-fluorophenyl, or another 3-fluoro-4-methoxyphenyl.

[0099] 22) Another aspect of the present invention relates to a compound of formula (I) as described in any one of embodiments 1) to 21), which is a compound of formula (IV) (i.e., the group -C(=O)NR). 1 -CH2(R 2 (R) 3 The absolute configuration of the ring carbon atoms connected to the ring is described in equation (IV) below: Formula (IV).

[0100] 23) Another embodiment relates to the compound according to embodiment 1), which is selected from the following compounds: (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzo[b]thiophene-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazol-5-ylmethyl-(1,1-dioxy-hexahydro-λ) 6 -Thiopiperan-4-yl)-amide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4-fluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(cyclohex-3-en-1-yl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzo[b]thiophene-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-difluoro-benzofuran-6-ylmethyl)-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-difluoro-benzofuran-6-ylmethyl)-(1,1-disidel-hexahydro-1λ) 6 -Thiopiperan-4-yl)-amide; (1R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,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)-pyrrolidone-2-carboxylic acid benzoxazol-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (2S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzo[d]azol-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4-hydroxy-cyclohexyl)-amide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S,4S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-4-fluoro-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1R,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; (2S,4S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-4-fluoro-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(benzo[d]azol-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidone-2-carboxamide; (S)-4-methylene-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S,4S)-4-fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid (1R,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-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-(4,4-difluorocyclohexyl)-N-(furano[3,2-c]pyridin-6-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1R,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; (1R*,5S*)-(2RS)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2S,5R)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,2S,5S)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,5R)-2-(4-methoxy-benzenesulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-toluenesulfonyl-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-((4-methoxyphenyl)sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-toluenesulfonyl-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((4-methoxyphenyl)sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-2-(4-methoxy-benzenesulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,3S,5R)-2-(toluene-4-sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,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; (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; (1R,2S,5S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methoxyphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxyphenylsulfonyl)pyrrolidin-2-carboxamide; (1R*,5S*)-(2RS)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1S,2S,5R)-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,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]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-(N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (1R,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; (1R,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-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(3-fluoro-4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(4-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(4-cyclopropyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S,5R)-5-methyl-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(4,4-difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1R,3S,4S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((6-methylpyridin-3-yl)sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide; (1R,3S,4S)-2-(6-methylpyridine-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)-pyrrolidin-2-carboxylic acid benzo[1,3]dioxacyclopenten-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (2S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-(3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (2S)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (2S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-(methylthio)benzyl)pyrrolidin-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)pyrrolidin-2-carboxamide; (2S)-N-(benzo[d]thiazo-5-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methoxyphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chlorobenzyl)-1-(N-cyclopropyl-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1,3]dioxacyclopenten-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(4-chlorobenzyl)-N-(4,4-dimethylcyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chlorobenzyl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-((4-ethynyl-2-hydroxycyclopentyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)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]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-((3S,5R)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((3S,5R)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((3S,6R)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (1S,2R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1,3]dioxacyclopenten-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]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-((3S,6r)-1,1-difluorospiro[2.5]octyl-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-((3S,6r)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1S*,3R*)-3-cyanocyclopentyl)-2-toluenesulfonylcyclopentane-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-((1R*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorophenylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-(N,4-dimethylphenylsulfonyl)-4-methylpyrrolidin-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-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-methylthio-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]dioxacyclopenten-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-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methylthio-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; (2S,4S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-fluoropyrrolidine-2-carboxamide; (2S,4S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (S)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-methylbenzyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (S)-N-(4-chlorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1S*,3R*)-3-cyano-cyclopentyl)-(4-methyl-benzyl)-amide; (2S,4S)-N-(4-chlorobenzyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-(R)-(N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2RS)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-methylbenzyl)-3-toluenesulfonyl azithiodin-2-carboxamide; (2RS)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-chlorobenzyl)-3-toluenesulfonyl methazolidine-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)-cyclopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-dihydroinden-5-ylmethyl-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic 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 ((1R*,3R*)-3-cyano-cyclohexyl)-(4-methyl-benzyl)-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-((1R,3S)-3-cyano-cyclopentyl)-amide; (1S,2R)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(7,7-difluorobicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-((1R*,3R*)-3-cyanocyclohexyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1R*,3S*)-3-cyano-cyclopentyl)-(3-fluoro-4-methyl-benzyl)-amide; (2S,4S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-fluoropyrrolidone-2-carboxamide; (2S,4S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)-4-methyl-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (1S,2R)-N-((1r,4S)-4-cyanocyclohexyl)-N-(4-(methyl-d3)benzyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(4-chloro-2-fluorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4,4-difluoro-cyclohexyl)-(6-fluoro-benzoxazo-5-ylmethyl)-amide; (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-2-((R)-4-methylphenylsulfonamide)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-2-((S)-4-methylphenylsulfonamide)cyclopentane-1-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((1R)-3-cyano-3-methylcyclopentyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-2-((R)-4-methylphenylsulfonyl)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-2-((S)-4-methylphenylsulfonyl)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R)-3-cyano-3-methylcyclopentyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (S)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-N-((1S*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-N-((1S*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((1R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methyl-benzothiazo-5-ylmethyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hexane-5-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; and (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide.

[0101] 24) Other compounds according to embodiment 1) are selected from the following compounds: (S)-N-(benzo[d]thiazo-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzo[d]thiazo-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-4-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3R,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(4-iodobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-4-methoxy-N-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-1-(4-ethyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-4-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-4-methoxy-N-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1,1-difluoro-spiro[2.5]oct-6-yl)-amide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1,1-difluoro-spiro[2.3]hex-5-yl)-amide; (1R*,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; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-bromo-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-bromo-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(3-methoxy-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-N-((2-chlorobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((2-bromobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazo-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazo-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxy-N-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(6-methyl-1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-3-yl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-3-yl)-amide; (1S*,2S*,5R*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*,5S*)-N-benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-((R)-N,4-dimethylphenylsulfonamide)-3-azabicyclo[3.1.0]hexane-2-carboxamide.

[0102] Compounds of formula (I) according to embodiments 1) to 24) and their pharmaceutically acceptable salts may be used as pharmaceutical agents, for example in the form of enteric (especially in the form of tablets or capsules for oral administration) or non-enteric administration (including topical application or inhalation) pharmaceutical compositions.

[0103] Pharmaceutical compositions can be produced in a manner familiar to those skilled in this art (see, for example, Remington, The Science and Practice of Pharmacy, 21st edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]), by combining a compound of formula (I) as described or a pharmaceutically acceptable salt thereof, as appropriate, with other valuable therapeutic substances, along with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials, and, if necessary, common pharmaceutical adjuvants, into a galenical administration form.

[0104] This invention also relates to a method for preventing / treating or treating the diseases or conditions mentioned herein, comprising administering to an individual a pharmaceutically active amount of a compound of formula (I) according to embodiments 1) to 24).

[0105] To avoid any ambiguity, if a compound is described as being suitable for the prevention / treatment or treatment of certain diseases, then such compounds are also suitable for the preparation of pharmaceutical agents for the prevention / treatment or treatment of such diseases. Similarly, such compounds are also suitable for methods of preventing / treating or treating such diseases, which involve administering an effective amount of such compound to an individual (mammal, especially a human) in need.

[0106] Compounds of formula (I) according to any one of embodiments 1) to 24) are suitable for the prevention / treatment or treatment of diseases or conditions related to OX2R receptors, and are particularly suitable for diseases and conditions in which the agonist effect of OX2R is exerted. Diseases and conditions in which the agonist effect of OX2R is exerted are particularly those related to difficulty maintaining wakefulness. Individuals presenting with diseases and conditions related to difficulty maintaining wakefulness complain of: feeling excessively sleepy; episodes of involuntary sleep onset, including sleep attacks (sleep attacks without aura symptoms); chronic primary sleep attacks (i.e., fatigue); recurrent naps on the same day; and sleep inertia (chronic difficulty in waking, accompanied by irritability, automatisms, or confusion).

[0107] Therefore, the compound of formula (I) according to embodiments 1) to 24) is suitable for improving the wakefulness of individuals (especially individuals suffering from somnolence or narcolepsy, or exhibiting excessive daytime sleepiness (EDS)).

[0108] The term "improving individual arousal" refers to improving the following symptoms, or to prevention / treatment or treatment: • Drowsiness, especially for prevention / treatment or treatment of the following: • Narcolepsy, especially narcolepsy type 1 and narcolepsy type 2; • Secondary narcolepsy associated with hereditary conditions (such as Pewter syndrome, Niemann-Pick C disease, or myotonic dystrophy); • Symptoms of secondary narcolepsy associated with tumors, especially those involving tumors in the hypothalamic region; • Symptoms of secondary narcolepsy associated with head trauma, especially narcolepsy associated with head trauma affecting the hypothalamic region; • Idiopathic somnolence; or • Klein-Lewin syndrome; • Excessive daytime sleepiness (EDS), specifically: • Improve symptoms of EDS in individuals with circadian rhythm sleep-wake disorders, especially those with delayed sleep-wake phase disorder, shift work disorder, or jet lag. • Specifically, improve symptoms of EDS caused by or related to a medical condition, particularly objective sleep disorder, obesity, diabetes, neurodegenerative diseases, autoimmune diseases, mental illness, or sleep deprivation syndrome. ■ Improves symptoms of EDS associated with objective sleep disorders (especially sleep apnea); ■ Improves symptoms of EDS associated with obesity and / or diabetes; ■ Improves symptoms of EDS associated with neurodegenerative diseases, especially those associated with: Alzheimer's disease, Parkinson's disease, Lewy body dementia, Perry syndrome, multiple system atrophy, or Huntington's disease.

[0109] ■ Improves narcolepsy-like symptoms in individuals with autoimmune diseases (especially neuromyelitis optica, multiple sclerosis, Guillain-Barré syndrome, or anti-Ma2 encephalitis); ■ Improve symptoms of EDS / treat drowsiness associated with mental illnesses (such as depression); or ■ Improve symptoms of EDS / treat somnolence associated with sleep deprivation syndrome; or • To improve symptoms of EDS / to treat drowsiness caused by medications or substances; or • Fatigue (especially chronic fatigue), specifically: • Mental fatigue accompanied by poor attention and memory; • Fatigue associated with infection (viral or bacterial), chronic inflammatory diseases, cancer, or neurodegeneration; or • Fatigue associated with primary Sjögren's syndrome, an autoimmune disease.

[0110] The term "narcolepsy type 1" describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep interruption, and cataplexy (loss of muscle tone in a state of full consciousness, usually triggered by positive emotions).

[0111] The term “narcolepsy type 2” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep interruptions and cataplexy (loss of muscle tone in a state of full consciousness, usually triggered by positive emotions).

[0112] Fatigue is characterized by a lack of energy ("feelings of fatigue and exhaustion are absolutely dominant").

[0113] Other diseases and conditions where the agonist effect of OX2R is present include: • Eating disorders; • Obesity, especially in individuals with narcolepsy; •Attention Deficit Disorder; • Neuropsychiatric disorders, especially mood disorders, particularly depression (such as major depressive disorder (MDD)); • Pain, especially inflammatory pain or chronic neuralgia; • Inflammation, especially inflammation following cardiac arrest, intracranial hemorrhage, or septic shock; and • Cognitive impairment, especially age-related learning and memory deficits or cognitive impairment attributable to sleep loss.

[0114] In addition, the activating effect of OX2R works in the following ways: • Disorders of consciousness, especially coma, vegetative state, and minimally conscious state induced by traumatic brain injury; • Recovery from unconsciousness following cardiac arrest or acute alcohol intoxication, or from unconsciousness induced by anesthetics.

[0115] It should be understood that when using compounds of formula (I) as described in embodiments 1) to 24) to improve the wakefulness of an individual (especially an individual suffering from somnolence or narcolepsy, or exhibiting excessive daytime sleepiness (EDS), other symptoms or disease characteristics of that individual may also be improved simultaneously. For example, when using compounds of formula (I) according to embodiments 1) to 24) to improve symptoms of EDS attributed to or related to diabetes, other symptoms or disease characteristics of that individual may also be improved simultaneously, such as improving diabetes parameters in addition to improving wakefulness in individuals with diabetes.

[0116] In the context of this invention, the term "individual" refers to a mammal, particularly a human; in the context of a diagnosis or disease, the terms "individual" and "patient" should be understood to be interchangeable.

[0117] Compounds of formula (I) as described in any of embodiments 1) to 24) are particularly suitable as therapeutic agents for the prevention / treatment or treatment of diseases and conditions associated with difficulty in maintaining wakefulness. They can be used as a single therapeutic agent or in combination with one or more additional therapeutic agents. Such therapeutic agents include modafinil, pitolisant, sodium oxybate, soriamfetol, 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).

[0118] Therefore, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material and the following: • The compound of formula (I) according to any one of embodiments 1) to 24); • And one or more additional treatments.

[0119] Therefore, this invention also relates to a set comprising... • A pharmaceutical composition comprising a pharmaceutically acceptable carrier material and: • The compound of formula (I) according to any one of embodiments 1) to 24); • Instructions on how to use this pharmaceutical composition to improve wakefulness in individuals exhibiting excessive daytime sleepiness (EDS).

[0120] Furthermore, any preferences and (sub)implementations indicated for compounds of formula (I) (whether for the compound itself, its salts, compositions containing the compound or its salts, or the use of the compound or its salts, etc.) are applicable to compounds of formulas (II), (III) and (IV) after necessary adjustments to the details.

[0121] The compounds of the present invention can be further characterized regarding their overall pharmacokinetic and pharmacological properties using conventional analyses well known in this art; for example, regarding the bioavailability of the compounds in different species (such as rats or dogs), including metabolic stability, which may affect (human) bioavailability and / or dosage requirements; or regarding the ability of the compounds to cross the blood-brain barrier, using, for example, human P-glycoprotein 1 (MDR 1) receptor assays, or in vivo assays to determine, for example, drug concentrations in the brain of rats after oral administration; or regarding the functional behavior of the compounds in different disease-related animal models (e.g., the overall stimulatory effects of the compounds measured using electroencephalogram (EEG) and electromyogram (EMG) signals [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 effects of the compounds 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 US A. 2017, 114(22):5731-5736]); or use conventional analyses well known in this technique to analyze the compound’s properties of drug safety and / or toxicology, such as inhibition and time-dependent inhibition of cytochrome P450 enzymes, activation of pregnane X receptor (PXR), glutathione binding, or phototoxicity. Detailed Implementation

[0122] Preparation of compound (I) Another aspect of the present invention is a method for preparing compounds of formula (I). Compounds of formula (I) according to the present invention can be prepared from commercially available or well-known starting materials according to the method described in the experimental section, by similar methods, or according to the general sequence of reactions outlined below, wherein R... 1 R 2 R 3 R 4 R B1 X 1 X 2 X 3Ring A and ring B are as defined with respect to formula (I). Other abbreviations used herein are explicitly defined, or as defined in the experimental section. In some cases, the general group R... 1 R 2 R 3 R 4 R B1 X 1 X 2 and X 3 This may be incompatible with the combinations described in the following procedures and therefore will require the use of protecting groups (PGs). The use of protecting groups is well known in this art (see, for example, "Protective Groups in Organic Synthesis", TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are present in the appropriate positions as needed. The resulting compound may also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.

[0123] General preparation method: Compound 11 belonging to formula (I) (where X) 2 =O and X 3=N) can be prepared by amide coupling reaction between a suitable carboxylic acid having structure 2 and a suitable amine (or corresponding salt, such as HCl salt or TFA salt) having structure 3 in a solvent such as THF, DMF, DCM or MeCN, in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC or the like and a base such as DIPEA, TEA or N-methylmorpholine (procedure 1). Compound 4 can be deprotected using standard deprotection methods known in the literature and familiar to those skilled in the art, to give 5 (or corresponding salt, such as HCl salt or TFA salt). Amine 5 is condensed with sulfonyl chloride 6 in a solvent such as DCM, DMF, or MeCN and in the presence of a base such as TEA or DIPEA to give 11. Alternatively, an amino acid having structure 7 can be reacted with sulfonyl chloride 6 in a solvent mixture (such as DMF / water and an inorganic base, such as NaHCO3) to give 10. Acid 10 can be converted to a compound having structure 11 by coupling with amine 3 (or its corresponding salt, such as HCl or TFA salt) in a solvent such as THF, DMF, DCM, or MeCN, in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA, or N-methylmorpholine, or by reacting with a reagent such as oxaloyl chloride and DMF or thionyl chloride in a solvent such as toluene, followed by condensation with 3 (or its corresponding salt, such as HCl or TFA salt) in a solvent such as DCM and in the presence of an organic base such as TEA or DIPEA, to convert 10 to its corresponding acyl chloride. Alternatively, a compound having structure 10 can be prepared by sulfonamide formation of ester 8 and sulfonyl chloride 6 in a solvent such as DCM, DMF, or MeCN, in the presence of a base such as TEA or DIPEA, followed by ester hydrolysis in a solvent mixture such as THF / water using a base such as LiOH or NaOH. Compounds having structures 2, 6, 7, and 8 are commercially available or prepared as described in the literature. Procedure 1. Synthesis of sulfonamide compound 11 Amines having structure 3 can be synthesized by reductive amination of an aldehyde or ketone (12 or 15) with a primary amine (such as 13 or 14 (or corresponding salts, such as HCl salts or TFA salts)) in a solvent such as MeOH or THF and in the presence of a reducing agent such as NaBH4, NaBH3CN, or Na(AcO)3BH, as described in process 2. Starting materials 12, 13, 14, and 15 are commercially available or prepared using commercially available reagents through conventional reactions known in this technique. Alternatively, amines having structure 3 can be prepared by an SN2 reaction of a primary amine 16 or 19 (or corresponding salts, such as HCl salts or TFA salts) with 17 or 18 (where LG is a halide, OMs, OTs, OTf, or any suitable detached group) in a solvent (such as MeCN) and in the presence of a base (such as K2CO3). In another aspect, where R... 2 =H amine 3 can be prepared in the presence of a catalyst such as P(tBu)3Pd G2 and a base such as Cs2CO3, in a solvent mixture such as THF / water, by Suzuki-Miyaura cross-coupling between an organotrifluoroborate ester (21) and a brominated alkyl group (22), as described by Molander et al. (Chemistry, 2012, 18(31), 9564-70). Organotrifluoroborate 21 can be prepared as described in the literature by reacting 16 (or its corresponding salt, such as an HCl salt or a TFA salt) with potassium bromotrifluoroborate 20 in a solvent mixture (such as THF / t-BuOH). Process 2. Synthesis of amines with general formula 3 Sulfonamide (SIA) compounds belonging to formula (I) with structure 31 (where X) 2 =NR 4 And X 3=N) can be prepared as described in process 3. Commercially available aryl thiols 23 can be oxidized to their corresponding sulfinates 24 by reacting with NBS and MeOH in a solvent such as DCM. Sulfinates 24 can be converted to sulfinamides having the general formula 25 by reacting with LiHMDS in a solvent such as THF and hydrolyzing with a saturated aqueous NH4Cl solution. The resulting sulfinamides can be protected with a suitable protecting group (PG) to give 26 using standard protection methods known in the literature and familiar to those skilled in the art. Compound 26 can be condensed with compound 8 in a solvent such as DCM or 1,2-dichloroethane in the presence of a chlorinating agent such as tert-butyl hypochlorite or N-chlorosuccinimide to give SIA intermediate 27. The ester functional group can be hydrolyzed to the corresponding carboxylic acid (28) in the presence of an aqueous LiOH solution and a solvent such as THF. In solvents such as THF, DMF, DCM, or MeCN, in the presence of coupling agents such as TBTU, HBTU, HATU, EDC (or similar) and bases such as DIPEA, TEA, or N-methylmorpholine, 28 is subsequently coupled with a secondary amine (3) (or its corresponding salt, such as an HCl salt or a TFA salt) to yield 29. The protecting group is cleaved using standard protecting methods known in the literature and familiar to those skilled in the art, yielding derivative 30. Alkylation of 30 can be performed using bases such as NaH or KOtBu and alkyl halides as alkylating agents to obtain 31. If not commercially available, aryl thiols 23 can be prepared using methods described in the literature or as described below in the experimental section.

[0124] Alternatively, -NR can be introduced early by condensation of a base (such as n-BuLi in THF) between primary amine 32 (or its corresponding salt, such as HCl or TFA salt) and 24. 4 The group was used to obtain sulfinamide 33. SIA was formed between 33 and 5 under similar conditions as described above to give the final compound 31. The non-mirror image isomers can be separated by preparative HPLC, rapid chromatography (FC) or chiral SFC chromatography at the final stage (31) or at stages 27, 29 or 30. Procedure 3. Synthesis of SIA compound 31 Sulfone compounds of formula (I) having structure 38 (where X) 2 =O and X 3=C) can be prepared as described in process 4. A aryl thiol 23 undergoes Michael addition with a commercially available α,β-unsaturated ester 34 in a solvent (such as piperidine) to produce a racemic thioether 35. Intermediate 35 can be oxidized in the presence of an oxidant such as MCPBA and in a solvent such as DCM to produce a sulfone 36. Derivative 36 can be hydrolyzed to its corresponding carboxylic acid 37 using the standard method described above. Subsequent amide coupling between 37 and a secondary amine (3) (or its corresponding salt, such as an HCl salt or a TFA salt) is carried out in a solvent such as THF, DMF, DCM, or MeCN in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC, pyClop (or similar) and a base such as DIPEA, TEA, or N-methylmorpholine to give 38. Procedure 4. Synthesis of sulfone compound 38 Sulfoxide imine compounds of formula (I) having structure 45 (where X) 2 =NH and X 3 =C) can be prepared as described in process 5. In a solvent mixture of H2O / THF, compound 35 can be hydrolyzed to 43 using a base such as LiOH. In a solvent such as THF, DMF, DCM, or MeCN, acid 43 is amide-coupled with amine 3 (or its corresponding salt, such as an HCl salt or a TFA salt) in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA, or N-methylmorpholine to give 44. In a solvent such as MeOH, sulfide 44 is treated with an oxidizing agent such as diacetate iodobenzene and ammonium carbamate to give sulfonyl imine 45. Alternatively, 35 can be oxidized in a solvent of hexafluoro-2-propanol using hydrogen peroxide in the first step to produce 39. Sulfonyl 39 can be treated with diacetate iodobenzene and magnesium peroxide in a solvent such as DCM in the presence of tert-butyl carbamate and rhodium(II) acetate to give Boc-protected sulfonyl imine 40. Ester 40 can be hydrolyzed as described above to give carboxylic acid 41. Amide coupling of 41 with amine 3 (or its corresponding salt, such as an HCl salt or a TFA salt) in a manner similar to that described in this paragraph yields a protected intermediate 42. Deprotection of the Boc protecting group can be carried out in the presence of an acid such as HCl or TFA and in a solvent such as 1,4-dimethylalkanes to give the desired product 45. The resulting non-mirror isomers (40, 41, 42, or 45) can be separated by preparative HPLC, rapid chromatography, or chiral SFC chromatography. Procedure 5. Synthesis of sulfoxide imine compound 45 Experimental Section Abbreviations (as used in this document and the above instructions): Acyl groups (such as OAc = acetate, AcOH = acetic acid) AcOH (acetic acid) AIBN2,2'-azobis(2-methylpropionitrile) anh. waterless aq. aqueous solution atm atmosphere tBME tert-butyl methyl ether Boc tert-butoxycarbonyl Boc2O ditert-butyl dicarbonate tBuOCl tert-butyl hypochlorite BSA bovine serum albumin Bu (butyl), such as tBu (tert-butyl / tertiary butyl). conc. thick DCE1,2-Dichloroethane DCM dichloromethane DEA diethylamine DIPEA (diisopropylethylamine) DME dimethoxyethane Dulbecco's modified eagle medium (DME) DMF N,N -Dimethylformamide DMSO (dimethyl sulfoxide) dppf1,1'-bis(diphenylphosphine)ferrocene EDC1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide ELSD Evaporation Light Scattering Detection eq equivalent ES Electrospray Et Ethyl EtI ethyl iodide Et2O diethyl ether Ethyl acetate (EtOAc) EtOH (ethanol) Example. FBS fetal bovine serum FC silica gel rapid chromatography FCS Fetal Bovine Serum h hours HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBSS Hank's balanced salt solution HBTU hexafluorophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl HEK293 human embryonic kidney 293 cells HEPES4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid Heptheptane 1 H-NMR proton nuclear magnetic resonance HPLC (High Performance Liquid Chromatography) HTRF homogeneous time-of-flight fluorescence IP1 Intracellular inositol-1-phosphate LC-MS liquid chromatography-mass spectrometry analysis LiHMDS bis(trimethylsilane)aminolithium Lit. Literature LG De-base M Precision quality (e.g., for LC-MS) M molar concentration [mol L] -1 ] MCPBA3-chloroperbenzoic acid Memethyl MeCN acetonitrile MeOH methanol MeI methyl iodide MHz megahertz μl microliters μm micrometer min minutes MS mass spectrometry analysis Ms methanesulfonyl, such as OMs N equivalent concentration Sodium hydride (NaH) NMPN-methyl-2-pyrrolidone Pd(OAc)₂palladium diacetate Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PG protection base PL-HCO3 polymer-supported bicarbonate Phphenyl Prep preparation type PTFE (polytetrafluoroethylene) PyCloP Chloropyrrolidine phosphonium hexafluorophosphate PyrSO3 sulfur trioxide pyridine complex Rf retention factor RAC racemic or racemic form rt room temperature sat. aq. saturated aqueous solution SIA sulfonylimide compounds SFC supercritical fluid chromatography soln. solution TBME tert-butyl methyl ether TBTU2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroboric acid t Bu tert-butyl TEA Triethylamine Tf trifluoromethanesulfonic acid, such as OTf TFA (trifluoroacetic acid) THF tetrahydrofuran t R Duration of stay Ts toluenesulfonyl, such as OTs UPLC (Ultra-High Performance Liquid Chromatography) I. Chemical Methods All temperatures are stated in °C. Commercially available starting materials were used as is without further purification. Unless otherwise specified, all reactions were carried out in dried glassware under a nitrogen atmosphere. Compounds were purified by silica gel rapid column chromatography or by preparative HPLC. The compounds described in this invention are characterized by LC-MS data (retention time t). R Molecular weights are given in min (molecular weights obtained from mass spectrometry are given in g / mol), and the conditions listed below are used. In the case where the compounds of the invention are present as a mixture of configurational isomers, especially as can be seen in their LC-MS spectra, the retention times of the largest number of conformations are given. Racemic mixtures can be separated into their mirror isomers by preparative HPLC or SFC. LC-MS conditions LC-MS (1) 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 μm, 2.1 x 50 mm, from Waters, kept at 60°C in an Acquity UPLC Column Manager. Solvents: A1: H2O + 0.05% formic acid; B1: MeCN + 0.045% formic acid. Method: Gradient: from 2% B to 98% B over 2.0 min. Flow rate: 1.0 mL / min. Detected by MS at 214 nm, residence time t...R Given in min.

[0125] LC-MS (2) LC-MS Conditions: Analytical UPLC on an Agilent Zorbax RRHD SB-Aq (2.1 x 50 mm, 1.8 μm) column; MS detection at 210 nM; UPLC / MS analysis performed on an Acquity UPLC system; column temperature 40 °C; gradients of water / 0.04% TFA (A) and MeCN (B). The proportion of the dissociated mixture, with a dissociation flow rate of 0.8 mL / min and a change in the proportion of the mixture from dissociation onset to time t, is summarized in the table below (using a linear gradient between two consecutive time points): LC-MS (3) LC-MS conditions: Analytical UPLC on a Waters BEH C18 (2.1 x 50 mm, 2.5 μm) column; MS detection at 210 nm; UPLC / MS analysis on an Acquity UPLC system; column temperature 40 °C; gradients of water / 0.04% NH3 [c(NH3) = 13 mmol / L] (A) and MeCN (B). The dissociation flow rate was 0.8 mL / min, and the characteristics of the proportion of the dissociated mixture as a function of time t from the start of dissociation are summarized in the table below (using a linear gradient between two consecutive time points): The preparative LC-MS method used: Preparative HPLC / MS purification (preparative HPLC) was performed on a Gilson HPLC system equipped with a Gilson 215 autosampler, a Gilson 333 / 334 pump, a Finnigan AQA MS detector system, and a Dionex UV detector, using Waters Xbridge C18 or Waters Atlantis columns, with linear gradients of water / formic acid 0.02% (A) and MeCN (B) (acidic preparative HPLC conditions) or water / ammonia 0.02% (A) and MeCN (B) (alkaline preparative HPLC conditions).

[0126] The preparative chiral SFC method used: Preparative chiral SFC purification was performed on the Sepiatec preparative SFC 360 system. The following parameters were used: Preparative chiral SFC 1: A ChiralPak AD-H column (30 × 250 mm, 5 μm) was used. The modifier was MeCN / MeOH 1:1, and the operation was 4 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0127] Preparative chiral SFC 2: A ChiralCel OZ-H column (30 × 250 mm, 5 μm) was used. The modifier was EtOH / MeCN 1:1, and the operation was 4 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 4°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0128] Preparative chiral SFC 3: ChiralPak IC column (30 × 250 mm, 5 μm). Modifier was EtOH (25%), run for 4.5 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0129] Preparative chiral SFC 4: ChiralPak AD-H column (30 × 250 mm, 5 μm). EtOH (25%) was used as the modifier. Operation time was 4:45 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0130] Preparative chiral SFC 5: ChiralPak IB column (30 × 250 mm, 5 μm). Modifier was MeCN / EtOH / DEA 50:50:0.1 (20%), operation time 6.94 min, flow rate 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0131] Preparative chiral SFC 6: A ChiralPak IE column (30 × 250 mm, 5 μm) was used. The modifier was MeCN / EtOH / DEA 50:50:0.1 (45%), and the operation time was 5.62 min with a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0132] Preparative chiral SFC 7: ChiralPak AZ column (30 × 250 mm, 5 μm). Modifier was MeOH (10%), run for 6 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0133] Preparative chiral SFC 8: A ChiralPak ID column (30 × 250 mm, 5 μm) was used. The modifier was AcCN / EtOH 1:1 (45%), and the operation was 6 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0134] Preparative chiral SFC 9: ChiralPak ID column (30 × 250 mm, 5 μm). Modifier was AcCN / EtOH 1:1 (35%), run for 6 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0135] Preparative chiral SFC 10: ChiralPak ID column (30 × 250 mm, 5 μm). Modifier was AcCN / EtOH 1:1 (50%), run for 6 min at a flow rate of 160 mL / min. The following system settings were used: back pressure 100 bar, pump head temperature 5°C, fractionation module temperature 20°C, and column section temperature 40°C.

[0136] FC FC (rapid chromatography) was performed using combiflash from Teledyne ISCO.

[0137] Phase separator The phase separator filter cartridge used was Isolute® purchased from Biotage.

[0138] solid phase extraction Ion exchange was performed using cation exchange adsorbent (Isolute® SXC) purchased from Biotage.

[0139] Preparation of the example: Method for preparing sulfonamide compounds (Example 1.x) Example 1.1: (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (1,1-di-sideoxy-hexahydro-1λ) 6-Thiopiperan-4-yl)-(4-fluoro-benzyl)-amide: 4-((4-fluorobenzyl)amino)tetrahydro-2H-thiopiperanone 1,1-dioxide: A solution of 4-aminotetrahydro-2H-thiopiperanone 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 room temperature under a 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 room temperature for 1 h. Then, sodium triacetoxyborohydride (6639 mg, 39.6 mmol, 3 eq) was added fractionally. The reaction mixture was stirred overnight at room temperature. Water and 2 M HCl aqueous solution were added, and the mixture was washed with EtOAc. The aqueous layer was alkalized with 1 M NaOH aqueous solution and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (DCM / MeOH 99:1) to give the title compound (1059 mg, 47%) as a white solid. LC-MS (2): t R = 0.43 min; [M+H] + 257.97. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-4-yl)-(4-fluoro-benzyl)-amide: A solution of toluenesulfonyl-L-proline (700 mg, 2.57 mmol), 4-((4-fluorobenzyl)amino)tetrahydro-2H-thiopiperan-1,1-dioxide, HATU (1468 mg, 3.86 mmol), and DIPEA (1.87 mL, 10.9 mmol) in DMF (25 mL) was stirred overnight at room temperature. HATU (294 mg, 0.772 mmol) was added again, and the solution was stirred for an additional 2 hours. 2 M HCl aqueous solution was added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by acidic preparative HPLC to give the title compound (855 mg, 65%) as a white solid. LC-MS (1): t R = 1.025 min; [M+H] + : 509.3. Example 1.2: (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzofuran-5-ylmethyl-(1,1-disideloxy-hexahydro-1λ) 6 -Thiopiperan-4-yl)-amide A solution of 4-((benzofuran-5-ylmethyl)amino)tetrahydro-2H-thiopiperanan 1,1-dioxide: 4-aminotetrahydro-2H-thiopiperanan 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 under nitrogen at room temperature. Benzofuran-5-carboxaldehyde (1424 mg, 9.55 mmol) and AcOH (1.09 mL, 19.1 mmol) were added 1-. After 1 h, sodium triacetoxyborohydride (4173 mg, 19.1 mmol) was added fractionally. The reaction mixture was stirred overnight at room temperature. 2 M HCl aqueous solution was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (DCM / MeOH 99:1) to give the title compound (1587 mg, 59%) as a yellow solid. LC-MS (2): t R = 0.49 min; [M+H] + 280.19. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-5-ylmethyl-(1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-4-yl)-amide: The product, as described in Example 1.1, was synthesized using 4-((benzofuran-5-ylmethyl)amino)tetrahydro-2H-thiopiperan-1,1-dioxide and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (1): t R = 1.036 min; [M+H] + : 531.3. Example 1.3: (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: N-Benzyl-4,4-dimethylcyclohexane-1-amine hydrochloride: At room temperature, a solution of benzaldehyde (15.5 μL, 0.15 mmol) in MeOH (0.1 mL) was added to a solution of 4,4-dimethylcyclohexane-1-amine (23 mg, 0.18 mmol) and DIPEA (31.4 μL, 0.18 mmol) in MeOH (0.550 mL), and the solution was stirred for 4 h at room temperature. NaBH4 (7.50 mg, 0.197 mmol) was added, and the mixture was stirred overnight at room temperature. 2 M HCl aqueous solution was added, and the mixture was washed with EtOAc. The aqueous layer was alkalized with saturated NaHCO3 aqueous solution and extracted with EtOAc. 1.25 M HCl solution was added to the solution in MeOH (0.500 mL), and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS (2):t R = 0.57 min; [M+H] + : 226.18. (S)-1-(Toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: As described in Example 1.1, it was synthesized using N-benzyl-4,4-dimethylcyclohexane-1-amine hydrochloride and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (1): t R = 1.437 min; [M+H] + 469.2. Examples 1.4 through 1.23 were synthesized using suitable amines or amine salt derivatives, suitable aldehydes or ketones as described in Example 1.3. The LC-MS data for Examples 1.4 through 1.23 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.24: (S)-N-((RS)-1-(4-chlorophenyl)ethyl)-N-(4,4-difluorocyclohexyl)-1-toluenesulfonylpyrrolidone-2-carboxamide Toluenesulfonyl-L-proline chloride: Oxythiocyanate (2.68 mL, 30.4 mmol, 2.733 eq) and DMF (0.028 mL) were added to a suspension of toluenesulfonyl-L-proline (3.00 g, 11.1 mmol, 1 eq) in toluene (78 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure to give the title compound (2.90 g, 91%) as a grayish-white solid.

[0140] N-(1-(4-chlorophenyl)ethyl)-4,4-difluorocyclohexane-1-amine: A mixture of racemic 4-chloro-α-methylbenzylamine (125 mg, 0.798 mmol), 4,4-difluorocyclohexane-1-one (160 mg, 1.2 mmol), AcOH (0.167 mL, 1.2 mmol), and 97% sodium triacetoxyborohydride (534 mg, 2.39 mmol) in THF (4.00 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between 1 M aqueous HCl and EtOAc. The layers were separated, and the aqueous layer was alkalized with solid NaHCO3 and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS (2): t R = 0.70 min; [M+H] + : 274.08. (S)-N-((RS)-1-(4-chlorophenyl)ethyl)-N-(4,4-difluorocyclohexyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: A solution of toluenesulfonyl-L-prolyl chloride (35.7 mg, 0.124 mmol, 1 eq), N-(1-(4-chlorophenyl)ethyl)-4,4-difluorocyclohexane-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 room temperature for 3 days. The reaction mixture was washed with brine. The organic layer was separated by a phase separator filter and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give the title compound as a white solid. LC-MS (1): t R = 1.365 min; [M+H] + : 525.3. Examples 1.25 to 1.32 were synthesized using suitable amines or amine salt derivatives and suitable aldehydes or ketones as described in Example 1.3. The LC-MS data for Examples 1.25 to 1.32 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.33 (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: (2S,4S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidone-1-carboxylic acid tert-butyl ester: (2S,4S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidone-1-carboxylic acid tert-butyl ester (48 mg, 0.2 mmol, 1 eq) was dissolved in DMF (1.00 mL). Then, after 15 min, HATU (80 mg, 0.21 mmol, 1.05 eq) and DIPEA (0.11 mL, 0.6 mmol, 3 eq) were added to N-benzyl-4,4-dimethylcyclohexane-1-amine (45 mg, 0.2 mmol, 1 eq). The reaction mixture was stirred overnight at room temperature. The mixture was purified by preparative HPLC to give the title compound (78 mg, 90%). LC-MS (2): t R = 1.11 min; [M+H] + : 434.13. (2S,4S)-N-benzyl-N-(4,4-dimethylcyclohexyl)-4-fluoropyrrolidone-2-carboxamide hydrochloride: tert-butyl (2S,4S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)-4-fluoropyrrolidone-1-carboxylic acid (77.9 mg, 0.18 mmol, 1.00 eq) was dissolved in DCM (6.00 mL). 4 M HCl was added to 1,4-dimethylethane (3.00 mL), and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to give the title compound (66.3 mg, 100%) as a yellow solid. LC-MS (2): t R = 0.79 min; [M+H] + : 333.36. (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: TEA (0.052 mL, 0.38 mmol, 2.1 eq) was added to a solution of (2S,4S)-N-benzyl-N-(4,4-dimethylcyclohexyl)-4-fluoropyrrolidone-2-carboxamide hydrochloride (66.3 mg, 0.18 mmol, 1.00 eq) in DCM (2 mL) at 0 °C, followed by the addition of p-toluenesulfonyl chloride (38.5 mg, 0.20 mmol, 1.1 eq), and the mixture was stirred overnight at room temperature. The mixture was purified by preparative HPLC to give the title compound (68 mg, 78%) as a white solid. LC-MS (1): t R = 1.388 min; [M+H] + : 487.3. Examples 1.34 to 1.42 were synthesized using suitable amines or amine salt derivatives and suitable aldehydes or ketones as described in Example 1.3. The LC-MS data for Examples 1.34 to 1.42 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.43 (1R*,5S*)-(2RS)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: (1R*,5S*)-(2RS)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid: A solution of cis-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (90 mg, 0.708 mmol, 1 eq) in saturated NaHCO3 aqueous solution (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 heated to room temperature and stirred for 17 h. DMF was removed under reduced pressure. The residue was acidified with 1 M HCl aqueous solution and extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (192 mg, 96%) as a white solid. LC-MS (2): t R = 0.76 min; [M+H] + : 282.16. (1R*,5S*)-(2RS)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzyl-(4,4-dimethyl-cyclohexyl)-amide: As described in Example 1.1, it was synthesized using N-benzyl-4,4-dimethylcyclohexane-1-amine hydrochloride and (1R*,5S*)-(2RS)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give the title compound as a white solid. LC-MS (1): t R = 1.456 min; [M+H] + : 481.4. Examples 1.44 to 1.46 were synthesized using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, and a suitable formic acid as described in Example 1.33. The LC-MS data for Examples 1.44 to 1.46 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.47 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: 5-(bromomethyl)benzo[d]azole: AIBN (25 mg, 0.149 mmol, 0.02 eq) was added to a solution of 5-methylbenzo[d]azole (1000 mg, 7.47 mmol, 1 eq) and N-bromosuccinimide (1729 mg, 9.71 mmol, 1.3 eq) in bromobenzene (20 mL), and the solution was stirred at 90 °C for 16 h. 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. R f (Hept / EtOAc)= 0.55. LC-MS (2): t R = 0.78 min; [M+H] + : 212.04. N-(benzo[d]azol-5-ylmethyl)-4,4-difluorocyclohexane-1-amine: A beige suspension was obtained by suspending 4,4-difluorocyclohexylamine hydrochloride (2455 mg, 13.9 mmol, 1 eq) and potassium carbonate (4843 mg, 34.7 mmol, 2.5 eq) in MeCN (100 mL) and stirring at room temperature. Then, 5-(bromomethyl)benzo[d]azol (2942 mg, 13.9 mmol, 1 eq) was added to MeCN (40 mL), and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by FC (Hept to Hept / (EtOAc+2% Et3N) 6:4) to give the title compound (3.037 g, 79%) as a pale yellow oil, which solidified upon standing. LC-MS (3): t R = 0.78 min; [M+H] + : 267.20. (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[d]azol-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: N-(benzo[d]azol-5-ylmethyl)-4,4-difluorocyclohexane-1-amine (205 mg, 0.77 mmol, 1 eq) was dissolved in DMF (7 mL) and DIPEA (0.329 mL, 1.92 mmol, 2.5 eq), followed by toluenesulfonyl-L-prolyl chloride (233 mg, 0.77 mmol, 1 eq). The resulting pale yellow solution was stirred at room temperature 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. f (Hept / EtOAc 2:8)= 0.50. LC-MS (1): t R = 1.133 min; [M+H] + : 518.2. Example 1.48 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: N-(benzo[d]acezo-5-ylmethyl)-4,4-dimethylcyclohexane-1-amine: As described in Example 1.47, it was synthesized using 4,4-dimethylcyclohexane-1-amine and 5-(bromomethyl)benzo[d]acezo to give the title compound, which is an orange oil. LC-MS (2): t R = 0.66 min; [M+H] + : 259.32. (S)-1-(Toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[d]azol-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: As described in Example 1.1, it was synthesized using N-(benzo[d]azol-5-ylmethyl)-4,4-dimethylcyclohexane-1-amine and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (1): t R =1.314 min; [M+H] + : 510.2. Examples 1.49 to 1.51 were synthesized using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, and N-toluenesulfonyl-L-proline as described in Example 1.33. The LC-MS data for Examples 1.49 to 1.51 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.52 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: Benzofuran-6-ylmethanol: Ethyl chloroformate (0.179 mL, 1.82 mmol, 1 eq) was added dropwise to an ice-cooled solution 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 solution was stirred at 0 °C for 1 h. A solution of sodium borohydride (206 mg, 5.45 mmol, 3 eq) in water (2.90 mL) was added dropwise to the reaction mixture at 0 °C, and stirring was continued at the same temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with 1 M HCl aqueous solution, saturated NaHCO3 aqueous solution, and brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (Hept to EtOAc 7:3) to give the title compound as a pale yellow oil. LC-MS (2): t R = 0.64 min; No quality detected.

[0141] Benzofuran-6-carboxaldehyde: A suspension of benzofuran-6-ylmethanol (140 mg, 0.841 mmol, 1 eq) and manganese oxide (IV) (activated, 185 mg, 2.1 mmol, 2.5 eq) in DCM (8.4 mL) was stirred overnight at room temperature. Manganese oxide (IV) (185 mg, 2.1 mmol, 2.5 eq) was added again to the mixture, and stirring was continued for 3 h at room temperature. The reaction mixture was filtered through a sintered polypropylene filter and the solids were washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS (2): t R = 0.77 min; No quality detected. 1 H NMR (500 MHz, DMSO) d :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, J 1 = 1.0 Hz, J 2 = 2.2 Hz, 1 H). N-(benzofuran-6-ylmethyl)-4,4-dimethylcyclohexane-1-amine: The title compound was synthesized using benzofuran-6-carboxaldehyde and 4,4-dimethylcyclohexane-1-amine as described in Example 1.1. LC-MS (2): t R =0.77 min; [M+H] + : 258.11. (S)-1-(Toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: The title compound was synthesized using N-(benzofuran-6-ylmethyl)-4,4-dimethylcyclohexane-1-amine and N-toluenesulfonyl-L-proline as described in Example 1.1. LC-MS (1): t R = 1.441 min; [M+H] + 509.4. Example 1.53 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: N-(benzofuran-6-ylmethyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using benzofuran-6-carboxaldehyde and 4,4-difluorocyclohexane-1-amine as described in Example 1.1. LC-MS (2): t R = 0.65min; [M+H] + : 266.21. (S)-1-(Toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: The title compound was synthesized using N-(benzofuran-6-ylmethyl)-4,4-difluorocyclohexane-1-amine and N-toluenesulfonyl-L-proline as described in Example 1.1. LC-MS (1): t R = 1.265 min; [M+H] + 517.2. Example 1.54 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: N-(benzo[d]thiazol-5-ylmethyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using 4,4-difluorocyclohexane-1-amine and benzothiazol-5-carboxaldehyde as described in Example 1.1. LC-MS (2): t R = 0.56min; [M+H] + : 283.23. (S)-1-(Toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazol-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: As described in Example 1.1, the title compound was synthesized using N-(benzo[d]thiazol-5-ylmethyl)-4,4-difluorocyclohexane-1-amine and N-toluenesulfonyl-L-proline. LC-MS (1): t R = 1.167 min; [M+H] + 534.2. Examples 1.55 to 1.60 were synthesized using suitable amines or amine salt derivatives, suitable aldehydes or ketones, and N-toluenesulfonyl-L-proline as described in Example 1.1. The LC-MS data for Examples 1.55 to 1.60 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.61 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[d]acetazole-5-ylmethyl-(tetrahydro-piperan-4-yl)-amide: synthesized using 4-aminotetrahydropiperan, 5-(bromomethyl)benzo[d]acetazole, and N-toluenesulfonyl-L-proline as described in Example 1.47. LC-MS (1): t R = 0.965 min; [M+H] + : 484.2. Example 1.62 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[d]acetazole-6-ylmethyl-(tetrahydro-piperan-4-yl)-amide: synthesized using 4-aminotetrahydropiperan, 6-(bromomethyl)benzo[d]acetazole (US2006173183A1), and N-toluenesulfonyl-L-proline as described in Example 1.47. LC-MS (1): t R = 0.946 min; [M+H] + : 484.3. Examples 1.63 to 1.65 were synthesized using a suitable amine or amine salt derivative, 6-(bromomethyl)benzo[d] acetazole, and N-toluenesulfonyl-L-proline as described in Example 1.47. The LC-MS data for Examples 1.63 to 1.65 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.66 (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide: The title compound was synthesized using a suitable amine or amine salt as described in Example 1.33. LC-MS (1): t R = 1.291 min; [M+H] + : 529.2. Examples 1.67 to 1.68 were synthesized using suitable amines or amine salt derivatives as described in Example 1.1 and N-toluenesulfonyl-L-proline. LC-MS data for Examples 1.67 to 1.68 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.69 (2S)-N-(benzofuran-6-ylmethyl)-N-(tetrahydro-2H-piperan-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: synthesized as described in Example 1.53 using oxane-3-amine hydrochloride, benzofuran-6-carboxaldehyde, and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (1): t R = 1.154 min; [M+H] + : 483.2. Example 1.70 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-4-yl)-amide: As described in Example 1.47, it was synthesized using 5-(bromomethyl)benzo[d]azole, 4-aminotetrahydro-2H-thiopiperan-1,1-dioxide, and N-toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS (2): t R = 0.84 min; [M+H] + : 532.17. Example 1.71 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (5-bromo-thiazol-2-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: As described in Example 1.24, it was synthesized using 4,4-difluorocyclohexylamine, 5-bromo-1,3-thiazol-2-carboxaldehyde, and toluenesulfonyl-L-prolyl chloride to give the title compound as a white solid. LC-MS(1): t R = 1.257 min; [M+H] + 562.2. Example 1.72 (1R*,5S*)-(2RS)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide: N-(benzo[d]azol-6-ylmethyl)-4,4-dimethylcyclohexane-1-amine: As described in Example 1.47, the title compound was synthesized using 6-(bromomethyl)benzo[d]azol (US2006173183A1) and 4,4-dimethylcyclohexane-1-amine to give a light brown solid. LC-MS (2): t R = 0.67 min; [M+H] + : 259.33. (1R*,5S*)-(2RS)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide: synthesized as described in Example 1.1 using N-(benzo[d]azol-6-ylmethyl)-4,4-dimethylcyclohexane-1-amine and (1R*,5S*)-(2RS)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, yielding the title compound as a white solid. LC-MS (1): t R = 1.337 min; [M+H] + : 522.3. Example 1.73 (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[d]azol-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide: As described in Example 1.33, the title compound was synthesized using N-(benzo[d]azol-6-ylmethyl)-4,4-dimethylcyclohexane-1-amine and N-Boc-cis-4-fluoro-L-proline to give a white solid. LC-MS (1): t R = 1.264 min; [M+H] + : 528.2. Examples 1.74 to 1.95 were synthesized according to the procedure described herein, followed by the use of a suitable amine or amine salt derivative, a suitable aldehyde or ketone, and a suitable substituted proline or proline ester. LC-MS data for Examples 1.74 to 1.95 are listed in the table below. Example 1.96 (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid (4,4-dimethyl-cyclohexyl)-(4-methyl-benzyl)-amide: Methyl ((4-methoxyphenyl)sulfonyl)-L-proline: At room temperature, 4-methoxybenzenesulfonyl chloride (300 mg, 1.42 mmol, 1 eq) was added to a solution of L-proline methyl 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), 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 MgSO4, filtered, 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 (350 mg, 82%) as a yellow solid. LC-MS (2): t R = 0.82 min; [M+H] + 300.24. Lithium ((4-methoxyphenyl)sulfonyl)-L-proline: 1 M LiOH aqueous solution (1.44 mL, 1.44 mmol, 1 eq) was added to a solution of methyl ((4-methoxyphenyl)sulfonyl)-L-proline (350 mg, 1.15 mmol, 1 eq) in THF (7.5 mL, 91.3 mmol, 79.23 eq), and the resulting mixture was stirred at room temperature for 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): t R = 0.69 min; [M+H] + : 286.21. 4,4-Dimethyl-N-(4-methylphenylmethyl)cyclohexane-1-amine: Synthesized using p-tolualdehyde and 4,4-dimethylcyclohexane-1-amine as described in Example 1.3, yielding the title compound as a colorless oil. LC-MS (2): t R = 0.75min; [M+H] + : 232.35. (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-dimethyl-cyclohexyl)-(4-methyl-benzyl)-amide: A solution of lithium ((4-methoxyphenyl)sulfonyl)-L-prolylate (20 mg, 0.0659 mmol, 1 eq), HATU (28.8 mg, 0.0758 mmol, 1.15 eq), and DIPEA (0.0339 mL, 0.198 mmol, 3 eq) in DMF (0.2 mL) was stirred at room temperature for 1 h. 4,4-dimethyl-N-(4-methylbenzyl)cyclohexane-1-amine (0.0725 mmol, 1.1 eq) was added to DMF (0.2 mL), and the reaction mixture was stirred for 1 h. The mixture was purified by acidic preparative HPLC to give the title compound (20.5 mg, 62%) as an orange solid. LC-MS (1): t R = 1.444 min; [M+H] + : 499.2. Examples 1.97 to 1.100 followed the procedure described in Example 1.96, using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, and lithium ((4-methoxyphenyl)sulfonyl)-L-proline ester for synthesis. LC-MS data for Examples 1.97 to 1.100 are listed in the table below. The LC-MS conditions used were LC-MS (1). Examples 1.101 to 1.145 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a toluenesulfonyl-L-proline chloride, or a suitable substituted proline or proline ester. LC-MS data for Examples 1.101 to 1.145 are listed in the table below. Example 1.146 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-[3-(3-fluoro-oxo-3-yl)-benzylmethyl]-amide: 3-(3-(diethoxymethyl)phenyl)oxetane-3-ol: n-Butyllithium (1.6 M hexane solution, 2.84 mL, 4.54 mmol, 1.2 eq) was added to a solution of 3-bromobenzaldehyde diethanolacetal (0.787 mL, 3.78 mmol, 1 eq) cooled to -78 °C in THF (12 mL) under nitrogen atmosphere. The mixture was stirred at -78 °C for 40 min. 3-oxetane (545 mg, 7.56 mmol, 2 eq) was added dropwise to a solution of 3-oxetane (3 mL) in THF, and the reaction mixture was stirred at -78 °C for 30 min. The mixture was then heated to room temperature and stirred for 30 min. The reaction mixture was quenched with a saturated aqueous NH4Cl solution 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 (0.373 g, 39%) as a colorless gel. 1 H NMR (500 MHz, DMSO) d 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): t R = 0.77 min; [M+H] + Not found. 3-(3-Fluoroxycyclobutane-3-yl)benzaldehyde: Diethylaminosulfur trifluoride (0.121 mL, 0.892 mmol, 1.5 eq) was added to a stirred solution of 3-(3-(diethoxymethyl)phenyl)oxetane-3-ol in DCM (8.5 mL) at -78 °C and stirred for 15 min. The reaction mixture was heated to 0 °C. 1 M NaOH was carefully added and the mixture was extracted with DCM. The organic layer was separated and washed twice with brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (39.5 mg, 37%) as a white solid.f (Hept / EtOAc 9:1) = 0.18. 1 H NMR (500 MHz, d6-DMSO) d : 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, 1H), 4.93-5.05 (m, 4 H). LC-MS (2): t R = 0.71 min; [M+H] + Not found. 4,4-Difluoro-N-(3-(3-fluorooxetane-3-yl)benzyl)cyclohexane-1-amine: A mixture of 4,4-difluorocyclohexane-1-amine (13.9 mg, 0.1 mmol, 1 eq), 3-(3-fluorooxetane-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 room temperature for 4 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated by a phase separator filter and concentrated under reduced pressure to give the title compound (34 mg, 100%) as a yellow oil. LC-MS (2): t R = 0.61min; [M+H] + 300.27. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-[3-(3-fluoro-oxo-3-yl)-benzylmethyl]-amide: As described in Example 1.24, the title compound was synthesized using 4,4-difluoro-N-(3-(3-fluorooxo-cyclobut-3-yl)benzylmethyl)cyclohexane-1-amine and toluenesulfonyl-L-prolylate chloride. LC-MS (1):t R = 1.212 min; [M+H] + : 551.2. Example 1.147 (1R*,5S*)-(2RS)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide: The title compound was synthesized as described in Example 1.1 using cis-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, p-toluenesulfonyl chloride, and N-(benzo[d]azol-5-ylmethyl). LC-MS (1): t R = 1.341 min; [M+H] + 522.2. Example 1.148 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (5-cyclopropyl-4-ethyl-isoazol-3-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: ((5-Cyclopropylisothiazolyl)methyl)tert-butyl aminocarbamate: 1-(5-Cyclopropyl-3-isothiazolyl)methylamine (800 mg, 5.79 mmol, 1 eq), tert-butyl di-dicarbonate (1.61 mL, 6.95 mmol, 1.2 eq), and TEA (0.806 mL, 5.79 mmol, 1 eq) were stirred in DCM (14.5 mL) for 5 min at 0 °C. The solution was then heated to room temperature and stirred overnight. The solution was diluted with EtOAc and washed with water, saturated NaHCO3 aqueous solution, and brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (Hept / EtOAc 6:4) to give the title compound (896 mg, 65%) as a grayish-white solid. LC-MS (2): t R = 0.85 min; [M+H] + : 239.17. ((5-Cyclopropyl-4-iodoisoazol-3-yl)methyl)tert-butyl carbamate: In a 25 mL double-necked flask, tert-butyl ((5-Cyclopropyl-4-iodoisoazol-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 the mixture was stirred at room temperature for 30 min. I2 (264 mg, 1.02 mmol, 1.2 eq) was added to the suspension and stirred at room temperature. After 30 min, the suspension was heated under reflux for 5 h and stirred overnight at room temperature. The suspension was diluted with DCM and filtered. The clarified solution was washed with 5% NaHSO3 aqueous solution, saturated NaHCO3 aqueous solution, H2O, and brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (hexane / EtOAc 8:2) to give the title compound as a white solid. LC-MS (2): t R = 0.95 min; [M+H] + 365.01. ((5-Cyclopropyl-4-vinylisoazol-3-yl)methyl)tert-butyl carbamate: ((5-Cyclopropyl-4-iodoisoazol-3-yl)methyl)tert-butyl 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-trivinylcyclotriboroxanepyridine complex (67.4 mg, 0.28 mmol, 1 eq) were dissolved in DME (2.60 mL) and water (0.90 mL). The reaction mixture was degassed for 3 min, then stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM, 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. f (Hept / EtOAc 7:3)= 0.43; LC-MS(3): t R = 1.01 min; [M+H] + : 265.28. ((5-Cyclopropyl-4-ethylisoazol-3-yl)methyl)tert-butyl aminocarbamate: ((5-Cyclopropyl-4-vinylisoazol-3-yl)methyl)tert-butyl aminocarbamate (66 mg, 0.25 mmol, 1 eq) was dissolved in EtOH (6 mL) and Pd / C (10% Pd, approximately 50% H2O, 26.6 mg, 0.025 mmol, 0.1 eq) was added. The reaction mixture was degassed under vacuum and filled with H2 via a gas bladder. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then subjected to a process via Celite. ® The solvent was removed by filtration under reduced pressure, yielding the title compound (64.7 mg; 97%) as a pale solid, which was used unchanged in the next step without further purification. LC-MS (3): t R = 1.01 min; [M+H] + : 267.23. (5-Cyclopropyl-4-ethylisothiazolyl-3-yl)methylamine hydrochloride: HCl (4 M in diethane, 1.36 mL, 5.45 mmol, 22 eq) was added dropwise to a solution of ((5-cyclopropyl-4-ethylisothiazolyl-3-yl)methyl)aminocarbamate tert-butyl ester (66 mg, 0.248 mmol, 1 eq) in DCM (2.5 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (62.7 mg, 100%) as a yellow oil, which was used unchanged in the next step without further purification. LC-MS (3): t R = 0.67 min; [M+H] + : 167.14. 1 1H NMR (500 MHz, d6-DMSO) d : 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). N-((5-cyclopropyl-4-ethylisoazol-3-yl)methyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using (5-cyclopropyl-4-ethylisoazol-3-yl)methylamine hydrochloride and 4,4-difluorocyclohexanone, as described in Example 1.146. LC-MS (3): tR = 1.04 min; [M+H] + : 285.25. (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (5-cyclopropyl-4-ethyl-isoazol-3-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: As described in Example 1.24, the title compound was synthesized using N-((5-cyclopropyl-4-ethylisoazol-3-yl)methyl)-4,4-difluorocyclohexane-1-amine and toluenesulfonyl-L-prolylate chloride. LC-MS (1): t R = 1.305 min; [M+H] + : 536.04. Examples 1.149 to 1.152 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. LC-MS data for Examples 1.149 to 1.152 are listed in the table below. Example 1.153 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-ethyl-5-methyl-isoazol-3-ylmethyl)-amide: A solution of ((5-methylisoazol-3-yl)methyl)aminocarbamate tert-butyl ester: 1-(5-methylisoazol-3-yl)methylamine (270 mg, 2.41 mmol, 1 eq), tert-butyl di-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) at 0 °C for 5 min. The solution was then heated to room temperature and stirred overnight. The solution was diluted with EtOAc and washed with water, saturated NaHCO3 aqueous solution, and brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (455 mg, 89%) as a grayish-white solid. LC-MS (3): t R = 0.78 min; [M+H] + : 213.28. ((4-Iodo-5-methylisoazol-3-yl)methyl)tert-butyl carbamate: In a 25 mL double-necked flask, tert-butyl ((5-methylisoazol-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 the mixture was stirred at room temperature for 30 min. I₂ (653 mg, 2.57 mmol, 1.2 eq) was added to the suspension, and the mixture was stirred overnight at room temperature. After 30 min, the suspension was heated under reflux for 5 h, and stirred overnight at room temperature. The suspension was diluted with DCM and filtered. The clear solution was washed with NaHSO₃, NaHCO₃, H₂O, and brine. The organic layer was dried over MgSO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (hexane / EtOAc 9:1) to give the title compound as a white solid. LC-MS (3): t R = 0.93 min; [M+H] + : 339.12. ((5-methyl-4-vinylisoazol-3-yl)methyl)tert-butyl carbamate: ((4-iodo-5-methylisoazol-3-yl)methyl)tert-butyl 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-trivinylcyclotriboroxanepyridine complex (107 mg, 0.444 mmol, 1 eq) were dissolved in DME (4.1 mL) and water (1.4 mL). The reaction mixture was degassed for 3 min, then stirred at 100 °C for 30 min. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept / EtOAc 9 / 1) to give the title compound (94 mg, 89%) as a light brown solid. LC-MS (3): t R = 0.90 min; [M+H] + 239.22. tert-butyl ((4-ethyl-5-methylisoazol-3-yl)methyl)aminocarbamate: tert-butyl ((5-methyl-4-vinylisoazol-3-yl)methyl)aminocarbamate (46.5 mg, 0.195 mmol, 1 eq) was dissolved in EtOH (4.5 mL) and Pd / C (10% Pd, approximately 50% H2O, 20.8 mg, 0.0195 mmol, 0.1 eq) was added. The reaction mixture was degassed under vacuum and then filled with H2 using a gasket. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then transmitted via Celite. ® The solvent was removed by filtration under reduced pressure to give the title compound (43 mg; 92%) as a pale solid, which was used unchanged in the next step without further purification. LC-MS (3): t R = 0.91 min; [M+H] + : 241.25. (4-Ethyl-5-methylisoazol-3-yl)methylamine hydrochloride: HCl (4M in diethane, 0.955 mL, 3.82 mmol, 22 eq) was added dropwise to a solution of (4-ethyl-5-methylisoazol-3-yl)methylamine (46.9 mg, 0.195 mmol, 1 eq) in DCM (2.0 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (62.7 mg, 100%) as a yellow oil, which was used unchanged in the next step without further purification. LC-MS (3): t R = 0.54 min; [M+H] + : 141.16. N-((4-ethyl-5-methylisoazol-3-yl)methyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using (4-ethyl-5-methylisoazol-3-yl)methylamine hydrochloride and 4,4-difluorocyclohexanone, as described in Example 1.146. LC-MS (3): t R = 0.95 min; [M+H] + : 259.32. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-ethyl-5-methyl-isoazol-3-ylmethyl)-amide: As described in Example 1.24, the title compound was synthesized using N-((4-ethyl-5-methylisoazol-3-yl)methyl)-4,4-difluorocyclohexane-1-amine and toluenesulfonyl-L-prolylate chloride. LC-MS (1): t R= 1.241 min; [M+H] + : 510.2. Examples 1.154 to 1.164 were synthesized according to the procedure described herein, followed by the use of a suitable amine or amine salt derivative, a suitable aldehyde, and a suitable amino acid or amino ester and a suitable sulfonyl chloride. LC-MS data for Examples 1.154 to 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-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide: As described above, the title compound was synthesized using (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylate and N-(benzo[d]thiazol-5-ylmethyl)-4,4-difluorocyclohexane-1-amine to give a white solid. LC-MS (2): t R = 1.05 min, [M+H] + : 546.08. Examples 1.166 to 1.188 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde, and a suitable amino acid or amino ester and a suitable sulfonyl chloride. LC-MS data for Examples 1.166 to 1.188 are listed in the table below. Example 1.189 (S)-1-toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide: Potassium trifluoroborate (((4,4-difluorocyclohexyl)amino)methyl)trifluoroborate: Potassium trifluoroborate (bromomethyl) (3347 mg, 15 mmol, 1 eq) was added to a dried microwave-safe vial equipped with a stir bar, sealed, and placed under a nitrogen atmosphere. Then, THF (5 mL), t-BuOH (3.75 mL), and 4,4-difluorocyclohexane-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 room temperature and then gradually heated to 60 °C while stirring overnight. The suspension was cooled to room temperature and concentrated, and the solids were suspended in hot (approximately 50 °C to 60 °C) MeCN (120 mL). A white precipitate was filtered through a 0.45 μm Whatmann filter. The filtrate was concentrated and the same procedure was repeated. The filtrate was concentrated and dissolved in a minimal amount of hot MeCN (30 mL). Et₂O was then 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): t R = 0.46min; [MH] + 215.98; 1 H NMR (500 MHz, d6-DMSO) δ: 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, 2H). 4,4-Difluoro-N-((5-fluorobenzofuran-6-yl)methyl)cyclohexane-1-amine: 6-bromo-5-fluorobenzofuran (WO20140274695) (148 mg, 0.69 mmol, 1 eq), potassium trifluoroborate (193 mg, 0.889 mmol, 1.289 eq), P(tBu)3PdG2 (35.4 mg, 0.069 mmol, 0.1 eq), and Cs2CO3 (674 mg, 2.07 mmol, 3 eq) were added to a dried microwave-safe vial equipped with a stir bar, sealed, and placed under a nitrogen atmosphere. Subsequently, THF (7 mL) and water (7 mL) were added, and the resulting mixture was degassed under a nitrogen stream for 5 min, followed by stirring overnight at 90 °C (with a preheated heating block). The residue was purified by cation exchange resin. The alkaline solvent was further purified by preparative HPLC to give the title compound (25.2 mg, 13%) as a yellow oil. LC-MS (2): t R=0.65 min; [M+H] + : 284.25. 4,4-Difluoro-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine: Pd / C (10% Pd, 50% H2O, 9 mg, 0.0085 mmol, 0.1 eq) was added to a solution of 4,4-difluoro-N-((5-fluorobenzofuran-6-yl)methyl)cyclohexane-1-amine (24 mg, 0.0846 mmol, 1 eq) in EtOH (1 mL), and the mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was then subjected to Celite... ® The solution was filtered and extracted with EtOH. The filtrate was concentrated under reduced pressure to give the title compound (23.7 mg, 97%) as a pale yellow oil. LC-MS (2): t R = 0.62 min; [M+H] + : 286.24. (S)-N-(4,4-difluorocyclohexyl)-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: As described in Example 1.24, it was synthesized using 4,4-difluoro-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-prolyl chloride to give the title compound as a white solid. LC-MS (1): t R = 1.260 min; [M+H] + : 537.2. Examples 1.190 to 1.196 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.190 to 1.196 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.197 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide: 2-(2,5-Dibromo-3-fluorophenoxy)ethane-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 fractionally at 0 °C, and the mixture was stirred overnight at 90 °C. 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 / EtOAc 7:3) to give the title compound (1.402 g, 50%) as a white solid. LC-MS (2): t R = 0.86 min; [M+H] + Not seen; 1 1H NMR (500 MHz, d6-DMSO) d 7.31(dd, J 1 = 2.0 Hz, J 2 = 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). 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)ethanol-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 4 h. The reaction mixture was cooled to 0 °C and 1 M NaOH aqueous solution was added dropwise. (The solution was then processed in Celite.) ® The white suspension was filtered through a filter pad and the filter cake was washed with EtOAc. The filtrate was washed twice with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to EtOAc 95:5) to give the title compound (1.126 g, 67%) as a white solid. LC-MS (2): t R = 1.06 min; [M+H] + Not found; 1 H NMR (400 MHz, d6-DMSO) d 7.36 (d, J= 8.1 Hz, 1 H), 7.24-7.28 (m, 1H), 4.44-4.53 (m, 2 H), 3.80-3.87 (m, 2 H). 4-Fluoro-2,3-dihydrobenzofuran-6-carboxaldehyde: Under nitrogen atmosphere at -78°C, a solution of 1.6 M n-butyllithium in hexane (1.65 mL, 2.64 mmol, 1 eq) was added dropwise to a stirred solution of 2,5-dibromo-1-(2-bromoethoxy)-3-fluorobenzene (900 mg, 2.39 mmol, 1 eq) in anhydrous THF (8.4 mL) for 45 min. Subsequently, another solution of 1.6 M n-butyllithium in hexane (1.65 mL, 2.64 mmol, 1.106 eq) was added, and the mixture was stirred again at -78°C for 45 min. Then, DMF (0.368 mL, 4.78 mmol, 2 eq) was added dropwise at -78°C, and the mixture was stirred at this temperature for 30 min. The reaction mixture was brought to room temperature and subsequently quenched with a saturated aqueous NH4Cl solution 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 EtOAc 9:1) to give the title compound (270 mg, 68%) as a white solid. LC-MS (2): t R = 0.79min; [M+H] + Not found; 1 H NMR (500 MHz, d6-DMSO) d 9.89 (d, J = 1.5 Hz, 1 H), 7.27(dd, J 1 = 1.0 Hz, J 2 = 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). 4,4-Difluoro-N-((4-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine: Synthesized as described in Example 1.146 using 4-fluoro-2,3-dihydrobenzofuran-6-carboxaldehyde and 4,4-difluorocyclohexane-1-amine, yielding the title compound as a pale yellow oil. LC-MS (2): t R = 0.64 min; [M+H]+: 286.32. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide: As described in Example 1.24, it was synthesized using 4,4-difluoro-N-((4-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-prolylate chloride to give the title compound as a white solid. LC-MS (1): t R = 1.256 min; [M+H] + : 537.4. Examples 1.198 to 1.208 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.198 to 1.208 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.209 (2S,4S)-4-fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid (1S,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)-pyrrolidone-2-carboxylic acid (1R,3R,6R)-bicyclo[4.1.0]hept-3-yl-(2,3-dihydro-benzofuran-6-ylmethyl)-amide, and Example 1.211 (2S,4S)-4-fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (1S,3R,6S)-bicyclo[4.1.0]hept-3-yl-(2,3-dihydro-benzofuran-6-ylmethyl)-amide: obtained by preparative chiral separation (SFC 1 method) of (2S,4S)-N-(bicyclo[4.1.0]heptane-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-4-fluoro-1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-carboxamide (Example 1.184), yielding Examples 1.209 (first dissolution), 1.210 (second dissolution), and Example 1.211 (third dissolution). Stereochemical systems were randomly partitioned. Example 1.209: LC-MS (1): t R = 1.246 min; [M+H] + : 529.2; Example 1.210: LC-MS (1): t R = 1.240 min; [M+H] +: 529.2 and Example 1.211: LC-MS (1): t R =1.234 min; [M+H] + : 529.2. Examples 1.212 to 1.234 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. LC-MS data for Examples 1.212 to 1.234 are listed in the table below. Example 1.235 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(7-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide: 4,4-Difluoro-N-((7-fluorobenzofuran-6-yl)methyl)cyclohexane-1-amine: As described in Example 1.189, it was synthesized using potassium trifluoroborate and 6-bromo-7-fluoro-2,3-dihydrobenzofuran to give the title compound as a yellow oil. LC-MS (2): t R = 0.66 min; [M+H] + : 284.20. 4,4-Difluoro-N-((7-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine: Synthesized using 4,4-difluoro-N-((7-fluorobenzofuran-6-yl)methyl)cyclohexane-1-amine as described in Example 1.189, yielding the title compound as a yellow oil. LC-MS (2): t R = 0.62 min; [M+H] + : 286.35. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(7-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide: As described in Example 1.189, it was synthesized using 4,4-difluoro-N-((7-fluoro-2,3-dihydrobenzofuran-6-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-prolylate chloride to give the title compound as a white solid. LC-MS (1): t R = 1.249 min; [M+H] + : 537.3. Examples 1.236 to 1.266 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.236 to 1.266 are listed in the table below. The LC-MS conditions used were LC-MS (1). 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: As described in Example 1.33, the title compound was synthesized using (S)-1-(tert-butoxycarbonyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (WO2012122450), N-((2,3-dihydrobenzofuran-6-yl)methyl)-4,4-difluorocyclohexane-1-amine and 4-methylbenzenesulfonyl chloride to give a white solid. LC-MS (2): t R = 1.01 min; [M+H] + : 518.33. Example 1.268 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-isopropyl-thiazolyl-2-ylmethyl)-amide: 4,4-Difluoro-N-((5-isopropylthiazolyl-2-yl)methyl)cyclohexane-1-amine: Synthesized as described in Example 1.1 using 4,4-difluorocyclohexane-1-amine and 5-(propyl-2-yl)-1,3-thiazolyl-2-carboxaldehyde, yielding the title compound as a yellow oil. LC-MS (2): t R = 1.02 min; [M+H] + : 275.08. (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-isopropyl-thiazolyl-2-ylmethyl)-amide: As described in Example 1.189, it was synthesized using 4,4-difluoro-N-((5-isopropylthiazolyl-2-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-prolylic acid chloride to give the title compound as a grayish-white solid. LC-MS (1): t R = 1.281 min; [M+H] + : 526.3. Example 1.269 (2S)-N-(4,4-difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: (2S)-N-(1-(benzofuran-6-yl)ethyl)-N-(4,4-difluorocyclohexyl)-1-toluenesulfonylpyrrolidin-2-carboxamide: As described in Example 1.189, it was synthesized using 1-(benzofuran-6-yl)ethyl-1-one, 4,4-difluorocyclohexane-1-amine, and toluenesulfonyl-L-proline chloride to give the title compound as a grayish-white solid. LC-MS (2):t R = 0.67 min; [M+H] + : 280.25. (2S)-N-(4,4-difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: Pd / C (10%, 5.2 mg, 0.0049 mmol, 0.1 eq) was added to a solution of (2S)-N-(1-(benzofuran-6-yl)ethyl)-N-(4,4-difluorocyclohexyl)-1-toluenesulfonylpyrrolidone-2-carboxamide (26 mg, 0.049 mmol, 1 eq) in EtOH (0.5 mL), and the reaction mixture was stirred overnight under H2 atmosphere. The reaction mixture was filtered through Celite® and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to give the title compound (21.6 mg, 83%) as a pale yellow gel. LC-MS(1): t R = 1.290 min; [M+H] + : 533.4. 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)pentan-4-alkynyl acid: p-Toluenesulfonyl chloride (320 mg, 1.66 mmol, 1.1 eq) was added to a stirred solution of L-propargyl glycine methyl hydrochloride (250 mg, 1.51 mmol, 1 eq) and DIPEA (0.647 mL, 3.78 mmol, 2.5 eq) in DCM (10 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed once with brine. The organic layer was separated by a phase separator filter cartridge and concentrated under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (305 mg, 72%) as a white solid. LC-MS (2): t R = 0.83 min; [M+H] + : 282.21. (S)-1-Toluenesulfonyl-2,3-dihydro-1H-pyrrole-2-carboxylic acid: Methyl(S)-2-((4-methylphenyl)sulfonamido)pentan-4-ynetic acid (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) were added to a microwave-safe vial equipped with a stir bar, and the vial was then sealed. THF (3.4 mL) was added under nitrogen, and the resulting mixture was degassed under a nitrogen stream for 5 min, followed by stirring at 45 °C for 24 h. Lithium hydroxide monohydrate (21.5 mg, 0.512 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 4 h, followed by dilution with EtOAc and water. The layers were separated. The aqueous layer was slowly acidified to pH 1-2 using 1 M HCl aqueous solution 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 unchanged in the next step without further purification. LC-MS (2): t R = 0.74 min; [M+H] + : 268.23. (S)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide: As described in Example 1.33, it was synthesized using (S)-1-toluenesulfonyl-2,3-dihydro-1H-pyrrole-2-carboxylic acid and N-((2,3-dihydrobenzofuran-6-yl)methyl)-4,4-difluorocyclohexane-1-amine to give the title compound as a beige solid. LC-MS(1): t R = 1.228 min; [M+H] + : 517.2. Examples 1.271 to 1.301 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.271 to 1.301 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.302 Racemic-5-methyl-2-(toluene-4-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-methyl-benzyl)-amide: 1-(tert-butyl)5-ethyl-3-methyl-4,5-dihydro-1H-pyrazole-1,5-dicarboxylate: Copper(II) chloride (26.9 mg, 0.2 mmol, 0.2 eq) was added to a solution of (E)-2-(1-chloropropion-2-yl)hydrazine-1-carboxylate tert-butyl ester (207 mg, 1 mmol, 1 eq), ethyl diazonate (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 room temperature for 5 h. The mixture was then subjected to ion exchange via Celite. ® The sample was filtered and washed with DCM. After solvent removal, the residue was purified by FC (Hept to EtOAc 1:1) to give the title compound (200 mg, 78%) as a yellow oil. Rf (Hept / EtOAc 1:1) = 0.25; 1 H NMR (500 MHz, CDCl3) d 4.70 (dd, J 1 = 5.8 Hz, J2 = 12.2 Hz, 1 H), 4.19-4.29 (m, 2 H), 3.18 (dd, J 1 = 17.9 Hz, J 2 = 12.6 Hz, 1 H), 2.85 (dd, J 1 = 18.0 Hz, J 2 = 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): t R = 0.76min; [M+H] + Not found. 5-(ethoxycarbonyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-onium trifluoroacetic acid: TFA (0.3 mL) was added to a solution of 1-(tert-butyl)-5-ethyl-3-methyl-4,5-dihydro-1H-pyrazole-1,5-dicarboxylate (80 mg, 0.312 mmol, 1 eq) in DCM (3 mL). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil, which was used as is in the next step without further purification. LC-MS (2): t R = 0.39 min; [M+H] + : 157.28. Ethyl 3-methyl-1-toluenesulfonyl-4,5-dihydro-1H-pyrazole-5-carboxylate: 5-(ethoxycarbonyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-onium 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 1 h. Water was added, and the mixture was extracted with DCM and separated via a separating filter. The solvent was removed under reduced pressure, and the residue was purified by FC (Hept ratio Hep / EtOAc 6:4) to give the title compound (22.6 mg, 23%) as a white solid. LC-MS (2): t R = 0.84 min; [M+H] + : 311.11. 3-Methyl-1-toluenesulfonyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid: Ethyl 3-methyl-1-toluenesulfonyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (23 mg, 0.0741 mmol, 1 eq) was dissolved in THF (0.37 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (4.71 mg, 0.111 mmol, 1.5 eq), and the mixture was stirred at room temperature for 4 h. The mixture was acidified with 1M HCl aqueous solution and extracted with DCM. The layers were separated using a phase separator. The solvent was removed under reduced pressure to give the title compound as a white solid, which was used as is in the next step without further purification. LC-MS (2): t R = 0.66 min; [M+H] + : 283.13. Racemic-5-methyl-2-(toluene-4-sulfonyl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-methyl-benzyl)-amide: As described in Example 1.1, it was synthesized using 3-methyl-1-toluenesulfonyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid and 4,4-difluoro-N-(4-methylbenzyl)cyclohexane-1-amine to give the title compound as a white solid. LC-MS(1): t R = 1.254 min; [M+H] + : 504.3. Examples 1.303 to 1.319 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. LC-MS data for Examples 1.303 to 1.319 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.320 (2S)-N-(3-aminoformylcyclopentyl)-N-(4-chlorobenzyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: Methyl 3-((4-chlorobenzyl)amino)cyclopentane-1-carboxylate: As described in Example 1.1, it was synthesized using 4-chlorobenzylamine and methyl 3-sideoxycyclopentane-1-carboxylate to give the title compound, which is a pale yellow oil. LC-MS(2): t R = 0.61 min; [M+H] + : 268.30. 3-((4-chlorobenzyl)amino)cyclopentane-1-carboxamide: Methyl 3-((4-chlorobenzyl)amino)cyclopentane-1-carboxylate (120 mg, 0.448 mmol) was dissolved in NH3 (7 M in methanol, 2.1 mL, 15 mmol) and the reaction mixture was stirred at 85 °C for 4 days. Fresh NH3 (7 M 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 / (MeOH+3% Et3N) 9:1) to give the title compound (61.3 mg, 54%) as a beige viscous solid. LC-MS (2): t R = 0.49 and 0.52 min; [M+H] + : 253.35. (2S)-N-(3-aminoformylcyclopentyl)-N-(4-chlorobenzyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: As described in Example 1.24, the title compound was synthesized using toluenesulfonyl-L-prolyl chloride and 3-((4-chlorobenzyl)amino)cyclopentane-1-carboxamide to give a white solid. LC-MS (1): t R = 1.026 min; [M+H] + : 504.4. Example 1.321 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4-chloro-benzyl)-(4-cyano-bicyclo[2.2.2]oct-1-yl)-amide: As described in Example 1.320, the title compound was synthesized using toluenesulfonyl-L-prolyl chloride, 4-aminobicyclo[2.2.2]octane-1-carboxylonitrile hydrochloride, and 4-chlorobenzaldehyde to give a white solid. LC-MS (1): t R = 1.316 min; [M+H] + : 526.4. Example 1.322 (2S)-N-((1R)-3-aminocarbamoyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: Methyl (1S,3R)-3-(diphenylmethylamino)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 (1R,3R)-3-aminocyclopentane-1-carboxylate hydrochloride (850 mg, 4.73 mmol) was added fractionally, followed by benzyl bromide (1.18 mL, 9.7 mmol). The reaction mixture was stirred at 40 °C for 22 h. The reaction mixture was partitioned 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 EtOAc 9:1) to give the title compound (1.335 g, 87%) as a colorless oil. f (Hept / EtOAc 9:1)= 0.26. LC-MS (2): t R = 0.72 min; [M+H] + 324.29. Methyl (3R)-3-(diphenylmethylamino)-1-methylcyclopentane-1-carboxylate: A solution of lithium diisopropylamino (1.0 M in THF / hexane, 2.32 mL, 2.32 mmol) was stirred at -78 °C. A solution of methyl (1S,3R)-3-(diphenylmethylamino)cyclopentane-1-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. A solution of methyl iodomethane (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 a saturated aqueous solution of NH4Cl (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 colorless oil. f (Hept / EtOAc 9:1)= 0.38. LC-MS (2): t R = 0.76 min; [M+H] + : 338.18. (3R)-3-(diphenylmethylamino)-1-methylcyclopentane-1-carboxylic acid: Methyl (3R)-3-(diphenylmethylamino)-1-methylcyclopentane-1-carboxylic acid (231 mg, 0.725 mmol) was dissolved in H₂O (8 mL), and THF (2 mL) and lithium hydroxide monohydrate (134 mg, 3.17 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 14 h, followed by stirring at 70 °C for 5.5 h. The reaction mixture was poured into a 1 M HCl aqueous solution at low temperature and extracted once with DCM and DCM / MeOH 10% (3 × 50 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure to give the title compound (293 mg, 100%) as a white solid. The compound was used as is in the next step without further purification. LC-MS (2): tR = 0.69; [M+H] + : 324.28. (3R)-3-(diphenylmethylamino)-1-methylcyclopentane-1-carboxamide: (3R)-3-(diphenylmethylamino)-1-methylcyclopentane-1-carboxylic acid (205 mg, 0.634 mmol) was dissolved in DMF (6 mL) at room temperature, followed by the addition of DIPEA (0.554 mL, 3.17 mmol) and HATU (497 mg, 1.27 mmol). After stirring for 5 minutes, NH4Cl (170 mg, 3.17 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was filtered through a PTFE 0.45 µm filter and purified by basic preparative HPLC to give the title compound (199 mg, 97%) as a pale orange viscous oil. LC-MS(2): t R = 0.62 and 0.64 min; [M+H] + 323.33 (3R)-3-amino-1-methylcyclopentane-1-carboxamide: (3R)-(diphenylmethylamino)-1-methylcyclopentane-1-carboxamide (116 mg, 0.36 mmol) was dissolved in MeOH (3.6 mL), and Pd / C (10% Pd, approximately 50% H2O 76.6 mg, 0.0719 mmol) was added. The reaction mixture was stirred at room temperature under H2 (5 bar) pressure for 18 h. The reaction mixture was then subjected to a process via Celite. ® The filtrate was filtered and concentrated to give the title compound (48 mg, 94%) as a colorless oil. The compound was used as is in the next step without further purification.

[0142] (3R)-3-((4-chlorobenzyl)amino)-1-methylcyclopentane-1-carboxamide: As described in Example 1.1, it was synthesized using (3R)-3-amino-1-methylcyclopentane-1-carboxamide and 4-chlorobenzaldehyde (62 mg, 0.432 mmol) to give the title compound as a grayish-white solid. LC-MS (2): t R = 0.52 and 0.56 min; [M+H] + : 267.37. (2S)-N-((1R)-3-aminocarbamoyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: As described in Example 1.24, it was synthesized using (3R)-3-((4-chlorobenzyl)amino)-1-methylcyclopentane-1-carboxamide and toluenesulfonyl-L-prolyl chloride to give the title compound as a white solid. LC-MS(1): t R = 1.088 min; [M+H] + : 518.4. Example 1.323 (2S)-N-(4-chlorobenzyl)-N-((1R)-3-cyano-3-methylcyclopentyl)-1-toluenesulfonylpyrrolidone-2-carboxamide: (2S)-N-((1R)-3-aminocarboxyl-3-methylcyclopentyl)-N-(4-chlorobenzyl)-1-toluenesulfonylpyrrolidone-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 through a phase separator. The organic phase was concentrated under reduced pressure, and the residue was purified by preparative HPLC under basic conditions to give the title compound (24 mg, 85%) as a white solid. LC-MS (1): t R = 1.259 min; [M+H] + 500.4. Example 1.324 (S)-1-(3-fluoro-4-methyl-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide: Following the procedure described herein, the title compound was synthesized using a suitable amine or amine salt derivative, a suitable aldehyde, a suitable amino acid or amino ester, and a suitable sulfonyl chloride, yielding a white solid. LC-MS (1): t R = 1.203 min; [M+H] +: 552.4. Examples 1.325 and 1.326: (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,6r)-1,1-difluorospiro[2.5]oct-6-yl)-1-methyl Benzylpyrrolidone-2-carboxamide: Following the procedure described herein, followed by the use of a suitable amine or amine salt derivative, a suitable aldehyde, and (S)-methylpyrrolidone-2-carboxylate hydrochloride, a 1:1 mixture of non-mirror image isomers of (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide is obtained. The non-mirror image mixture was separated by chiral SFC (SFC 5 method) to yield (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide (first dissolution non-mirror image isomer) and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,6r)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide (second dissolution non-mirror image isomer) as white solids. Stereochemical systems were randomly partitioned. (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: LC-MS(1): t R = 1.241min, [M+H] + : 560.5.(S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3S,6r)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: LC-MS (1): t R = 1.243 min, [M+H] + 560.4. Examples 1.327 and 1.328: (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: Following the procedure described herein, and subsequently using a suitable amine or amine salt derivative, a suitable aldehyde, and toluenesulfonyl-L-proline, (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide in a 1:1 mixture of non-mirror image isomers. The non-mirror image mixture was separated by chiral SFC (SFC 6 method) to yield (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide (first dissolution non-mirror image isomer) and (S)-N-(benzo[d]thiazol-5-ylmethyl)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide (second dissolution non-mirror image isomer) as white solids. Stereochemical systems were randomly partitioned. (S)-N-(benzo[d]thiazolyl-5-ylmethyl)ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hexyl-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: LC-MS (1):t R = 1.176 min, [M+H] + : 532.4.(S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3S,5r)-1,1-difluorospiro[2.3]hexane-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide: LC-MS (1): t R = 1.186 min, [M+H] + 532.4. As described in Example 1.326, Examples 1.329 to 1.332 were synthesized using a suitable amine or amine salt derivative, a suitable aldehyde, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.329 to 1.332 are listed in the table below. The LC-MS conditions used were LC-MS (1). Examples 1.333 to 1.334 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.333 to 1.334 are listed in the table below. The LC-MS conditions used were LC-MS (1). Example 1.335 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: (2-Chlorobenzo[d]thiazol-5-yl)methanol: LiAlH4 (17.9 mg, 0.472 mmol) was added fractionally to a stirred (exothermic) solution of ethyl 2-chlorobenzo[d]thiazol-5-carboxylate (100 mg, 0.393 mmol) in THF (3.9 ml) under argon atmosphere at 0 °C. The reaction mixture was stirred for 10 min. Na2SO4 salt (1000 mg) was added (gas escape), and the mixture was vigorously stirred for 3.5 h. The product was then analyzed by Celite. ® The suspension was filtered and evaporated under reduced pressure to give the title compound (80 mg, 100%) as a yellow solid. LC-MS (2): t R = 0.70 min, [M+H] + : 200.19. 2-Chlorobenzo[d]thiazol-5-carboxaldehyde: A round-bottomed, double-necked flask filled with (2-chlorobenzo[d]thiazol-5-yl)methanol (80 mg, 0.401 mmol) was rinsed and refilled three times with argon. Activated MnO2 (106 mg, 1.2 mmol) was added and the mixture was diluted with DCM (4 mL, 62.6 mmol). The reaction mixture was stirred overnight at room temperature. Activated MnO2 (106 mg, 1.2 mmol, 3 eq) was added again and the reaction mixture was stirred for another 24 h. The reaction mixture was then subjected to a Celite reaction. ® The sample was filtered and washed with DCM. The solvent was concentrated under reduced pressure to give the title compound (52 mg, 66%) as a white solid. LC-MS (2): t R =0.81 min, [M+H] + Not found. N-((2-chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexane-1-amine: As described in Example 1.3, the title compound was synthesized using 2-chlorobenzo[d]thiazol-5-carboxaldehyde and 4,4-difluorocyclohexane-1-amine hydrochloride to give a colorless oily form. LC-MS (2): tR = 0.66 min, [M+H]+: 317.20. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: As described in Example 1.1, it was synthesized using N-((2-chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexane-1-amine and toluenesulfonyl-L-proline to give the title compound as a white solid. LC-MS(1): t R = 1.329 min, [M+H] + : 568.4. Examples 1.336 to 1.345 were synthesized according to the procedure described herein, followed by the use of a suitable amine, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.336 to 1.345 are listed in the table below. The LC-MS conditions used were LC-MS (1). Examples 1.346 and 1.347: (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazol-5-ylmethyl-(1R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide and (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide: separated by chiral SFC of (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptane-3-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidin-2-carboxamide (SFC) 8. Methods) obtained by synthesizing benzothiazol-5-carboxaldehyde, L-proline, and 3-fluoro-4-toluenesulfonyl chloride according to the procedure described herein. (S)-1-(3-fluoro-4-methyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazol-5-ylmethyl-(1R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide: LC-MS (1): t R = 1.292 min, [M+H] + : 527.17.(S)-1-(3-fluoro-4-methyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide: LC-MS (1): t R = 1.288 min, [M+H] + : 527.17 . Examples 1.348 to 1.350 were obtained by chiral SFC separation (SFC 9 method) of (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptane-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide, synthesized using benzothiazol-5-carboxaldehyde, bicyclo[4.1.0]heptane-3-amine, and N-p-toluenesulfonyl-L-proline according to the procedure described herein. LC-MS data for Examples 1.348 to 1.350 are listed in the table below. The LC-MS conditions used were LC-MS (1). Examples 1.351 and 1.352: (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazol-5-ylmethyl-(1R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide and (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazol-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide: separated by chiral SFC of (2S)-N-(benzo[d]thiazol-5-ylmethyl)-N-(bicyclo[4.1.0]heptane-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-carboxamide (SFC) 10. Method) obtained by synthesizing benzothiazol-5-carboxaldehyde, bicyclo[4.1.0]heptane-3-amine, and lithium ((4-methoxyphenyl)sulfonyl)-L-prolylate according to the procedure described in Example 1.96. (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzothiazol-5-ylmethyl-(1R,3R,6R)-bicyclo[4.1.0]hept-3-yl-amide: LC-MS (1): t R = 1.209min, [M+H] + : 525.18.(S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide: LC-MS(1): t R = 1.205 min, [M+H] + : 525.18. Example 1.353 (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide: N-(4-Chlorobenzyl)-4,4-difluorocyclohexane-1-amine: DIPEA (9.42 mL, 0.055 mol, 1.1 eq) was added to a solution of 4,4-difluorocyclohexane-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 solution was stirred overnight at room temperature until clear. NaBH4 (2.08 g, 0.055 mol, 1.1 eq) was added fractionally, and the mixture was stirred at room temperature for 45 min. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3. Most of the solvent was evaporated under reduced pressure, and the residue was diluted with EtOAc. The layers were separated, the organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept / EtOAc 1:1) to give the title compound.

[0143] (S)-2-((4-chlorobenzyl)(4,4-difluorocyclohexyl)aminocarbamoyl)pyrrolidone-1-carboxylic acid tert-butyl ester: DIPEA (11.1 mL, 0.065 mol, 2 eq) was added 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). The resulting solution was stirred at room temperature. After 10 min, N-(4-chlorobenzyl)-4,4-difluorocyclohexane-1-amine (9.52 g, 0.0356 mol, 1.093 eq) was added to a solution of DMF (20 mL). The brown solution was stirred overnight. The reaction mixture was diluted with EtOAc and extracted with 1 M HCl aqueous solution, saturated NaHCO3 aqueous solution, water, and brine. The extract was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept to Hept / EA 6:4) to give the title compound.

[0144] (S)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide: Diane (61.8 mL, 0.247 mol, 10 eq) containing 4 MHCl was added dropwise to a solution of (S)-2-((4-chlorobenzyl)(4,4-difluorocyclohexyl)carbamoyl)pyrrolidin-1-carboxylic acid tert-butyl ester (11.8 g, 0.0247 mol, 1 eq) in DCM (100 mL) at 0 °C. The reaction mixture was stirred and allowed to reach room temperature overnight. The reaction mixture was cooled to 0 °C and quenched with a saturated aqueous solution of NaHCO3. The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound.

[0145] (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-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)pyrrolidin-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 overnight at room temperature. The reaction mixture was purified by preparative HPLC under basic conditions to give the title compound.

[0146] Examples 1.354 to 1.371 were synthesized according to the procedure described herein, followed by the use of N-(4-chlorobenzyl)-4,4-difluorocyclohexane-1-amine and a suitable sulfonyl chloride. The LC-MS data for Examples 1.354 to 1.371 are listed in the table below. The LC-MS conditions used were LC-MS (1). Examples 1.372 to 1.378 followed the procedure described in Example 1.33, using a suitable aldehyde, a suitable amine or amine salt, a suitable amino acid, and a suitable sulfonyl chloride for synthesis. LC-MS data for Examples 1.372 to 1.378 are listed in the table below. Example 1.379 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: (2-Bromobenzo[d]thiazol-5-yl)methanol: A solution of 1 M DIBAL in DCM (13 mL, 13 mmol, 4 eq) was added dropwise to a stirred solution of ethyl 2-bromobenzo[d]thiazol-5-carboxylate (950 mg, 3.32 mmol, 1 eq) in THF (30 mL) at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, then heated to 0 °C and stirred at 0 °C for 3 h. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was used as is in the next step without further purification. LC-MS (2): t R = 0.70 min; [M+H] + : 244.05. 2-Bromobenzo[d]thiazol-5-carboxaldehyde: In a round-bottom double-necked flask under an argon atmosphere, activated manganese oxide (IV) (813 mg, 9.25 mmol, 3 eq) was added 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), and the mixture was stirred overnight at room temperature. Activated manganese oxide (IV) (813 mg, 9.25 mmol, 3 eq) was added again, and the reaction mixture was stirred overnight once more. The reaction mixture was then subjected to a Celite reaction. ® The solution was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound. LC-MS (2): t R = 0.77min; [M+H] + : 241.91. N-((2-bromobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using 2-bromobenzo[d]thiazol-5-carboxaldehyde and 4,4-dimethylcyclohexane-1-amine, following the procedure described in Example 1.1. LC-MS (2): t R = 0.67 min; [M+H] + 361.05. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-bromo-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide: The title compound was synthesized using N-((2-bromobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexane-1-amine and toluenesulfonyl-L-proline, following the procedure described in Example 1.1. LC-MS (1): t R= 1.336 min; [M+H] + : 611.07. Examples 1.380 to 1.381 followed the procedure described in Example 1.96, using N-((2-bromobenzo[d]thiazolyl)methyl)-4,4-difluorocyclohexane-1-amine, L-proline methyl hydrochloride, and a suitable sulfonyl chloride for synthesis. The LC-MS data for Examples 1.380 to 1.381 are listed in the table below. Example 1.382 (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methoxy-benzothiazol-5-ylmethyl)-amide: (2-Chlorobenzo[d]thiazol-5-yl)methanol: DIBAL (1.0 M in dichloromethane, 5.5 mL, 5.48 mmol, 4 eq) was added sequentially to a stirred solution of ethyl 2-chlorobenzo[d]thiazol-5-carboxylate (350 mg, 1.38 mmol, 1 eq) in THF (12.5 mL) under argon at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then heated to room temperature and stirred overnight. The reaction mixture was diluted with water. The mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound, which was used as is in the next step without further purification. LC-MS (2): t R = 0.70 min; [M+H] + 200.20. 2-Chlorobenzo[d]thiazol-5-carboxaldehyde: In a round-bottom double-necked 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 oxide (IV) (365 mg, 4.16 mmol, 3 eq) was added. The mixture was stirred for 3 h at room temperature, filtered via Celite® and washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used as is in the next step without further purification. LC-MS (2): t R = 0.82 min; [M+H] + Not found. N-((2-chlorobenzo[d]thiazol-5-yl)methyl)-4,4-difluorocyclohexane-1-amine: The title compound was synthesized using 2-chlorobenzo[d]thiazol-5-carboxaldehyde and 4,4-dimethylcyclohexane-1-amine, following the procedure described in Example 1.1. LC-MS (2): tR = 0.66 min; [M+H] + : 317.21. 4,4-Difluoro-N-((2-methoxybenzo[d]thiazo-5-yl)methyl)cyclohexane-1-amine: N-((2-chlorobenzo[d]thiazo-5-yl)methyl)-4,4-difluorocyclohexane-1-amine (100 mg, 0.316 mmol, 1 eq) was treated with methanol (1.97 mL, 0.789 mmol, 2.5 eq) containing 0.5 M NaOMe in a sealed microwave tube and heated to 50°C for 1 hour using conventional heating (50°C). The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (DCM / MeOH 9.5:0.5) to give the title compound. LC-MS (2): t R = 0.65 min; [M+H] + 313.26. (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methoxy-benzothiazol-5-ylmethyl)-amide: The title compound was synthesized using 4,4-difluoro-N-((2-methoxybenzo[d]thiazol-5-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-proline, following the procedure described in Example 1.1. LC-MS(1): t R = 1.285 min; [M+H] + : 563.17. Examples 1.383 to 1.394 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.383 to 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)-pyrrolidone-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-benzothiazol-5-ylmethyl)-amide: N-((2-fluoro-3-(hydroxymethyl)phenyl)thioaminoformyl)benzamide: 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) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The suspension was filtered and washed with MeCN. The solid was dried under reduced pressure to give the title compound. LC-MS (2): t R = 0.84 min; [M+H] + : 305.2. 1-(3-Bromo-2-fluorophenyl)thiourea: N-((2-fluoro-3-(hydroxymethyl)phenyl)thioaminoformyl)benzamide (3100 mg, 10.2 mmol, 1 eq) was treated with 2M NaOH aqueous solution (25.4 mL, 50.8 mmol, 5 eq) and heated to 100 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was 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): t R = 0.65 min; [M+H] + : 249.03. 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 room temperature. The mixture was stirred overnight at 85 °C. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aqueous solution of NaHCO3. The organic layer was washed once with water, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (DCM / MeOH 9.5:0.5) to give the title compound. LC-MS (2):t R = 0.75 min; [M+H] + : 247.01. 5-Bromo-4-fluorobenzo[d]thiazole: Isoamyl nitrite (1.42 mL, 10.1 mmol, 2.1 eq) was added to a solution of 5-bromo-4-fluorobenzo[d]thiazole-2-amine (1190 mg, 4.82 mmol, 1 eq) in THF (7.9 mL) at room temperature and the solution was refluxed for 2 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by FC (Hept to EtOAc 7.5:2.5) to give the title compound. LC-MS (2): t R = 0.84 min; [M+H] + : 274.94. 4-Fluorobenzo[d]thiazol-5-carboxynitrile: Zinc cyanide (300 mg, 2.5 mmol, 0.7 eq), Zn (58.5 mg, 0.894 mmol, 0.25 eq), triphenylmethyleneacetone 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]thiazolium (830 mg, 3.58 mmol, 1 eq) in NMP (7.7 mL) at room temperature and under a N2 atmosphere. The mixture was stirred at 110 °C for 24 h. After cooling to room temperature, the reactants were 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 obtain the title compound. LC-MS (2): t R = 0.73 min; [M+H] + Not found. 4-Fluorobenzo[d]thiazolyl-5-carboxaldehyde: Sodium hypophosphite (530 mg, 6.17 mmol, 5 eq) and Raney nickel (85% in H2O, 1245 mg, 12.3 mmol, 10 eq) were added to a mixture of 4-fluorobenzo[d]thiazolyl-5-carboxynitrile (220 mg, 1.23 mmol, 1 eq) in pyridine (2.7 mL), water (1.3 mL), and AcOH (1.3 mL) at room temperature. The reaction mixture was stirred at 50 °C for 2 h, diluted with EtOAc, and filtered through a 0.45 µm PTFE syringe filter. The filtrate was extracted with 1 M HCl, saturated NaHCO3 aqueous solution, and water. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound. LC-MS (2): t R= 0.67 min; [M+H] + Not found. 4,4-Difluoro-N-((4-fluorobenzo[d]thiazol-5-yl)methyl)cyclohexane-1-amine: The title compound was synthesized using 4-fluorobenzo[d]thiazol-5-carboxaldehyde and 4,4-difluorocyclohexane-1-amine hydrochloride as described in Example 1.3. LC-MS (2): t R = 0.56 min, [M+H] + 301.07. (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-benzothiazol-5-ylmethyl)-amide: The title compound was synthesized using 4,4-difluoro-N-((4-fluorobenzo[d]thiazol-5-yl)methyl)cyclohexane-1-amine and toluenesulfonyl-L-proline, following the procedure described in Example 1.1. LC-MS (1): t R =1.189 min; [M+H] + : 551.15. Examples 1.396 to 1.412 were synthesized according to the procedure described herein, subsequently using a suitable amine or amine salt derivative, a suitable aldehyde or ketone, a suitable amino acid or amino ester, and a suitable sulfonyl chloride. The LC-MS data for Examples 1.396 to 1.412 are listed in the table below. The LC-MS conditions used were LC-MS (1). Method for preparing sulfonamide (SIA) compounds (Example 2.x) Example 2.1 (2S)-N-benzyl-N-(4,4-dimethylcyclohexyl)-1-(4-methylphenylsulfonyl)pyrrolidine-2-carboxamide: tert-butyl (p-toluenesulfinyl)aminoformate: A solution of 4-methylbenzenesulfinamide (200 mg, 1.22 mmol, 1 eq) in THF (5.5 mL, 1.22 mmol, 1 eq) was cooled to 0 °C under a nitrogen atmosphere. A solution of bis(trimethylsilyl)aminolithium (1.0 M in THF, 3.06 mL, 3.06 mmol, 2.5 eq) was added, and the mixture was stirred at 0 °C for 30 min to obtain an orange solution. Tert-butyl di-dicarbonate (0.426 mL, 1.84 mmol, 1.5 eq) was added dropwise, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (a mixture of two non-mirror image isomers, 108 mg, 34%) as a white solid. LC-MS (2): t R =0.84 min; [M-CH3] + : 241.19. (chloro(sidek))(p-tolyl)-λ 6 tert-butyl (-thionyl)aminoformate: A solution of tert-butyl (p-toluenesulfinyl)aminoformate (388 mg, 1.45 mmol, 1 eq) and N-chlorodiimide (593 mg, 4.35 mmol, 3 eq) in MeCN (13.9 mL, 265 mmol, 182.8 eq) was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid (824 mg) used as crude matter. LC-MS (2): t R = 1.06 min; [M+H] + : 289.89. (N-(tert-butoxycarbonyl)-4-methylphenylsulfonyl)-L-prolyl methyl ester: (chloro(sidek)(p-tolyl)-λ 6A solution of tert-butyl thiocarbamate (824 mg, 1.42 mmol, 1 eq) and methyl proline hydrochloride (607 mg, 3.55 mmol, 2.5 eq) in a mixture of MeCN (27.5 mL, 526 mmol, 369.9 eq) and DIPEA (0.73 mL, 4.27 mmol, 3 eq) was stirred at room temperature for 3 hours. The reaction mixture was quenched with cold water and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept / EtOAc 7:3) to give the title compound (546 mg, quantified) as a yellow oil. LC-MS (2): t R = 0.95 min and 0.96 min; [M+H] + 383.16. (N-(tert-butoxycarbonyl)-4-methylphenylsulfonyl)-L-proline lithium: 1 M LiOH aqueous solution (0.324 mL, 0.324 mmol, 1.25 eq) was added to a solution of (N-(tert-butoxycarbonyl)-4-methylphenylsulfonyl)-L-proline methyl ester (100 mg, 0.259 mmol, 1 eq) in THF (1.69 mL, 20.5 mmol, 79 eq), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the title compound (104 mg, quantified) as a white solid. LC-MS (2): t R = 0.85 min; [M+H] + 369.20. (((S)-2-(benzyl(4,4-dimethylcyclohexyl)carbamoyl)pyrrolidin-1-yl)(sidekoxy)(p-tolyl)-λ 6tert-butyl (N-(tert-butoxycarbonyl)-4-methylphenylsulfonyl)-L-prolyl (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 room temperature for 1 h. Then, a solution of N-phenylmethyl-4,4-dimethylcyclohexane-1-amine hydrochloride (13 mg, 0.0597 mmol, 1.1 eq) in DMF (0.2 mL) was added, and the mixture was stirred again for one hour. The reaction mixture was acidified with formic acid and purified directly by basic preparative HPLC to give the title compound (18 mg, 58%) as a white solid. LC-MS (2): t R = 1.21 min and 1.22 min; [M+H] + : 569.31. (2S)-N-benzyl-N-(4,4-dimethylcyclohexyl)-1-(4-methylphenylsulfonyl)pyrrolidin-2-carboxamide: (((S)-2-(benzyl(4,4-dimethylcyclohexyl)carboxyl)pyrrolidin-1-yl)(sidek group)(p-tolyl)-λ 6 A solution of tert-butyl thiocarbamate (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 preparative HPLC to give the title compound (6.6 mg, 57%) as an orange solid. LC-MS (1): t R = 1.341 min; [M+H] + : 468.3. The same procedure can be achieved as follows: At room temperature, add iodotrimethylsilane (2 eq) to a solution of the Boc-protected compound (1 eq) in MeCN (0.13 M). Stir the resulting solution for 5 minutes, then add a few drops of NH4OH. Evaporate the solution under reduced pressure and purify the residue by FC or preparative HPLC.

[0147] Examples 2.2 through 2.5 were synthesized using suitable amines or amine salt derivatives as described in Example 2.1 and lithium (N-(tert-butoxycarbonyl)-4-methylphenylsulfonyl)-L-prolylate. LC-MS data for Examples 2.2 through 2.5 are listed in the table below. Example 2.6 (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-1-(4-methoxyphenylsulfonyl)pyrrolidine-2-carboxamide: (triphenylmethylimine)-λ 4 - Sulfones: At room temperature, Et3N (3.46 mL, 24 mmol, 2.1 eq) and thionyl chloride (0.844 mL, 11.5 mmol, 1 eq) were added dropwise to a solution of triphenylmethylamine (3000 mg, 11.5 mmol, 1 eq) in Et2O (90 mL). A pale yellow suspension was obtained by stirring at room temperature for 2 h. The suspension was then subjected to Celite... ® The mixture was filtered, washed with Et₂O, and the solvent was evaporated under reduced pressure. The resulting pale yellow solid (3.51 g, 100%) was used in the next step without further purification.

[0148] (4-methoxy- N (-Triphenylmethylphenylsulfonyl)-L-proline methyl ester: A solution of 0.5 M 4-methoxyphenyl magnesium bromide in THF (23.0 mL, 11.5 mmol, 1 eq) was added dropwise to (triphenylmethylimine)-λ under argon atmosphere at 0 °C. 4 L-sulfone (3513 mg, 11.5 mmol, 1 eq) was added to a stirred solution in THF (71 mL). The resulting yellow solution was stirred at 0 °C for 5 min. tBuOCl (1457 mg, 12.1 mmol, 1.05 eq) was added dropwise at 0 °C (exothermic) and the mixture was stirred for another 15 min. This was followed by the addition of L-proline methyl hydrochloride (2062 mg, 12.1 mmol, 1.05 eq) and Et3N (3.53 mL, 25.3 mmol, 2.2 eq) to a solution in THF (15 mL). The resulting orange suspension was stirred overnight at room temperature. The pale yellow suspension was poured onto a saturated aqueous solution of NaHCO3 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 pale yellow foam. LC-MS (2): t R= 1.12 min; [M+H] + : 541.2. (4-methoxy- N (-Triphenylmethylphenylsulfonyl)-L-prolyl: LiOH (1 M in H2O, 21.1 mL, 21.1 mmol, 5 eq) was added to (4-methoxy- N -triphenylmethylphenylsulfonyl)- L 1,4-Proline methyl ester (2286 mg, 4.23 mmol, 1 eq) was dissolved in THF (21 mL) and the mixture was stirred overnight. The reaction mixture was diluted with water and the pH was adjusted to 5 with 1 M HCl aqueous solution. The product was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.917 g, 86%) as an orange foam. LC-MS (2): t R = 1.11 min; [M+H] + : 527.2. (2S)-N-(benzofu...

Claims

1. A compound of formula (I) Formula (I) in Ring B is a 6-member aromatic ring, in which: X 1 Indicates N or CR B2 , where R B2 Indicates hydrogen, halogen, (C 1-3 )alkyl or (C 1-3 )alkoxy; and R B1 Independently representing hydrogen, (C 1-4 )alkyl, (C 1-3 Alkoxy, halogen, monocyclic (C) 3-4 )cycloalkyl or (C1)fluoroalkyl; X 2 Indicates O or NR 4 , where R 4 Indicates hydrogen, (C 1-3 )alkyl, monocyclic (C 3-6 )cycloalkyl or phenyl; X 3 Represent CH or N such that: When X 3 When CH is represented, ring A indicates a monocyclic ring (C 5-6 ) Cycloalkyl-diyl or monocyclic 5- or 6-membered heterocyclic alkyl-diyl containing one ring O atom; or When X 3 When N is represented, ring A represents: Includes X 3 and 4- to 6-membered saturated monocyclic heterocyclic alkyl-diyl groups with zero or one ring O atom; wherein the heterocyclic alkyl-diyl group is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen, (C 1-3 )alkoxy, hydroxyl and (C 1-3 )alkylene; Includes X 3 and 4- to 6-membered monounsaturated monocyclic heterocyclic alkyl-diyl groups with zero or one additional ring N atom; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of ); wherein the monounsaturated heterocyclic alkane-diyl group is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently (C 1-3 alkyl; or Includes X 3 6 to 8-membered saturated spiro, fused or bridged bicyclic heterocyclic alkyl-dimethyl; R 1 express: 3-Cyano-3,3-dimethylpropyl or 4-cyanobutyl; Saturated monocyclic (C 4-6 )cycloalkyl; wherein the (C 4-6 ) cycloalkyl groups are unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )alkoxy, carbamoyl, hydroxyl, and cyano groups; Monounsaturated monocyclic (C) 56 ) cycloalkyl; wherein the monounsaturated (C 56 The double bond of the cycloalkyl group does not contain the group -N(CO)CH(R) 2 (R) 3 ) carbon atoms; Saturated bicyclic (C 6-8 )spirocycloalkyl; wherein the (C 6-8 Spirocycloalkyl groups are unsubstituted or monosubstituted or disubstituted; wherein such substituents are independently halogens; Saturated fused or bridged bicyclic (C 6-8 )cycloalkyl; wherein the (C 6-8 ) cycloalkyl groups are unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano, and carbamoyl; or A 5- or 6-membered saturated monocyclic heterocyclic alkyl group comprising a cyclic heteroatom group selected from O, S, or SO2; wherein the heterocyclic alkyl group is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen and (C 1-3 )fluoroalkyl; R 2 Indicates hydrogen or methyl; R 3 express: An 8- to 10-membered partially aromatic fused bicyclic system comprising a total of zero to three independently selected cyclic heteroatoms chosen from N, O, or S; wherein the 8- to 10-membered ring system is bonded in the aromatic ring moiety to the remainder of the molecule; wherein the 8- to 10-membered ring system is unsubstituted or monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 Alkyl, halogen, and side-oxygen groups; Naphthyl or an 8- to 10-membered heteroaryl group comprising a total of one to three independently selected cyclic heteroatoms chosen from N, O, and S; wherein the 8- to 10-membered heteroaryl group is unsubstituted or monosubstituted or disubstituted, wherein the substituents are independently selected from (C 1-3 A group consisting of alkyl groups and halogens; or A phenyl group or a 5- or 6-membered heteroaryl group comprising one to three independently selected cyclic heteroatoms chosen from N, O, and S; wherein the phenyl group or the 5- or 6-membered heteroaryl group is independently unsubstituted or monosubstituted, disubstituted, or trisubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen, (C 1-3 )alkoxy, (C 1-3 )Fluoroalkoxy, monocyclic (C 3-6 )cycloalkyl, (C 1-3 ) alkylthio, (C 1-3 )Fluoroalkyl, cyano, NR N1 R N2 , where R N1 and R N2 Independently representing hydrogen or (C 1-4 )alkyl; Or its medically acceptable salt; The following compounds are excluded: N-Benzyl-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (R)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; (S)-N-benzyl-N-((R)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; (S)-N-benzyl-N-((S)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; (R)-N-benzyl-N-((S)-1,1-tetrahydrothiophene-3-yl)-1-toluenesulfonylpyrrolidine-2-carboxamide; N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2R)-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (2S)-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (S)-N-((R)-1,1-Tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide; (S)-N-((S)-1,1-tetrahydrothiophene-3-yl)-N-(furan-2-ylmethyl)-1-toluenesulfonylpyrrolidine-2-carboxamide; and N-[(2-methoxyphenyl)methyl]-1-[(4-methylphenyl)sulfonyl]-N-[(tetrahydro-2-thienyl)methyl]-2-pyrrolidinecarboxamide.

2. The compound of formula (I) as claimed in claim 1, wherein R B1 Independent representation (C) 1-4 )alkyl, (C 1-3 Alkoxy, halogen, monocyclic (C) 3-4 )cycloalkyl or (C1)fluoroalkyl; Or its medically acceptable salt.

3. The compound of formula (I) as claimed in claim 1 or 2, wherein X 3 Represent CH or N such that: When X 3 When CH is represented, ring A indicates a monocyclic ring (C 5-6 ) Cycloalkyl-diyl or monocyclic 5- or 6-membered heterocyclic alkyl-diyl containing one ring O atom; or When X 3 When N is represented, ring A represents: Includes X 3 and 4- or 5-membered saturated monocyclic heterocyclic alkyl-diyl groups with zero ring O atoms; wherein the heterocyclic alkyl-diyl group is unsubstituted or monosubstituted or disubstituted; wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen, (C 1-3 )alkoxy, hydroxyl and (C 1-3 )alkylene; Includes X 3 And an unsubstituted 5- or 6-membered saturated monocyclic heterocyclic alkyl-dimethyl group with one ring O atom; Includes X 3 and a 5-membered monounsaturated monocyclic heterocyclic alkyl-diyl group with zero extra ring N atoms; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X atoms. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 ) carbon atoms; Includes X 3 and a 5-membered monounsaturated monocyclic heterocyclic alkyl-diyl group with an additional ring N atom; wherein the double bond of the monounsaturated heterocyclic alkyl-diyl group does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 The carbon atom of the heterocyclic alkyl-diyl group; wherein the heterocyclic alkyl-diyl group is unsubstituted or substituted with (C) 1-3 Alkyl monosubstituted; or Includes X 3 6 to 7 saturated spiro, fused or bridged bicyclic heterocyclic alkyl-dimethyl; Or its medically acceptable salt.

4. The compound of formula (I) according to any one of claims 1 to 3, wherein X 3 Indicates CH and ring A is: ;or ； The asterisk indicates the substituent -C(=O)NR. 1 -CH2(R 2 (R) 3 () connection points; Or its medically acceptable salt.

5. The compound of formula (I) according to any one of claims 1 to 3, wherein X 3 Let N represent the ring A and let A represent: Pyrrolidine-diyl; wherein the pyrrolidine-diyl is unsubstituted or via (C) 1-3 )alkyl, halogen, (C 1-3 )alkoxy, hydroxy or (C 1-3 ) alkylene monosubstituted; or via (C 1-3 Alkyl or halogen disubstituted; Azolidin-dimethyl; Dihydrogen-1 H -pyrrole-diyl; wherein the dihydro-1 H The double bond of the pyrrole-dimethyl group does not contain X. 3 Or linked to the group -CO-N(R) 1 )CH(R 2 (R) 3 ( ) carbon atoms; or Includes X 3 6 to 7 saturated spiro, fused or bridged bicyclic heterocyclic alkyl-dimethyl; Or its medically acceptable salt.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R 1 express: 3-Cyano-3-methylbutyl; Saturated monocyclic (C 5-6 )cycloalkyl; wherein the (C 5-6 )Cycloalkyl groups are monosubstituted or disubstituted; wherein such substituents are independently selected from the group consisting of: methyl, fluorine, hydroxyl and cyano; Cyclohex-3-en-1-yl; Saturated bicyclic (C 6-8 Spirocycloalkyl; Saturated fused or bridged bicyclic (C 6-8 )cycloalkyl; wherein the (C 6-8 ) Cycloalkyl groups are either unsubstituted or difluorinated; or Tetrahydro-2 H -Thiopiperan-1,1-dioxide Or 1,1-dioxo-tetrahydro-2 H -Thiopiperan-3-yl; Or its medically acceptable salt.

7. The compound of formula (I) according to any one of claims 1 to 6, wherein R 3 express: A 9- or 10-membered partially aromatic fused bicyclic system comprising a total of zero to three independently selected cyclic heteroatoms chosen from N, O, and S; wherein the 9- or 10-membered ring system is bonded in the aromatic ring portion to the remainder of the molecule; wherein the 9- or 10-membered ring system is unsubstituted or monosubstituted with a halogen. A 9- or 10-membered heteroaryl group comprising a total of one to three cyclic heteroatoms independently selected from N, O, and S; wherein the 9- or 10-membered heteroaryl group is unsubstituted, or monosubstituted or disubstituted, wherein the substituents are independently selected from (C 1-3 A group consisting of alkyl groups and halogens; or Phenyl; wherein the phenyl group is monosubstituted or disubstituted, wherein the substituents are independently selected from the group consisting of: (C 1-3 )alkyl, halogen, (C 1-3 )alkoxy and (C 1-3 )alkylthio; Or its medically acceptable salt.

8. A compound of formula (I) according to any one of claims 1 to 7, which is also a compound of formula (IV): Formula (IV); Or its medically acceptable salt.

9. The compound of formula (I) as claimed in claim 1, wherein the compound is selected from the group consisting of: (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzo[b]thiophene-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazol-5-ylmethyl-(1,1-dioxy-hexahydro-λ) 6 -Thiopiperan-4-yl)-amide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]azol-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4-fluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzo[b]thiophene-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(cyclohex-3-en-1-yl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (1R,3S,4S)-2-(toluene-4-sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzo[b]thiophene-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-difluoro-benzofuran-6-ylmethyl)-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-difluoro-benzofuran-6-ylmethyl)-(1,1-disideloxy-hexahydro-1λ) 6 -Thiopiperan-4-yl)-amide; (1R*,5S*)-(2RS)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzofuran-6-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,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)-pyrrolidone-2-carboxylic acid benzoxazol-5-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid benzofuran-6-ylmethyl-(4-hydroxy-cyclohexyl)-amide; (2S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzo[d]azol-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4-hydroxy-cyclohexyl)-amide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-(benzo[d]azol-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-dimethylcyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (2,3-dihydro-benzofuran-6-ylmethyl)-(4,4-dimethyl-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S,4S)-4-fluoro-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S,4S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-4-fluoro-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(5-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1R,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; (2S,4S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-4-fluoro-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(4-fluoro-2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(benzo[d]azol-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(benzo[d]azol-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (2S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidone-2-carboxamide; (S)-4-methylene-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S,4S)-4-fluoro-1-(4-methoxy-benzenesulfonyl)-pyrrolidone-2-carboxylic acid (1R,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-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-(4,4-difluorocyclohexyl)-N-(furano[3,2-c]pyridin-6-ylmethyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1R,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; (1R*,5S*)-(2RS)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2S,5R)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,2S,5S)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,5R)-2-(4-methoxy-benzenesulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,3S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-toluenesulfonyl-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-((4-methoxyphenyl)sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-toluenesulfonyl-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((4-methoxyphenyl)sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide; (1R,3S,5R)-2-(4-methoxy-benzenesulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,3S,5R)-2-(toluene-4-sulfonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R,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; (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; (1R,2S,5S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((S)-4-methoxyphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxyphenylsulfonyl)pyrrolidin-2-carboxamide; (1R*,5S*)-(2RS)-3-(4-methoxy-benzenesulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1S,2S,5R)-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,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]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R*,5S*)-(2RS)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1S,2S,5R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-3-((4-methoxyphenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-(N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (1R,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; (1R,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-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(3-fluoro-4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(4-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (S)-1-(4-cyclopropyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S,5R)-5-methyl-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (2S)-N-(4,4-difluorocyclohexyl)-N-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2,3-dihydro-benzofuran-6-ylmethyl)-amide; (1R,3S,4S)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-((6-methylpyridin-3-yl)sulfonyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide; (1R,3S,4S)-2-(6-methylpyridine-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)-pyrrolidin-2-carboxylic acid benzo[1,3]dioxacyclopenten-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-(3-fluoro-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-1-(3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (2S)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (2S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-(methylthio)benzyl)pyrrolidin-2-carboxamide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)pyrrolidin-2-carboxamide; (2S)-N-(benzo[d]thiazo-5-ylmethyl)-1-(N-cyclopropyl-3-fluoro-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(benzofuran-6-ylmethyl)-1-(N-cyclopropyl-4-methoxyphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chlorobenzyl)-1-(N-cyclopropyl-4-methylphenylsulfonyl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1,3]dioxacyclopenten-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-(4-chlorobenzyl)-N-(4,4-dimethylcyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chlorobenzyl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-((4-ethynyl-2-hydroxycyclopentyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)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]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (2S)-N-((3S,5R)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((3S,5R)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((3S,6R)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (1S,2R)-N-(bicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydrobenzofuran-6-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzo[1,3]dioxacyclopenten-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]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-(4-chloro-2-fluorobenzyl)-N-((3S,6r)-1,1-difluorospiro[2.5]octyl-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (2S)-N-((3S,6r)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidine-2-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1S*,3R*)-3-cyanocyclopentyl)-2-toluenesulfonylcyclopentane-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-((1R*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorophenylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2S,4S)-N-(4-chlorobenzyl)-N-(4,4-difluorocyclohexyl)-1-(N,4-dimethylphenylsulfonyl)-4-methylpyrrolidin-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-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-methylthio-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]dioxacyclopenten-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-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-cyano-cyclohexyl)-(4-methylthio-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; (2S,4S)-N-(4-chlorobenzyl)-N-(1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-fluoropyrrolidine-2-carboxamide; (2S,4S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (S)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-methylbenzyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (S)-N-(4-chlorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1S*,3R*)-3-cyano-cyclopentyl)-(4-methyl-benzyl)-amide; (2S,4S)-N-(4-chlorobenzyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-(R)-(N,4-dimethylphenylsulfonamide)-4-methylpyrrolidin-2-carboxamide; (2RS)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-methylbenzyl)-3-toluenesulfonyl azithiodin-2-carboxamide; (2RS)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-(4-chlorobenzyl)-3-toluenesulfonyl methazolidine-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)-cyclopentanecarboxylic acid (3-cyano-3,3-dimethyl-propyl)-dihydroinden-5-ylmethyl-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic 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 ((1R*,3R*)-3-cyano-cyclohexyl)-(4-methyl-benzyl)-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4-chloro-benzyl)-((1R,3S)-3-cyano-cyclopentyl)-amide; (1S,2R)-N-((1R*,3S*)-3-cyanocyclopentyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(7,7-difluorobicyclo[4.1.0]hept-3-yl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-((1R*,3R*)-3-cyanocyclohexyl)-N-((2,3-dihydro-1H-inden-5-yl)methyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid ((1R*,3S*)-3-cyano-cyclopentyl)-(3-fluoro-4-methyl-benzyl)-amide; (2S,4S)-N-(4-chloro-2-fluorobenzyl)-N-(1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)-4-fluoropyrrolidone-2-carboxamide; (2S,4S)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonyl)-4-methyl-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (1S,2R)-N-((1r,4S)-4-cyanocyclohexyl)-N-(4-(methyl-d3)benzyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-N-(4-chloro-2-fluorobenzyl)-N-((1R*,3S*)-3-cyanocyclopentyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid benzoxazo-6-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1S,2R)-2-(toluene-4-sulfonyl)-cyclopentanecarboxylic acid (4,4-difluoro-cyclohexyl)-(6-fluoro-benzoxazo-5-ylmethyl)-amide; (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-2-((R)-4-methylphenylsulfonamide)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-2-((S)-4-methylphenylsulfonamide)cyclopentane-1-carboxamide; (2S)-N-(4-chlorobenzyl)-N-((1R)-3-cyano-3-methylcyclopentyl)-1-toluenesulfonylpyrrolidin-2-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-2-((R)-4-methylphenylsulfonyl)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-2-((S)-4-methylphenylsulfonyl)cyclopentane-1-carboxamide; (1S,2R)-N-(4-chlorobenzyl)-N-((1R)-3-cyano-3-methylcyclopentyl)-2-toluenesulfonylcyclopentane-1-carboxamide; (S)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-N-((3S,5r)-1,1-difluorospiro[2.3]hex-5-yl)-N-(4-methylbenzyl)-1-((S)-4-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-N-((1S*,3R*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-N-((1S*,3S*)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonamide)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-N-(4-chlorobenzyl)-N-((1R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((1R,3S)-3-cyanocyclopentyl)-1-((R)-N,4-dimethylphenylsulfonyl)-N-(4-methylbenzyl)pyrrolidin-2-carboxamide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-toluenesulfonylpyrrolidone-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((3-fluoro-4-methylphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4,4-difluoro-cyclohexyl)-(2-methyl-benzothiazo-5-ylmethyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-chloro-benzothiazol-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((4-methoxyphenyl)sulfonyl)pyrrolidine-2-carboxamide; (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (S)-N-(benzo[d]thiazo-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-(benzo[d]thiazo-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-4-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidone-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3R,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1S,3S,6S)-bicyclo[4.1.0]hept-3-yl-amide; (S)-1-(4-iodobenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,5s)-1,1-difluorospiro[2.3]hex-5-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((3R,6s)-1,1-difluorospiro[2.5]oct-6-yl)-1-((R)-4-methoxy-N-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-1-(4-ethyl-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-4-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidine-2-carboxamide; (S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-((1S,3S,6S)-bicyclo[4.1.0]hept-3-yl)-1-((R)-4-methoxy-N-methylphenylsulfonamide)pyrrolidine-2-carboxamide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1,1-difluoro-spiro[2.5]oct-6-yl)-amide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(1,1-difluoro-spiro[2.3]hex-5-yl)-amide; (1R*,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; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (2-bromo-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methylbenzenesulfonyl)-pyrrolidin-2-carboxylic acid (2-bromo-benzothiazo-5-ylmethyl)-(4,4-difluoro-cyclohexyl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(3-methoxy-cyclohexyl)-amide; (S)-1-(3-fluoro-4-methoxy-benzenesulfonyl)-pyrrolidin-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (S)-N-((2-chlorobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((2-bromobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methylphenylsulfonyl)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazo-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazo-5-yl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-3-fluoro-N,4-dimethylphenylsulfonamide)pyrrolidin-2-carboxamide; (S)-N-((2-chlorobenzo[d]thiazolyl)methyl)-N-(4,4-difluorocyclohexyl)-1-((R)-4-methoxy-N-methylphenylsulfonyl)pyrrolidine-2-carboxamide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(6-methyl-1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-3-yl)-amide; (S)-1-(toluene-4-sulfonyl)-pyrrolidin-2-carboxylic acid (4-chloro-benzyl)-(1,1-dioxy-hexahydro-1λ) 6 -Thiopiperan-3-yl)-amide; (1S*,2S*,5R*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*,5S*)-3-(toluene-4-sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid benzothiazolyl-5-ylmethyl-(4,4-difluoro-cyclohexyl)-amide; (1R*,2S*,5S*)-N-benzo[d]thiazolyl-5-ylmethyl)-N-(bicyclo[4.1.0]hept-3-yl)-3-toluenesulfonyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and (1R,2S,5S)-N-(benzo[d]thiazolyl-5-ylmethyl)-N-(4,4-difluorocyclohexyl)-3-((R)-N,4-dimethylphenylsulfonamide)-3-azabicyclo[3.1.0]hexane-2-carboxamide; Or its medically acceptable salt.

10. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient, and at least one therapeutically inert excipient.

11. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which is used as a pharmaceutical agent.

12. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, used to improve wakefulness.

13. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof: It is used to treat hypersomnia, including narcolepsy, narcolepsy associated with genetic conditions, narcolepsy associated with tumors, narcolepsy associated with head trauma, idiopathic hypersomnia, or Kleine-Levin syndrome. It is used to improve symptoms of excessive daytime sleepiness (EDS), including: Improve symptoms of EDS in individuals with circadian rhythm sleep-wake disorder; Improve symptoms of EDS caused by or related to a medical condition, particularly objective sleep disorder, obesity, diabetes, neurodegenerative diseases, autoimmune diseases, mental illness, or sleep deprivation syndrome. To improve the symptoms of EDS caused by drugs or substances; It is used to treat fatigue; or It is used to treat eating disorders, obesity, neuropsychiatric disorders, pain, inflammation, or cognitive impairment associated with reduced arousal.

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

15. A method for improving arousal, comprising administering to an individual in need an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 9 or a medically acceptable salt thereof.

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