Kappa-opioid receptor antagonists

Abstract

Disclosed herein are kappa-opioid receptor (KOR) antagonist compounds of Formula (I) and their pharmaceutically acceptable salts, as well as pharmaceutical compositions thereof. The compounds are useful in methods of treating a variety of diseases and disorders suitable for KOR antagonism, including substance abuse disorders, depression, anxiety, and other psychiatric conditions.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480059359.8 (22) Application Date 2024.08.14 (30) Priority Data 63 / 520,496 2023.08.18 US (85) PCT International Application Entering National Phase Date 2026.03.17 (86) PCT International Application Application Data PCT / US2024 / 042281 2024.08.14 (87) PCT International Application Publication Data WO2025 / 042657 EN 2025.02.27 (71) Applicant Scripps Research Institute Address USA (72) Inventors Edward Roberts Miguel Angel Guerrero Morales Leslie Rosen (74) Patent Agency Beijing J&J Intellectual Property Agency Co., Ltd. 11227 Patent Agents Zhang Shanshan and He Xin (51) Int.Cl. C07D 401 / 14 (2006.01) C07D 405 / 14 (2006.01) C07D 413 / 14 (2006.01) C07D 487 / 04 (2006.01) C07D 487 / 10 (2006.01) A61P 25 / 00 (2006.01) A61P 29 / 00 (2006.01) A61K 31 / 4709 (2006.01) (54) Invention Title κ-Opioid Receptor Antagonist (57) Abstract This document discloses κ-opioid receptor (KOR) antagonist compounds of formula (I) and their pharmaceutically acceptable salts, as well as pharmaceutical compositions thereof. The compound can be used to treat a variety of diseases and disorders applicable to KOR antagonism, including substance abuse disorders, depression, anxiety, and other mental illnesses. Claims 13 pages, Description 53 pages, CN 121866250 A 2026.04.14 CN 1 21 86 62 50 A 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Ar is a 5- or 6-membered heteroaryl group substituted with (R3)n (wherein 1 to 4 heteroaryl members are independently selected from N, O and S); n is 0, 1 or 2; Y is -N(R2)-, -N(R2)C(=N-CN)NR9- or -N(R2)C(O)-; R1 and R1a are independently selected from H, C1-C6 alkyl and halogen; Optionally, R1 or R1a together with Y and the carbon atoms to which they are bonded form a fused 5- to 6-membered heterocyclic alkyl group (wherein 1 to 4 ring members are independently selected from N, O and S); Alternatively, R1 and R1a together with the carbon atoms to which they are bonded form fused C3-C8 cycloalkyl or 5- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).R2 and R2a are independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)); R3 is independently a C1-C6 alkyl or a C1-C6 haloalkyl in each case; R4, R5, R6, R7, and R8 are independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 Haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O) (C6-C10 aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), - CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C10 aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C10 aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)); R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl); R and R' are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group in R1, R1a, R2, R2a, R3, R4, R5, R6, R7, R8, R9, R, and R' is optionally substituted with 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl; and the compound is not: . Claims 1 / 13 page 2 CN 121866250 A 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a 5-membered heteroaryl group. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl, imidazolyl, azole, isozolyl, diazolyl, isozolyl, and isozolyl groups.4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl and diazolyl. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ar is diazolyl. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is -N(R2)-. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2 is H. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2a is optionally substituted -(C1-C6 alkyl)C3-C8 cycloalkyl or -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)). 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2a is optionally substituted -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)). 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R2a is selected from optionally substituted: and. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2a is or. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2a is substituted with 1 to 3 halogens. 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein n is 0. 14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein n is 1. 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein one of R1 and R1a is H and the other is a halogen. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein one of R1 and R1a is H and the other is F. 17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each of R1 and R1a is H. 18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R1 or R1a, together with Y and the carbon atoms bonded thereto, forms a fused 5- to 6-membered heterocyclic alkyl group. 19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and 18, wherein R1 or R1a, together with Y and the carbon atoms bonded thereto, forms a fused 5-membered heterocyclic alkyl group. 20. The compound or pharmaceutically acceptable salt thereof according to claim 19, wherein the fused 5-membered heterocyclic alkyl group has the following formula: 21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R4 is selected from H, CN, halogens, and22. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R4 is a C1-C6 alkyl. 23. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R5 and R7 are independently selected from H, halogens, and CN. 24. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein at least one of R5 and R7 is H. 25. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein each of R5 and R7 is H. 26. The compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C8 cycloalkyl. 27. The compound of any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R6 is a C1-C6 alkyl. 28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein R8 is selected from H, CN, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and -CONRR'. 29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein R8 is a halogen or a 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S). 30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein R8 is F. 31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ar is pyrazolyl or diazolyl; n is 0 or 1; Y is NH; each of R1 and R1a is H; R2a is an optionally substituted 3- to 6-membered heterocyclic alkyl (wherein one ring member is O); R4 is selected from H, CN, halogen, and C1-C6 alkyl; R5 and R7 are independently selected from H, halogen, and CN, wherein at least one of R5 and R7 is H; R6 is selected from halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl; and R8 is selected from H, CN, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl (wherein one to four heteroaryl members are independently selected from N, O, and S) and -CONRR'. 32. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following table: Claims 3 / 13 pages 4 CN 121866250 A Claims 4 / 13 pages 5 CN 121866250 A Claims 5 / 13 pages 6 CN 121866250 A Claims 6 / 13 pages 7 CN 121866250 AClaims 7 / 13 pages 8 CN 121866250 A Claims 8 / 13 pages 9 CN 121866250 A Claims 9 / 13 pages 10 CN 121866250 A Claims 10 / 13 pages 11 CN 121866250 A Claims 11 / 13 pages 12 CN 121866250 A. 33. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, and a pharmaceutically acceptable carrier. 34. A method for treating a disorder in a subject suffering from a disorder, wherein the disorder is a disorder therapeutically applicable to κ-opioid receptor (KOR) antagonism, the method comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32. 35. A method for treating a disorder in a subject suffering from the disorder, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein the disorder is selected from substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, seizures, and sleep disruption associated with pain, mental disorders, or drug treatment of mental disorders. 36. The method of claim 35, wherein the disorder is substance abuse or addiction. 37. The method of claim 36, wherein substance abuse or addiction is selected from gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, and substance-induced depression or mood disorders. 38. The method of claim 35, wherein the disorder is a mental disorder. 39. The method of claim 38, wherein the mental disorder is selected from anxiety disorders, depressive disorders, mood disorders, schizophrenia spectrum disorders, stress-related disorders, obsessive-compulsive disorders, social phobia, generalized anxiety disorder (GAD), social anxiety disorder, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorders (ASD). 40. The method of claim 35, wherein the condition is sleep disruption associated with pain, mental disorder, or pharmacological treatment of a mental disorder. 41. The method of claim 35 or 40, wherein the pain is chronic pain or neuropathic pain. 42. The method of any one of claims 35, 40, and 41, wherein the sleep is REM sleep. 43. The method of any one of claims 35 and 40 to 42, wherein the sleep disruption is sleep disturbance, sleep deprivation, or a combination thereof. Claims 13 / 13 pages 14 CN 121866250 A κ-Opioid Receptor Antagonist

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 520,496, filed August 18, 2023, which is incorporated herein as fully set forth herein. Background Art

[0002] The kappa-opioid receptor (KOR) is a member of the opioid receptor family that binds dynorphin, an opioid peptide that is the primary endogenous ligand. KOR has a broad and distinctive distribution in the brain, spinal cord, and peripheral tissues, and particularly in brain regions involved in reward, cognitive function, and stress response. Evidence suggests that dynorphin levels rise under pain and stress conditions, and that disruption of KOR produces anti-stress effects. Such discoveries have led to the development of KOR antagonists for the treatment of depression, anxiety, addiction disorders, and other stress-related mental illnesses [M. Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014 ("Urbano 2014"); Jacobson et al., Annu. Rev. Pharmacol. Toxicol., 60:615-636 (2020); see also: Handbook in Experimental Pharmacology, 271: edited by Lee-Yuan Liu-Chen Saadet Inan (2022)].

[0003] Pharmacological studies of prototypical KOR antagonists (i.e., morphine-derived ligands nor-BNI and GNTI, and non-morphine-derived JDTI) have established the therapeutic potential of the KOR / dynorphin system [Urbano 2014]. However, such typical KOR antagonists exhibit delayed onset of action ranging from hours to days, followed by antagonistic effects lasting for weeks at the minimum effective dose. Furthermore, such compounds show poor blood-brain barrier penetration. For these reasons, recent research has focused on developing (shorter)-acting KOR antagonists with improved pharmacokinetics.

[0004] The mechanism by which KOR antagonists provide therapeutic effects is generally understood. Both direct regulation of KOR and regulation of downstream signaling pathways regulated by dynorphin-KOR signaling can contribute to therapeutic efficacy. Indeed, KOR antagonists have been extensively studied precisely because they are known to block significant stress-induced neuroadaptation; namely, increased expression of dynorphin in the nucleus accumbens (NAc). The NAc is a part of the mesolimbic system...The NAc is a component of the nervous system (NAC) and plays a role in the pathology and triggering of mental illness. Besides repeated exposure to substance abuse, stress also triggers a complex series of intracellular events involving the transcription factor CREB (cAMP-responsive element-binding protein) in the NAC. KOR antagonists alleviate depressive-like signs resulting from increased dynorphin expression mediated by CREB [W. A. ​​Carlezon et al., Depression and Anxiety, 33:895-906, 2016]. According to the model proposed by Carlezon et al., stress activates CREB in the NAC, leading to increased dynorphin expression. Increased dynorphin then promotes KOR activation. KOR is expressed at the terminals and cell bodies of mesocorticolimbic dopamine (DA) neurons, and KOR activation inhibits DA release. Therefore, treatment with KOR antagonists blocks the action of dynorphin, restores DA function, and thus provides antidepressant and anti-anxiety-like effects.

[0005] The neuropeptides oxytocin and vasopressin also play a role in pathways that operate in neuropsychiatric disorders including depression, anxiety, autism, schizophrenia, PTSD, addiction, ADHD, etc. [Cid-Jofre et al., Int. J. Mol. Sci., 22:12077, (2021)]. These are amplified neuropeptide pathways, downstream of dynorphin responses, and they can be regulated by KOR antagonists, which allow for multi-step modulation of adaptive psychopathology. In fact, multi-step interdiction in amplified pathways is a recognized principle in disease-modifying therapeutics.

[0006] Binding sites for μ and κ opioids have been found in the pituitary gland, which are important for the release of oxytocin and vasopressin [Jordan et al., J. Neuroendocrinol., 8: 883-887, (1996); Shuster et al., Neuroscience, 96(2), 373-383, (2000); Morris et al., J Clin. Pharmacol., 50:1112-1117, (2010)]. Oxytocin secretion is centrally inhibited by both μ and κ agonists, and is directly inhibited by κ agonists through κ receptor activation [Lutz-Bucher & Koch, Euro J Pharmacol., 66: 375-378, (1980)]. Therefore, κ and μ opioids...Both antagonists increase oxytocin levels; however, when administered intraventricularly, only the κ antagonist enhances both oxytocin and vasopressin levels [Van de Heijning et al., Eur J Pharmacol., 197:175-180, (1991), ibid., ibid., 209:199-206, (1991)]. Additionally, the endogenous κ opioid receptor agonist dynorphin regulates serotonin (5-HT) release and, for example, affects social deficits in rodents during substance withdrawal: as demonstrated in humans, these effects can lead to relapse [Pomrenze et al., Neuron 110:4125-4143, (2022)].

[0007] Physiologically, dynorphin / KOR signaling promotes REM sleep. Furthermore, while KOR antagonists do not promote drowsiness in the absence of pain, they do normalize interrupted sleep in chronic pain, revealing a pathophysiological role in KOR signaling, which is selectively recruited to promote alertness and improve survival. Notably, while this mechanism may be beneficial in the short term, disruption of sleep homeostasis over longer periods can become maladaptive, leading to persistent chronic pain. Therefore, novel approaches to treating chronic pain could arise from normalizing sleep disruptions associated with chronic pain through KOR antagonism [Ito, et al., Brain: 00; 1–14 (2022)]. Furthermore, sleep disturbances are not only caused by chronic pain, but they are also common symptoms of major depressive disorder (MDD), and they are a significant adverse effect of most existing classes of antidepressants, most notably selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) [EC Settle, J. Clin. Psychiatry 59: 25-30 (1998)]. Therefore, KOR antagonism can normalize sleep disturbances without somnolence, which is a broad advantage in therapeutic interventions for MDD and in clinical settings characterized by sleep disturbances as an adverse effect of drug therapy.

[0008] To date, the mechanism of action of KOR antagonists and a considerable amount of development and testing have been conducted on them, including recent clinical trials.Clinical studies (e.g., aticaprant and ALKS-5461) provide strong evidence that KOR antagonists offer therapeutic effects in people with a wide range of conditions, including mood disorders, anxiety disorders, and substance abuse disorders, as defined, for example, in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The Research Domain Criteria (RDoC) project provides an additional framework for classifying psychopathological disorders: the RDoC aims to classify such disorders based on both observable behavioral and neurobiological dimensions. In this context, KOR antagonists have therapeutic effects on at least two types within the domains defined by the RDoC; namely, those related to reward and those related to adverse effects of stress. Within these domains, the use of KOR antagonists for treating anhedonia (“positive valence system”) and for blocking adverse effects of stress (“negative valence system”) has been recognized.

[0009] KOR antagonists offer benefits from advances made in the art, with their utility recognized in the treatment of major depressive disorder and substance abuse-related disorders, particularly in the context of rapid-acting treatments that avoid the drawbacks associated with typical KOR antagonists discussed above. Further advances have shown that KOR antagonists can be used specifically to treat stress-mediated symptoms, as well as for the treatment of social anxiety disorders and phobias. Prophylactic treatment is also suggested to prevent adverse conditions caused by stress, and in this regard, KOR antagonists have been proposed as a preventative treatment for PTSD in individuals at risk of PTSD. Other therapeutic applications of KOR antagonists include the treatment of impairments in reward-related functioning, as it frequently occurs in patients with mood and anxiety spectrum disorders and may also present with other types of conditions such as schizophrenia or schizoaffective disorder.

[0010] KOR antagonism is an established therapeutic approach for the treatment of a wide variety of disorders and conditions. Despite advances in this field, new and improved KOR antagonists remain needed to treat a variety of conditions, including substance abuse disorders, major depressive disorder, anhedonia, and stress-related symptoms. Summary of the Invention

[0011] In several embodiments, this disclosure addresses this and other needs by providing a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0012] .

[0013] Ar is a 5- or 6-membered heteroaryl group substituted with (R3)n (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S).

[0014] n is 0, 1, or 2.

[0015] Y is -N(R2)-, -N(R2)C(=N-CN)NR9-, or -N(R2)C(O)-.

[0016] In some embodiments, R1 and R1a are independently selected from H, C1-C6 alkyl, and halogen.

[0017] In other embodiments, R1 or R1a together with Y and the carbon atoms to which they are bonded form fused C3-C8 cycloalkyl or 5- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0018] In still other embodiments, R1 and R1a together with the carbon atoms to which they are bonded form fused 5- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0019] R2 and R2a are independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S) and -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S)).

[0020] R3 is independently a C1-C6 alkyl or a C1-C6 haloalkyl in each case.

[0021] R4, R5, R6, R7, and R8 are independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C10 aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C10 aryl, C3-C8 cycloalkyl, O (C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C10 aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), -(C1-C6 alkyl)(5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S)).

[0022] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0023] R and R' are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl.

[0024] Any alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group among R1, R1a, R2, R2a, R3, R4, R5, R6, R7, R8, R9, R and R' is optionally substituted with 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN and C1-C6 haloalkyl.

[0025] It should be understood that, despite the definitions disclosed herein, formula (I) is not: .

[0026] In other embodiments, this disclosure provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0027] In yet other embodiments, this disclosure provides a method for treating a disorder in a subject suffering from a disorder, wherein the disorder is a therapeutically applicable disorder of κ-opioid receptor (KOR) antagonism. The method includes administering to the subject a compound as disclosed herein or a pharmaceutically acceptable salt thereof.

[0028] In still other embodiments, this disclosure provides a method for treating a disorder in a subject suffering from a disorder selected from those disclosed herein, such as substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, and seizures. The method includes administering to the subject a compound as disclosed herein or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disorder as disclosed herein in a subject. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for preparing a medicament for treating a disorder as disclosed herein. Detailed Description

[0030] This disclosure relates in part to compounds that antagonize the κ-opioid receptor (KOR). One advantage of these compounds is their high potency, particularly their selectivity for KOR relative to the μ-opioid receptor (MOR).

[0031] Definition

[0032] “Alkyl” means a straight-chain or branched hydrocarbon group comprising 1 to about 20 carbon atoms. For example, an alkyl group may have 1 to 10 carbon atoms or 1 to 6 carbon atoms. Some exemplary alkyl groups include straight-chain alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.; and also include branched isomers of straight-chain alkyl groups, such as, but not limited to, etc. Thus, alkyl groups include primary alkyl, secondary alkyl, and tertiary alkyl groups. Alkyl groups may be unsubstituted orThe alkenyl group is optionally substituted with one or more substituents as described herein (e.g., halogen).

[0033] Each of the terms “halogen,” “halide,” and “halo” refers to -F or fluorine, -Cl or chlorine, -Br or bromine, or -I or iodine. Specification 4 / 53 pages 18 CN 121866250 A

[0034] The term “alkenyl” refers to a straight-chain or branched hydrocarbon group having 1 to 3, 1 to 2, or at least one carbon-carbon double bond and comprising 2 to about 20 carbon atoms. The alkenyl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0035] “Alkyne” or “alkynyl” refers to a straight-chain or branched unsaturated hydrocarbon having a specified number of carbon atoms and at least one triple bond. Examples of (C2-C8) alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, and 4-octyne. The alkynyl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0036] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, such as a C3-C8 cycloalkyl group. A cycloalkyl group may be linked by any atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0037] When used alone or as part of another term, “aryl” means a carbocyclic aromatic group, whether fused or not, having a specified number of carbon atoms, or, if not specified, a maximum of 14 carbon atoms, such as C6-C10 aryl or C6-C14 aryl. Some examples of aryl include phenyl, naphthyl, biphenyl, phenanthrene, and naphthacenyl (see, for example, Lang's Handbook of Chemistry (Dean, JA editor), 13th edition. Tables 7-2

[1985] ). “Aryl” also refers to an aryl ring as part of a fused polycyclic system, such as an aryl ring fused with a cycloalkyl group as defined herein. An exemplary aryl is phenyl. Aryl groups may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0038] The term “heteroatom” refers to N, O, and S. Compounds of this disclosure containing N or S atoms may optionally be oxidized to the corresponding N-oxide, sulfoxide, or sulfone compound.

[0039] "Heteroaryl" (alone or in combination with any other part described herein) is a compound containing one or more (e.g.,A monocyclic aromatic ring structure comprising 5 to 10 (e.g., 5 or 6) ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, independently selected from O, S, and N heteroatoms (1 to 4, 1 to 3, or 1 to 2). Heteroaryl groups are also intended to contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary nitrogen rings. A carbon or heteroatom is the connecting point of the heteroaryl ring structure, resulting in a stable compound. Some examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, quinoxalinyl, indolatinyl, benzo[b]thiopheneyl, quinazolinyl, purine, indole, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, azole, thiazolyl, thiopheneyl, isozolyl, thiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl, and indoleyl. The heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0040] A “heterocyclic alkyl” is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic, or polycyclic ring system having 3 to 14 (e.g., 3 to 6) atoms, wherein 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S, or N. The cyclic heteroatoms may also contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary nitrogen. The heterocyclic alkyl group may be fused with another ring system, for example with an aryl or heteroaryl group of 5 to 6 ring members. The fusion point of the heterocyclic alkyl ring is on a carbon or heteroatom, such that a stable ring is maintained. Some examples of heterocyclic alkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuranyl, and dihydroindolyl. Heterocyclic alkyl groups may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0041] The terms “nitrile” or “cyano” are used interchangeably and refer to the -CN group.

[0042] Unless the context clearly specifies otherwise, nouns without quantifiers as used herein and in the appended claims mean one / some and more / some. When scope is used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., specification 5 / 53 page 19 CN 121866250 A, such as chemical formula), all combinations and sub-combinations of the scope and specific embodiments are intended to be included. When referring to numbers or numerical ranges, the term “about / approximately” means that the mentioned numbers or numerical ranges are approximate values ​​within experimental variability (or statistical experimental error), and therefore in some cases the numbers or numerical ranges will vary from 1% to 15% of said numbers or numerical ranges. The term "comprising" (and related terms such as variations thereof, "having" or "including") is not intended to exclude "constituting" or "substantially consisting of" the features in certain other embodiments described herein (e.g., embodiments of any substance composition, composition, method, or process, etc.).

[0043] The compounds described herein can exist in a variety of isomeric forms, including configurational, geometrical, and conformational isomers, including, for example, cis or trans conformations. The compounds can also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to cover all isomeric forms of the compounds of this disclosure, including tautomeric forms. The compounds of this disclosure can also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may be produced by dehydration. The specific composition of the open-chain and cyclized forms may depend on how the compound is isolated, stored, or administered. For example, the compound may exist primarily in the open-chain form under acidic conditions but cyclized under neutral conditions. All forms are included in this disclosure.

[0044] Some of the compounds described herein may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The compounds described herein may be in optical isomeric or diastereomeric forms. Therefore, this disclosure covers compounds as described herein in the form of optical isomers, diastereomers, and mixtures thereof (including racemic mixtures), and their uses. Optical isomers of the compounds of this disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed techniques, or by chemical separation of stereoisomers using an optically active resolving agent.

[0045] Unless otherwise stated, the term "stereoisomer" means a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Thus, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomers of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomeric pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other stereoisomers of the compound. The stereoisomers described above can be considered as compositions comprising two stereoisomers present in their respective weight percentages as described herein.

[0046] If there is a difference between the structure shown and the given name of the structure, the structure shown shall prevail. Additionally, if the stereochemistry of a structure or a portion thereof is not indicated by, for example, thick or dashed lines, then the structure or a portion thereof is...The term "isotope" should be interpreted to encompass all its stereoisomers. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relevant stereochemistry. Those skilled in the art of organic synthesis will know whether a compound is prepared as a single enantiomer by the methods used to prepare it.

[0047] The term "isotope" as used herein refers to an isotopically enriched compound. As used herein, and unless otherwise stated, the term "isotopically enriched" means an atom having an isotopic composition different from that of the natural abundance of the atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition different from that of the natural abundance of the atom. In isotope, "isotope enrichment" refers to the percentage by which a particular isotope of a given atom in a molecule replaces the natural isotopic composition of that atom. For example, a 1% enrichment of deuterium at a given location means that 1% of the molecules in a given sample contain deuterium at that specific location. Since the naturally occurring distribution of deuterium is about 0.0156%, the enrichment of deuterium at any location in a compound synthesized using a non-enriching starting material is about 0.0156%.

[0048] Therefore, as used herein, and unless otherwise stated, the term "isotope enrichment factor" refers to the ratio between the isotopic composition of a particular isotope and the naturally occurring isotopic composition.

[0049] With respect to the compounds provided herein, when the location of a specific atom is specified as having deuterium or "D", it should be understood that the abundance of deuterium at that location is substantially greater than the naturally occurring abundance of deuterium, which is about 0.015%. In some specific implementations, the sites designated as having deuterium typically have a minimum isotopic enrichment factor of at least 1000 (15% deuterium inclusion), at least 2000 (30% deuterium inclusion), at least 3000 (45% deuterium inclusion), at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion) at each designated deuterium atom. The isotope enrichment and isotope enrichment factors of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0050] As used herein, and unless otherwise stated to the contrary, the term "compound" is inclusive because itsThis encompasses compounds or their pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers. Thus, for example, a compound may include a pharmaceutically acceptable salt of a tautomer of that compound. Similarly, a compound may include a pharmaceutically acceptable salt of an isotope of that compound.

[0051] In this disclosure, "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic or inorganic acid or base salt of the compounds described herein. Representative pharmaceutically usable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetates, amsonates (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium, calcium edetate, camphor sulfonate, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, edetates, ethanedisulfonates, estolates, esylates, fiunarates, gluconates, glutamates, glycolyllarsanilates, hexafluorophosphates, hexylresorcinol salts, hydrabamine, and hydrobromide. Hydrochloride, hydroxynaphthylcarboxylate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthylcarboxylate, oleate, oxalate, palmitate, bis(hydroxynaphthyl)ate (1,1-methylene-bis(2-hydroxy-3-naphthyl)ate, einbonate), pantothenate, phosphate / bisphosphonate, picrate, polygalacturonic acid ester, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, and valerate. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0052] The term "treatment" and its variations refer to the improvement or eradication of a disease or symptoms related to a disease. In many embodimentsIn this specification, the term refers to minimizing or slowing the spread, progression, or worsening of a disease by administering one or more of the preventive or therapeutic compounds described herein to a patient suffering from a disease.

[0053] The term "prevention" and variations thereof refer to the prevention of the onset, recurrence, or spread of a disease in a patient by administering the compounds described herein.

[0054] The term "effective amount" refers to an amount of a compound or other active ingredient as described herein that is sufficient to provide a therapeutic or preventive benefit in the treatment or prevention of a disease, or sufficient to delay or minimize symptoms associated with the disease. Furthermore, a therapeutically effective amount of a compound as described herein means an amount in which a single therapeutic agent or a therapeutic agent in combination with other treatments provides a therapeutic benefit in the treatment or prevention of a disease. When used in combination with a compound as described herein, the term may cover an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease, or enhances the therapeutic efficacy of another therapeutic agent or works synergistically with another therapeutic agent.

[0055] “Patient” or “object” includes animals such as humans, cattle, horses, sheep, lambs, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the animal is a mammal, such as a nonprimate and a primate (e.g., monkeys and humans). In one embodiment, the patient is a human, such as a human infant, child, adolescent, or adult. In this disclosure, the terms “patient” and “object” are used interchangeably.

[0056] Compounds

[0057] In several embodiments, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: .

[0058] Ar is a 5- or 6-membered heteroaryl group substituted with (R3)n (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S).

[0059] n is 0, 1, or 2.

[0060] Y is -N(R2)-, -N(R2)C(=N-CN)NR9-, or -N(R2)C(O)-.

[0061] In some embodiments, R1 and R1a are independently selected from H, C1-C6 alkyl, and halogen.

[0062] In other embodiments, R1 or R1a together with Y and the carbon atoms to which they are bonded form a fused C3-C8 cycloalkyl or a 5- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0063] In still other embodiments, R1 and R1a together with the carbon atoms to which they are bonded form a fused 5- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0064] R2 and R2a are independently selected from H, C1-C6 alkyl, and optionally with a 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).The fused C3-C8 cycloalkyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S) and -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)).

[0065] R3 is independently a C1-C6 alkyl or a C1-C6 haloalkyl in each case.

[0066] R4, R5, R6, R7, and R8 are independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C10 aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C10 aryl, C3-C8 cycloalkyl, O (C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C10 aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), 5 to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S)).

[0067] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl).

[0068] R and R' are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl.

[0069] Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group in R1, R1a, R2, R2a, R3, R4, R5, R6, R7, R8, R9, R, and R' is optionally substituted with 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl.

[0070] It should be understood that, despite the definitions disclosed herein, formula (I) is not: .

[0071] In some embodiments, Ar is a 5-membered heteroaryl group. Illustrative heteroaryl groups include pyrazolyl, imidazolyl, azole, isozolyl, diazolyl, iso-Diazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one embodiment, Ar is selected from pyrazolyl and diazolyl, and an exemplary heteroaryl is diazolyl.

[0072] In other embodiments, optionally in combination with any other embodiments described herein, Y is -N(R2)-. In one illustrative embodiment, R2 is H.

[0073] In several embodiments, R2a is optionally substituted -(C1-C6 alkyl)C3-C8 cycloalkyl or -(C1-C6 alkyl) (3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)). For example, in some embodiments, R2a is optionally substituted -(C1-C6 alkyl) (3 to 6-membered heterocyclic alkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)). In some exemplary embodiments, R2a is selected from optionally substituted: .

[0074] In some specific embodiments, R2a is or .

[0075] Optionally in combination with any of the embodiments described herein, R2a is substituted with 1 to 3 halogens.

[0076] In some embodiments, n is 0. In other embodiments, n is 1.

[0077] In yet another embodiment, one of R1 and R1a is H and the other is a halogen. For example, one of R1 and R1a is H and the other is F. In other embodiments, each of R1 and R1a is H.

[0078] In several embodiments, this disclosure also provides compounds of formula I, wherein R1 or R1a together with Y and the carbon atoms to which they are bonded form a fused 5- to 6-membered heterocyclic alkyl group. In one embodiment, the fused 5- to 6-membered heterocyclic alkyl group is a fused 5-membered heterocyclic alkyl group. In an exemplary embodiment, the fused 5-membered heterocyclic alkyl group has the following formula: Specification 9 / 53 pages 23 CN 121866250 A

[0079] .

[0080] In other embodiments, R4 is selected from H, CN, halogens, and C1-C6 alkyl. In some embodiments, R4 is C1-C6 alkyl.

[0081] In still other embodiments, optionally in combination with any other embodiments described herein, R5 and R7 are independently selected from H, halogens, and CN. In one embodiment, at least one of R5 and R7 is H. In another embodiment, each of R5 and R7 is H.

[0082] According to several embodiments, R6 is selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl. Specifically, R6 is C1-C6 alkyl.

[0083] In other embodiments, R8 is selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5 toR8 is a 10-membered heteroaryl group (where 1 to 4 heteroaryl members are independently selected from N, O, and S) and -CONRR'. For example, R8 is a halogen or a 5 to 10-membered heteroaryl group (where 1 to 4 heteroaryl members are independently selected from N, O, and S). In one illustrative embodiment, R8 is F.

[0084] In several embodiments, this disclosure also provides compounds of formula I, wherein:

[0085] Ar is pyrazolyl or diazolyl;

[0086] n is 0 or 1;

[0087] Y is NH;

[0088] each of R1 and R1a is H;

[0089] R2a is an optionally substituted 3- to 6-membered heterocyclic alkyl group (wherein one ring member is O);

[0090] R4 is selected from H, CN, halogens, and C1-C6 alkyl;

[0091] R5 and R7 are independently selected from H, halogens, and CN, wherein at least one of R5 and R7 is H;

[0092] R6 is selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl; and

[0093] R8 is selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5 to 10 heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and -CONRR'.

[0094] Some specific examples of other embodiments constituting the present disclosure are shown in Table 1 and in the following examples.

[0095] Table 1. Representative compounds of formula (I). Instructions for Use, Page 10 / 53, 24 CN 121866250 A

[0096] Instructions for Use, Page 11 / 53, 25 CN 121866250 A Instructions for Use, Page 12 / 53, 26 CN 121866250 A Instructions for Use, Page 13 / 53, 27 CN 121866250 A Instructions for Use, Page 14 / 53, 28 CN 121866250 A Instructions for Use, Page 15 / 53, 29 CN 121866250 A Instructions for Use, Page 16 / 53, 30 CN 121866250 A Instructions for Use, Page 17 / 53, 31 CN 121866250 A Instructions for Use, Page 18 / 53, 32 CN 121866250 A

[0097] Pharmaceutical Composition

[0098] This disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers thereof, which are miscible with a pharmaceutically acceptable carrier. In some embodiments, in accordance with recognized pharmaceutical compounding practices, the composition further comprises one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, excipients, stabilizers, emulsifiers, preservatives, colorants, buffers, and flavoring agents.

[0099] In one embodiment, the pharmaceutical composition comprises a compound selected from the compounds shown in Table 1 or its pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers, and a pharmaceutically acceptable carrier.

[0100] The pharmaceutical compositions of this disclosure are formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific condition being treated, the specific subject being treated, the clinical condition of the subject, the cause of the condition, the site of delivery of the medicament, the method of administration, the timing of administration, and other factors known to the medical practitioner.

[0101] The “therapeuticly effective amount” of the compound or its pharmaceutically acceptable salts, stereoisomers, isotopes, and / or tautomers administered is governed by considerations that it is the minimum amount required to exhibit antagonism against κ opioid receptors. Such an amount may be below the amount that would be toxic to normal cells or the subject as a whole. Generally, the initial therapeutically effective dose of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers) is about 0.01 to about 200 mg / kg or about 0.1 to about 20 mg / kg patient body weight / day, with a typical initial range of about 0.3 to about 15 mg / kg / day. Oral unit dosage forms (e.g., tablets and capsules) may contain about 0.1 mg to about 1000 mg of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers). In another embodiment, such a dosage form contains about 50 mg to about 500 mg of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers). In yet another embodiment, page 19 / 53 of CN 121866250 A, such a dosage form contains about 25 mg to about 200 mg of the compound of this disclosure (or its pharmaceutically acceptable salts, stereoisomers, or tautomers). In yet another embodiment, such a dosage form comprises about 10 mg to about 100 mg of the compound of this disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such a dosage form comprises about 5 mg to about 50 mg of the compound of this disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form may be administered once or twice daily.

[0102] In some embodiments, the compound as described herein, or its pharmaceutically acceptable salt or solvate, is substantially pure because it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, said other small organic molecules being, for example, unreacted intermediates or synthetic byproducts generated in one or more steps of, for example, a synthetic method.

[0103] The compositions of this disclosure may be formulated in dose units orally, topically, parenterally, by inhalation or spraying orThe medication is administered rectally. The term "parenteral" as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques.

[0104] Suitable oral compositions as described herein include, but are not limited to, tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs.

[0105] In another embodiment, pharmaceutical compositions suitable for a single unit dose are also covered, the pharmaceutical composition comprising the compound of this disclosure or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0106] Compositions of this disclosure suitable for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions. For example, a liquid formulation of the compound of this disclosure comprises one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically palatable formulation of the compound of this disclosure.

[0107] For tablet compositions, the compounds of this disclosure are mixed with non-toxic, pharmaceutically acceptable excipients for the preparation of tablets. Some examples of such excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated using known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained therapeutic effect over the desired time period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used.

[0108] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0109] For aqueous suspensions, the compounds of this disclosure are mixed with excipients suitable for maintaining a stable suspension. Some examples of such excipients include, but are not limited to, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic.

[0110] Oral suspensions may also contain dispersants or wetting agents, such as naturally occurring phospholipids, such as lecithin, or condensation products of alkyl esters with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanol, or condensation products of ethylene oxide with esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with esters derived from fatty acids and hexitol anhydrides, such as polyvinyl sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as acetone, succinate, and hydroxypropyl esters.Ethylparaben or p-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0111] Oily suspensions can be formulated by suspending the compounds of this disclosure in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in mineral oils (e.g., liquid paraffin). The oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol.

[0112] Sweeteners (e.g., those shown above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (e.g., ascorbic acid).

[0113] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the compounds of this disclosure mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0114] The pharmaceutical compositions of this disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers may be naturally occurring gums (e.g., gum arabic or tragacanth), naturally occurring phospholipids (e.g., soybean, lecithin), and esters or metaesters derived from fatty acids and hexitols, anhydrides (e.g., sorbitan monooleate and the condensation product of said metaester with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate)). The emulsion may also contain sweeteners and flavoring agents.

[0115] Syrups and elixirs may be formulated with sweeteners (e.g., glycerin, propylene glycol, sorbitol, or sucrose). Such formulations may also contain demulcents, preservatives, flavoring agents, and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable, aqueous, or oily suspension. The suspension may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Water, Ringer's solution, and isotonic sodium chloride solution may be used as acceptable carriers and solvents. Additionally, sterile non-volatile oils are commonly used as solvents or suspending media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (e.g., oleic acid) may be used to prepare injectable formulations.

[0116] The compounds of this disclosure may be administered in suppository form for rectal administration of the medicine. These groupsThe compound can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycol.

[0117] The composition for parenteral administration is administered in a sterile medium. Depending on the carrier and concentration (concentration of the drug in the formulation) used, the parenteral formulation can be a suspension or a solution containing dissolved drug. Excipients (e.g., local anesthetics, preservatives, and buffers) may also be added to the parenteral composition.

[0118] Method of use

[0119] In another embodiment, this disclosure provides a method for antagonizing KOR. The method includes contacting the receptor with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. According to several embodiments, the contact may occur, for example, in vivo or in vitro.

[0120] In some embodiments, this disclosure also provides a method for treating a disorder in a subject suffering from a disorder that is therapeutically applicable to antagonism of the κ-opioid receptor (KOR).

[0121] As described in the overview above, KOR is a member of the opioid receptor family, which binds to the opioid peptide dynorphin as the primary endogenous ligand. The term "antagonist" generally refers to a molecule that interacts with a receptor by binding to the receptor at its natural ligand binding site or at a site other than the binding site and thereby acts as an antagonist. Thus, the expression "antagonism of KOR" etc. refers to an antagonistic interaction with KOR by binding to KOR at a site belonging to dynorphin or at a site other than the binding site (i.e., allosteric binding). Specification 21 / 53 pages 35 CN 121866250 A

[0122] In another embodiment, this disclosure provides a method for treating a disorder in a subject suffering from the disorder, comprising administering to the subject a compound as described herein or a pharmaceutically acceptable salt thereof. The disorder is selected from one or more of the following: substance abuse or addiction, mental disorders, obesity and eating disorders, migraine, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, and seizures.

[0123] In some embodiments, the disturbance is sleep disruption caused by or accompanying pain, a mental disorder as described herein, or pharmacological treatment of a mental disorder. The pain may be chronic pain or neuropathic pain. In several embodiments, sleep disruption may be characterized as a sleep disorder, such as a sleep disorder caused by a disorder of initiating and maintaining sleep (DIMS, insomnia), excessive sleepiness, a sleep-wake schedule disorder, or partial wakefulness (parasomnia) [Cormier RE. Sleep Disturbances. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods:The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. Chapter 77]. In other embodiments, sleep disruption is sleep deprivation, such as sleep deprivation occurring by abnormal frequency and / or duration of wakefulness. In some embodiments, disrupted sleep is characterized by the interruption of a sleep stage, such as rapid eye movement (REM) sleep. Treatment in this context, according to the methods described herein, can lead to sleep normalization, i.e., reduction or elimination of sleep disturbance. In several embodiments, normalized sleep includes restoration of REM sleep, prolongation of REM sleep duration, reduction of REM sleep interruption frequency, and combinations thereof.

[0124] In some embodiments, the disorder is one of substance abuse or addiction. For example, the disorder may be selected from gambling, drug addiction, substance abuse, alcohol dependence, alcohol abuse, and substance-induced depression or mood disorders.

[0125] In other embodiments, the disorder is a mental disorder. Examples of mental disorders suitable for treatment by the methods described herein include anxiety disorders, depressive disorders, mood disorders, schizophrenia spectrum disorders, stress-related disorders, obsessive-compulsive disorders, social phobia, generalized anxiety disorder (GAD), social anxiety disorder, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorder (ASD).

[0126] As understood in the art, the term “anxiety disorder” generally refers to a variety of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders, including generalized anxiety disorder, panic disorder, stress-related disorders, obsessive-compulsive disorders, phobias, social anxiety disorder, separation anxiety disorder, and post-traumatic stress disorder (PTSD). In one embodiment, the anxiety disorder is a social anxiety disorder. In another embodiment, the anxiety disorder is a phobia.

[0127] Generalized anxiety disorder is characterized by chronic and persistent anxiety that is not focused on any particular object or situation. People with generalized anxiety disorder may experience nonspecific, persistent fear and worry, and / or exhibit exaggerated attention to routine events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0128] People with panic disorder may experience unexpected, brief episodes of intense fear and anxiety. Accompanying symptoms include trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. The APA defines such an episode as one that occurs suddenly and lasts less than 10 minutes.The fear or discomfort that peaks within minutes can last for hours and can be triggered by stress, fear, or even movement; the specific cause is not always obvious. The diagnosis of panic disorder additionally adds chronic consequences to the episode: these include worry about the potential effects of the episode, persistent fear of future episodes, or significant behavioral changes caused by the episode. Thus, people with panic disorder may experience symptoms beyond the specific panic episode. For example, panic sufferers may notice normal changes in their heartbeat, which forms the basis for a false focus on heart health or the onset of another panic episode. In some cases, a person may experience heightened awareness of bodily functions (hypervigilance) during a panic episode, where any perceived physiological changes are interpreted as potentially life-threatening illness, i.e., extreme hypochondria. Instruction manual 22 / 53 pages 36 CN 121866250 A

[0129] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by repetitive obsessive thoughts (distressing, persistent, and intrusive thoughts or images) and compulsive behaviors (impulses to perform specific behaviors or rituals). OCD thought patterns exist in beliefs that evoke causal relationships that do not actually exist. Compulsive behaviors can be completely illogical, such as walking in a certain pattern to alleviate obsessive thoughts of impending harm. Compulsive behaviors can be completely unexplained and often exist in the impulse to complete a ritual triggered by tension. A small number of OCD patients may experience only obsessive thoughts without obvious compulsive behaviors; even fewer patients experience only compulsive behaviors.

[0130] Phobias are the single largest category of anxiety disorders, including all situations in which a specific stimulus or situation triggers fear or anxiety. Patients typically anticipate terrible consequences from encountering the object they fear: some examples include social phobia, specific phobia, agoraphobia, and phobias of animals, places, or bodily fluids.

[0131] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. PTSD can occur after extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also be caused by prolonged exposure to severe stressors; for example, a soldier may tolerate fighting alone but suffers from the stress of prolonged combat. Common PTSD symptoms include flashbacks, avoidance behavior, and depression.

[0132] The methods described herein can be used to treat depressive disorders, depression, or depressive illnesses. Some examples include major depressive disorder, medication-resistant depression, dysthymia, and bipolar disorder.

[0133] In some embodiments, the methods described herein can be used to treat mood disorders or affective disorders. Some examples include major depressive disorder (MDD), bipolar disorder, anhedonia, dysthymia, major depression, and psychotic major depression.Major depressive disorder (PMD), psychotic depression, postpartum depression, seasonal affective disorder (SAD), and catatonic depression, which are rare but severe forms of major depressive disorder that include motor behavioral disorders and other symptoms.

[0134] The terms “anhedonia” and “anhedonia symptoms” used herein are interchangeable and are defined as the inability to experience pleasure from activities that are normally found to be pleasurable, such as exercise, hobbies, music, sexual activity, or social interaction. Anhedonia is similar to the criteria for “depressive disorder with melancholic features” as defined in DSM-5 as melancholic depression, characterized by loss of pleasure in most or all activities, reactive failure to pleasurable stimuli, a trait of depressed mood that is more pronounced than the trait of sadness or loss, worsening of symptoms in the early morning hours, early awakening, psychomotor retardation, excessive weight loss, or excessive guilt. It should be understood that, in several embodiments, treatment of a depressive disorder with melancholic features includes treatment of both the depressive disorder and the associated melancholic features. In one embodiment, the mood disorder is anhedonia. In another embodiment, the mood disorder is major depressive disorder. In yet another embodiment, the mood disorder is seasonal affective disorder (SAD).

[0135] In other embodiments, the methods described herein can be used to treat schizophrenia or schizoaffective disorder, or obesity or eating disorders such as bulimia, anorexia nervosa, etc.

[0136] In yet another embodiment, the methods are used to treat migraines. Prophylactic treatment, by which the administration of the KOR antagonist compound described herein prevents migraines in individuals at risk of or prone to migraine recurrence.

[0137] In another embodiment, the methods described herein can be used to treat postnatal depression (PND). A significant drop in progesterone levels immediately after birth can lead to the onset of PND. Symptoms of PND range from mild depression to more severe psychosis requiring hospitalization. PND may also be accompanied by or manifest as severe anxiety and irritability. Typical treatment regimens are frustrating, PND is not suitable for treatment with classic antidepressants, and women with PND show a higher incidence of premenstrual syndrome (PMS).

[0138] In several embodiments, the methods described herein can be used to treat neurodegenerative diseases or disorders, including mood and behavioral disorders associated with neurodegenerative diseases, as described on pages 23 / 53 of the specification, CN 121866250 A. The scope of neurodegenerative diseases considered herein includes those related to neurodegenerative disorders.Diseases and disorders related to the progressive loss of neuronal structure or function, or neuronal death. Neurodegenerative diseases and disorders include, but are not limited to: Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic and ischemic injury; ataxia and seizures; seizures caused by schizoaffective disorder or by medications used to treat schizophrenia; benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusions, such as spinal cord injury and head injury; dementia, including multi-infarct dementia and Alzheimer's disease; altered consciousness; Down syndrome. Drug-induced or pharmacologically induced Parkinsonism, such as neuroleptic-induced acute akathisia, acute dystonia, Parkinson's syndrome, tardive dyskinesia, neuroleptic malignant syndrome, and drug-induced postural tremor; epilepsy; Fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced motor disorders; intellectual disability; motor disorders, including akinesia and akinetic (rigid) syndromes, including basal ganglia calcification, corticobasal ganglia degeneration, multiple system atrophy, Parkinson's syndrome-ALS dementia complex, Parkinson's disease, post-encephalitis Parkinson's syndrome, and progressive supranuclear palsy; muscle spasticity and disorders associated with muscle spasticity or weakness, including chorea (e.g., benign hereditary chorea, drug-induced chorea, unilateral throwing disorder, etc.). Huntington's disease, neuroacanthosis, Sydenham's chorea, and symptomatic chorea; movement disorders (e.g., convulsions, including complex convulsions, simple convulsions, and symptomatic convulsions); myoclonus (including generalized myoclonus and focal myoclonus); tremor (e.g., resting tremor, postural tremor, and intention tremor); and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysarthria and torticollis); neuronal damage, including eye injury, retinopathy, or jaundice.Melasma; neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; renal tubular sclerosis; and neurodegenerative changes induced by viral infections such as acquired immunodeficiency syndrome (AIDS) and encephalopathy. The methods also consider the treatment or prevention of loss of neuronal functional characteristics in neurodegenerative disorders.

[0139] In some embodiments, the methods described herein can be used for the treatment of epilepsy. Epilepsy is a brain disorder characterized by recurrent seizures over time. The various types of epilepsy intended for treatment include generalized epilepsy, childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures upon awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0140] In some embodiments, the methods described herein can be used to treat status epilepticus. Status epilepticus (SE) may include convulsive status epilepticus, early status epilepticus, definitive status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; nonconvulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges.

[0141] Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizure, and may include early status epilepticus, definitive status epilepticus, refractory status epilepticus, or ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Definitive status epilepticus is characterized by the persistence of epileptic seizure-like status despite first-line therapy; therefore, second-line therapy is administered. Refractory status epilepticus is characterized by the persistence of epileptic seizure-like status despite first-line and second-line therapy; general anesthetics are usually administered. Ultra-refractory status epilepticus is characterized by the persistence of epileptic seizure-like status despite first-line and second-line therapy and general anesthetic therapy for 24 hours or longer.

[0142] Nonconvulsive status epilepticus includes focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus.Status epilepticus, simple partial nonconvulsive status epilepticus, and mild nonconvulsive status epilepticus; and generalized nonconvulsive status epilepticus, such as late onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0143] In some embodiments, the methods described herein can be used to treat epileptic seizures. The term “seizure” as used herein refers to a change in physical manifestations or behavior that occurs following an episode of abnormal electrical activity in the brain. Additionally, the term “seizure” is often used interchangeably with “convulsion,” which refers to a rapid and uncontrolled shaking of the body. During a convulsion, the body’s muscles repeatedly contract and relax. The type of behavior and brain activity defines two classes of epileptic seizures, specifically generalized and partial (also known as focal or localized). The classification of epileptic seizures provides information for the diagnosis of epilepsy.

[0144] Electrical impulses generated throughout the brain cause generalized seizures, while impulses localized to a part of the brain cause partial seizures. The part of the brain that produces a seizure is sometimes referred to as a focus.

[0145] Generalized seizures are classified according to six types. The most common and severe, and therefore the most well-known, is the generalized tonic-clonic seizure: also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls down. After loss of consciousness, there is a generalized rigidity lasting 30 to 60 seconds – the “tonic” phase – followed by violent convulsions lasting 30 to 60 seconds – the “clonic” phase – after which the patient enters a deep state – the “postictal” or post-ictal phase. During a grand mal seizure, a person can suffer injury and accidents, such as biting their tongue and urinary incontinence.

[0146] Second, absence seizures cause brief loss of consciousness, usually lasting a few seconds, and are rarely or never accompanied by symptoms. The most common patients are children, who usually interrupt their activity and have a blank stare. These seizures begin and end abruptly and can occur several times a day. Patients are usually unaware of the seizure except for the possibility of “losing time.” Third, myoclonic seizures consist of sporadic twitches, usually occurring on both sides of the body. Patients sometimes describe the twitches as brief electric shocks. When severe, these seizures can cause dropping or involuntary throwing of objects. Fourth, clonic seizures consist of repetitive and rhythmic twitches involving both sides of the body simultaneously. Fifth, tonic seizures are characterized by muscle rigidity. Finally, atonic seizures consist of a sudden and generalized loss of muscle tone, particularly in the arms and legs, often leading to falls.

[0147] In several embodiments, the seizures described herein include: epileptic seizures.Seizures; Acute repetitive seizures; Cluster seizures; Continuous seizures; Persistent seizures; Prolonged seizures; Recurrent seizures; Status epilepticus, such as refractory convulsive status epilepticus and nonconvulsive status epilepticus; Refractory seizures; Myoclonic seizures; Tonic seizures; Tonic-clonic seizures; Simple partial seizures; Complex partial seizures; Secondary generalized seizures; Atypical absence seizures; Absence seizures; Atonic seizures; Benign Rolandic seizures; Febrile seizures; Emotional seizures; Focal seizures; Grindelchadrosis; Generalized tonic-clonic seizures; Infantile spasms; Jacksonian seizures; Massive bilateral myoclonus (Instructions for use 25 / 53 pages 39 CN 121866250 A) Seizures); multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; minor seizures; Sylvan seizures; visual reflex seizures; and withdrawal seizures.

[0148] Examples

[0149] The present disclosure is further illustrated by the following examples. The following examples are non-limiting and constitute further embodiments of the present disclosure.

[0150] General Methods. Unless otherwise stated, commercially available reagents and solvents are used without purification. Extraction solvent: ACS grade. Reaction solvent: reagent grade. Reagents: Unless otherwise stated, the highest quality reagents available from Alfa Aesar, Fisher, Combi-Blocks and Aldrich. TLC: silica gel 60 F254 aluminum plate, (whatman, Al Sil G / UV type, 250 μm layer); visualized by UV absorption. Rapid chromatography was performed on silica gel 60 (0.40 to 0.63 mm, 230 to 440 mesh, EM Science). The Biotage Flash+ system was used for medium-pressure column chromatography. NMR: 1H and 13C spectra were obtained on a Bruker AV NEO 500 MHz spectrometer and a Bruker AVIII 400 MHz spectrometer. 1H and 13C NMR data are reported as chemical shifts (δ) relative to the residual signal of the deuterated solvent in parts per million (ppm): chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, br = broad peak), coupling constant in Hz. NMR was obtained using an Agilent 1260 LC / MS system with an Agilent 6120 quadrupole LC / MS detector.The reaction was monitored infinity. Purity was determined by LCMS using an Agilent SB-C18 column (1.8 μm, 2.1 × 50 mm) and detected using UV at wavelengths of 254 and 230 nm. Elution was performed at 25°C with CH3CN in water containing 0.1% HCO2H at a flow rate of 1.0 mL / min over 5 minutes in a gradient from 10% to 90%. The purity of all tested compounds was greater than 95%. High-resolution mass spectrometry was obtained using electrospray ionization (ESI) in positive ion mode on an Agilent 6230 TOF LC / MS system.

[0151] Synthesis of Compounds

[0152] The following exemplary procedures are provided to illustrate the synthesis of the specific compounds described in this disclosure. Those skilled in the art can readily adapt the procedures, starting materials, and reagents to synthesize all the compounds described herein.

[0153] Example 1: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinolin-2-yl)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-3-amine (11)

[0154] A mixture of Int-1 (100 mg, 0.327 mmol), Int-2 (92 mg, 0.5 mmol), and DIPEA (87 µL, 0.5 mmol) in iPrOH was heated at 130 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product (Int-3) was purified by column chromatography using hexane / EtOAc in a yield of 92% (136 mg). Instructions for Use, Pages 26 / 53, 40 CN 121866250 A

[0155] A mixture of Int-3 (130 mg, 0.285 mmol) and 4M dioxane HCl (1.07 mL, 4.28 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated and used without further purification to give Int-4.

[0156] A mixture of Int-4 (12 mg, 0.034 mmol), Int-5 (25 mg, 0.102 mmol), and DIPEA (12 μL, 0.068 mmol) in CH3CN (200 μL) was stirred at 100 °C for 20 hours. The mixture was diluted with EtOAc and then...The sample was washed with brine and a saturated aqueous solution of NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 95:5) to give 11, in 29% (4.2 mg) yield. HRMS (ESI-TOF), calculated value of C23H28FN5O2 [M + H]+: 426.2300, found value: 426.2302.

[0157] Example 2: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinolin-2-yl)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-3-amine (16)

[0158]

[0159] Compound 16 was obtained from the reaction of Int-4 with a suitable toluenesulfonate by the procedure in Example 1, in a yield of 28% (4.1 mg). HRMS (ESI-TOF), calculated value of C23H28FN5O2 [M + H]+: 426.2300, measured value: 426.2302.

[0160] Example 3A: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-3-amine (12) 27 / 53 pages 41 CN 121866250 A

[0161] A mixture of Int-6 (30 mg, 0.1 mmol), Int-2 (28 mg, 0.15 mmol), and DIPEA (26 µL, 0.15 mmol) in nBuOH was heated at 140 °C for 3 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product (Int-7) was purified by column chromatography using hexane / EtOAc in a yield of 86% (39 mg).

[0162] A mixture of Int-7 (100 mg, 0.22 mmol) and 4M dioxane HCl (0.83 mL, 3.3 mmol) in CH2Cl2 (0.3 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated and used without further purification to give Int-8. LCMS: (M+1) m / z = 354.

[0163] Int-8 (12 mg, 0.034 mmol), Int-5 (16 mg, 0.068 mmol) and DIPEA (12 μL, 0.068 mmol) were stirred in CH3CN (200 mL) for 30 minutes at room temperature.The mixture in μL was stirred at 100 °C for 20 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 12, in a yield of 22% (3.2 mg). HRMS (ESI-TOF), calculated value of C24H30FN5O [M + H]+: 424.2507, found value: 424.2516.

[0164] Example 3B: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisoazol-5-yl)quinolin-2-yl)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-3-amine (17)

[0165] A mixture of Int-9 (50 mg, 0.16 mmol), Int-2 (45 mg, 0.25 mmol), and DIPEA (43 µL, 0.25 mmol) in iPrOH was heated at 130 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 76% (57 mg). Instructions for Use, Pages 28 / 53, 42 CN 121866250 A

[0166] A mixture of Int-10 (50 mg, 0.11 mmol) and 4M dioxane HCl (412 µL, 1.65 mmol) in CH2Cl2 (0.4 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated and Int-11 was ready for use without further purification.

[0167] A mixture of Int-11 (10 mg, 0.028 mmol), Int-5 (20.5 mg, 0.084 mmol), and DIPEA (10 μL, 0.056 mmol) in CH3CN (200 μL) was stirred at 100 °C for 20 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 17, in a yield of 26% (3.1 mg). HRMS (ESI-TOF), calculated value of C24H29FN4O2 [M + H]+: 425.2347, measured value: 425.2347.

[0168] Example 4: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinolin-2-yl)-3-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (36)

[0169] A mixture of Int-1 (100 mg, 0.327 mmol), Int-12 (98 mg, 0.49 mmol), and DIPEA (85 µL, 0.49 mmol) in iPrOH was heated at 130 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product (int-13) was purified by column chromatography using hexane / EtOAc in 88% (136 mg). Instructions for Use, pages 29 / 53, CN 121866250 A

[0170] A mixture of Int-13 (130 mg, 0.277 mmol) and 4M dioxane HCl (1.04 mL, 4.15 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure, and Int-14 was ready for use without further purification. HRMS (ESI-TOF), calculated value of C20H24FN5O [M + H]+: 370.2038, measured value: 370.2040.

[0171] A mixture of Int-14 (12 mg, 0.032 mmol), Int-15 (32 mg, 0.128 mmol), and DIPEA (11 μL, 0.064 mmol) in CH3CN (200 μL) was stirred at 80 °C for 48 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 36, with a yield of 13% (1.9 mg). HRMS (ESI-TOF), calculated value of C25H32FN5O2 [M + H]+: 454.2613, measured value: 454.2633.

[0172] Example 5: 5-(6-ethyl-8-fluoro-4-methyl-2-((3aR,6aR)-1-((tetrahydro-2H-pyran-4-yl)methyl)hexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)quinoline-3-yl)-3-methyl-1,2,4-Synthesis of diazole (21)

[0173] A mixture of Int-1 (60 mg, 0.196 mmol), Int-16 (50 mg, 0.236 mmol), and DIPEA (85 µL, 0.49 mmol) in iPrOH was heated at 130 °C for 2 h under microwave irradiation. The mixture was concentrated under reduced pressure. The product (Int-17) was purified by column chromatography using hexane / EtOAc in 95% (90 mg).

[0174] A mixture of Int-17 (80 mg, 0.166 mmol) and 4 M dioxane HCl (622 µL, 2.5 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure, and Int-18 was usable without further purification. HRMS (ESI-TOF), calculated value of C21H24FN5O [M + H]+: 382.2038, measured value: 382.2038.

[0175] A mixture of Int-18 (10 mg, 0.026 mmol), Int-19 (6.0 mg, 0.052 mmol), NaBH(OAc)3 (11 mg, 0.052 mmol), and AcOH (3 μL, 0.052 mmol) in 1,2-dichloroethane (0.4 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using CH2Cl2 / MeOH to give 21 in 66% (8.3 mg) yield. HRMS (ESI-Instructions 30 / 53 pages 44 CN 121866250 A TOF), C27H34FN5O2 [M + H]+ calculated value: 480.2769, measured value: 480.2773.

[0176] Example 6: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-3-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (33)

[0177] Int-20 (70 mg, 0.123 mmol), Int-12 (69 mg, 0.345 mmol), DIPEA (82 µL, 0.47The mixture of Int-21 (100 mg, 0.1214 mmol) and 4M dioxane HCl (800 µL, 3.2 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure, and Int-22 was ready for use without further purification. HRMS (ESI-TOF), calculated value of C21H26FN5 [M + H]+: 368.2245, measured value: 368.2251.

[0179] A mixture of Int-22 (12 mg, 0.032 mmol), Int-15 (32 mg, 0.13 mmol) and DIPEA (17 μL, 0.096 mmol) in CH3CN (300 μL) was stirred at 110 °C under microwave irradiation for 12 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 33, in a yield of 28% (4.1 mg). HRMS (ESI-TOF), calculated value of C26H34FN5O [M + H]+: 452.2820, measured value: 452.2830.

[0180] Example 7: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methylisoazol-5-yl)quinoline-2-yl)-3-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (35) 31 / 53 pages 45 CN 121866250 A

[0181] A mixture of Int-23 (14 mg, 0.046 mmol), Int-12 (10 mg, 0.048 mmol), and DIPEA (20 µL, 0.115 mmol) in iPrOH was heated at 130°C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product (Int-24) was purified by column chromatography using hexane / EtOAc, with a yield of 60% (1).3 mg).

[0182] A mixture of Int-24 (12 mg, 0.026 mmol) and 4M dioxane HCl (32 µL, 0.128 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure, and Int-25 was ready for use without further purification. HRMS (ESI-TOF), calculated value of [M + H]+: 369.2085, measured value: 369.2089.

[0183] A mixture of Int-25 (10 mg, 0.027 mmol), Int-15 (28 mg, 0.109 mmol), and DIPEA (24 μL, 0.136 mmol) in CH3CN (500 μL) was heated at 110 °C for 11 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 35 mg, with a yield of 57% (7 mg). HRMS (ESI-TOF), calculated value of [M+H]+: 453.2660, measured value: 453.2661.

[0184] Example 8: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-3-methyl-N-(((S)-tetrahydrofuran-3-yl)methyl)pyrrolidine-3-amine (38)

[0185] Compound 38 was obtained from the reaction of Int-14 with a suitable toluenesulfonate in a procedure similar to that of Example 4, in a yield of 44% (7.1 mg). HRMS (ESI-TOF), calculated value of C25H32FN5O2 [M + H]+: 454.2613, measured value: 454.2617.

[0186] Example 9: Synthesis of (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-3-methyl-N-(((R)-tetrahydrofuran-3-yl)methyl)pyrrolidine-3-amine (39) 32 / 53 pages 46 CN 121866250 A

[0187] 39 was obtained from the reaction of Int-14 with a suitable toluenesulfonate in a procedure similar to that of Example 4, in a yield of 40% (6.3%).mg). HRMS (ESI-TOF), calculated value of C25H32FN5O2 [M + H]+: 454.2613, measured value: 454.2616.

[0188] Example 10A: (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-3-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (33)

[0189] A mixture of Int-20 (70 mg, 0.123 mmol), Int-12 (69 mg, 0.345 mmol), and DIPEA (82 µL, 0.47 mmol) in iPrOH was heated at 130°C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in 98% (106 mg).

[0190] A mixture of Int-21 (100 mg, 0.1214 mmol) and 4M dioxane HCl (800 µL, 3.2 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure, and Int-22 was ready for use without further purification. HRMS (ESI-TOF), calculated value of C21H26FN5 [M + H]+: 368.2245, measured value: 368.2251.

[0191] A mixture of Int-22 (12 mg, 0.032 mmol), Int-15 (32 mg, 0.13 mmol), and DIPEA (17 μL, 0.096 mmol) in CH3CN (300 μL) was stirred at 110 °C under microwave irradiation for 12 hours. The mixture was diluted with EtOAc and washed successively with brine and saturated NaHCO3 aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 33, in a yield of 28% (4.1 mg). HRMS (ESI-TOF), calculated value of C26H34FN5O [M + H]+: 452.2820, measured value: 452.2830.

[0192] Example 10B: (S)-1-(6-ethyl-8-fluoro-4-methyl-3-(1-methyl-1H-pyrazol-3-yl)quinoline-2-yl)-3-Methyl-N-(((S)-tetrahydrofuran-3-yl)methyl)pyrrolidine-3-amine (50) Specification 33 / 53 pages 47 CN 121866250 A

[0193] In a procedure similar to Example 10A, 50 was obtained from the reaction of Int-22 with a suitable toluenesulfonate in a yield of 43% (6.2 mg). HRMS (ESI-TOF), calculated value of C26H34FN5O [M+H]+: 452.2820, measured value: 452.2832.

[0194] Example 11: Synthesis of 5-(6-ethyl-8-fluoro-4-methyl-2-((S)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1,7-diazaspiro[4.4]nonane-7-yl)quinoline-3-yl)-3-methyl-1,2,4-diazole (40)

[0195] A mixture of Int-1 (50 mg, 0.16 mmol), Int-26 (44 mg, 0.196 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 130 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 94% (75 mg).

[0196] A mixture of Int-27 (65 mg, 0.131 mmol) and 4M dioxane HCl (492 µL, 1.97 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure to give Int-28 in 86% (45 mg) yield, and the product was ready for use without further purification. LCMS: (M+1) m / z = 396.

[0197] A mixture of Int-28 (12 mg, 0.03 mmol), Int-15 (15.5 mg, 0.06 mmol), and DIPEA (11 μL, 0.06 mmol) in CH3CN (300 μL) was heated at 120 °C for 12 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 40, with a yield of 68% (9.8 mg). HRMS (ESI-TOF), calculated value of C27H34FN5O3 [M + H]+: 480.2769, measured value: 480.2760.

[0198] Example 12: Synthesis of 5-(6-ethyl-8-fluoro-4-methyl-2-((S)-1-(((S)-tetrahydrofuran-3-yl)methyl)-1,7-diazaspiro[4.4]nonane-7-yl)quinoline-3-yl)-3-methyl-1,2,4-diazole (41) 34 / 53 pages 48 CN 121866250 A

[0199] 41 was obtained from the reaction of Int-28 with a suitable toluenesulfonate in a manner similar to that of Example 11, in a yield of 46% (6.7 mg). HRMS (ESI-TOF), calculated value of C27H34FN5O2 [M + H]+: 480.2769, measured value: 480.2779.

[0200] Example 13: Synthesis of 5(1S,5R)-3-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-amine (42)

[0201] A mixture of Int-1 (50 mg, 0.16 mmol), Int-29 (39 mg, 0.196 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 120 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 93% (70 mg).

[0202] A mixture of Int-30 (60 mg, 0.128 mmol) and 4M dioxane HCl (481 µL, 1.93 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure to give Int-31 in 82% (39 mg) yield, which was ready for use without further purification. LCMS: (M+1) m / z = 368.

[0203] A mixture of Int-31 (12 mg, 0.032 mmol), Int-15 (34 mg, 0.13 mmol), and DIPEA (17 μL, 0.096 mmol) in CH3CN (300 μL) was heated at 120 °C for 14 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 42, with a yield of 36% (5.2 mg).HRMS (ESI-TOF), calculated value of C25H30FN5O2 [M + H]+: 452.2456, measured value: 452.2458.

[0204] Example 14: Synthesis of (3S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-4-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (43) Specification 35 / 53 pages 49 CN 121866250 A

[0205] A mixture of Int-1 (50 mg, 0.16 mmol), Int-29 (46 mg, 0.196 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 120 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 89% (67 mg).

[0206] A mixture of Int-33 (60 mg, 0.127 mmol) and 4M dioxane HCl (480 µL, 1.91 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through a PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure to give Int-34 in 87% (41 mg) yield, which was ready for use without further purification. LCMS: (M+1) m / z = 370.

[0207] A mixture of Int-34 (12 mg, 0.032 mmol), Int-15 (17 mg, 0.065 mmol), and DIPEA (11 μL, 0.065 mmol) in CH3CN (300 μL) was heated at 120 °C for 11 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 43, with a yield of 63% (9.2 mg). HRMS (ESI-TOF), calculated value of C25H32FN5O2 [M + H]+: 454.2613, measured value: 454.2601.

[0208] Example 15: Synthesis of (3S,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-4-methyl-N-(((S)-tetrahydrofuran-3-yl)methyl)pyrrolidine-3-amine (44)

[0209] In a manner similar to that in Example 14, 44 was obtained from the reaction of Int-34 with a suitable toluenesulfonate in a yield of 42% (6.1 mg). HRMS (ESI-TOF), calculated value of C27H34FN5O2 [M + H]+: 454.2613, measured value: 454.2626.

[0210] Example 16: Synthesis of (3aS,6aR)-2-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)hexahydrocyclopentan[c]pyrrole-3a(1H)-amine (45) 36 / 53 pages 50 CN 121866250 A

[0211] A mixture of Int-1 (50 mg, 0.16 mmol), Int-35 (45 mg, 0.196 mmol), and DIPEA (84 µL, 0.48 mmol) in iPrOH was heated at 120°C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in 85% (68 mg).

[0212] A mixture of Int-36 (60 mg, 0.12 mmol) and 4M dioxane HCl (454 µL, 1.81 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and filtered through PL-HCO3 MP Agilent resin and washed with methanol (3×). The organic phase was concentrated under reduced pressure to give Int-37 in 88% (42 mg) yield, which was ready for use without further purification. LCMS: (M+1) m / z = 396.

[0213] A mixture of Int-37 (12 mg, 0.03 mmol), Int-15 (31 mg, 0.12 mmol), and DIPEA (21 μL, 0.12 mmol) in CH3CN (300 μL) was heated at 110 °C for 18 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 45, with a yield of 32% (4.6 mg). HRMS (ESI-TOF), calculated value of C27H34FN5O2 [M + H]+: 480.2769, measured value: 480.2780.

[0214] Example 17: (3S,4R)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-Synthesis of 2-yl)-4-methyl-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (4,6)

[0215] A mixture of Int-1 (50 mg, 0.16 mmol), Int-38 (38 mg, 0.19 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 120 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 51% (38 mg). Instructions for Use, pages 37 / 53, CN 121866250 A

[0216] A mixture of Int-39 (15 mg, 0.032 mmol) and 4M dioxane HCl (40 µL, 0.16 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 50 minutes. The mixture was concentrated under reduced pressure. Int-40 was quantitatively obtained and used without further purification. LCMS: (M+1) m / z = 370.

[0217] A mixture of Int-40 (13 mg, 0.032 mmol), Int-15 (33 mg, 0.128 mmol), and DIPEA (28 μL, 0.16 mmol) in CH3CN (300 μL) was heated at 110 °C for 11 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to obtain 46, with a yield of 48% (7.0 mg). HRMS (ESI-TOF), calculated value of C25H32FN5O2 [M + H]+: 454.2613, measured value: 454.2617.

[0218] Example 18: Synthesis of (3R,4S)-1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-4-fluoro-N-(((R)-tetrahydrofuran-2-yl)methyl)pyrrolidine-3-amine (47)

[0219] A mixture of Int-1 (50 mg, 0.16 mmol), Int-38 (38 mg, 0.19 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 120 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 51% (38 mg).

[0220] A mixture of Int-42 (15 mg, 0.032 mmol) and 4M dioxane HCl (40 µL, 0.16 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 50 minutes. The mixture was concentrated under reduced pressure. Int-43 was quantitatively obtained and used without further purification. LCMS: (M+1) m / z = 374.

[0221] A mixture of Int-43 (13 mg, 0.032 mmol), Int-15 (33 mg, 0.127 mmol), and DIPEA (28 μL, 0.159 mmol) in CH3CN (300 μL) was heated at 110 °C for 11 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 47 in 35% (5.1 mg) yield. HRMS (ESI-TOF), calculated value of C24H29F2N5O2 [M + H]+: 458.2363, measured value: 458.2361. Instructions for Use, Pages 38 / 53, 52, CN 121866250 A

[0222] Example 19: Synthesis of 2-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinoline-2-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azabicyclo[2.1.1]hexane-4-amine (48)

[0223] A mixture of Int-1 (50 mg, 0.16 mmol), Int-44 (42 mg, 0.21 mmol), and DIPEA (56 µL, 0.32 mmol) in iPrOH was heated at 120 °C for 3 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by column chromatography using hexane / EtOAc in a yield of 92% (70 mg).

[0224] A mixture of Int-45 (65 mg, 0.139 mmol) and 4M dioxane HCl (520 µL, 2.08 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 50 minutes. The mixture was concentrated under reduced pressure. Int-46 was quantitatively obtained and used without further purification. LCMS: (M+1) m / z = 368.

[0225] Int-46 (15 mg, 0.037 mmol), Int-47 (25 mg, 0.11 mmol), and DIPEA (26 μL, 0.148 mmol) were stirred in CH3CN (300 mL) for 50 minutes at room temperature.The mixture in μL was heated at 100 °C for 12 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 48 μL, with a yield of 27% (4.7 mg). HRMS (ESI-TOF), calculated value of C26H32FN5O2 [M + H]+: 466.2613, found value: 466.2612.

[0226] Example 20: Synthesis of (S)-4-((7-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-diazol-5-yl)quinolin-2-yl)-1,7-diazaspiro[4.4]nonane-1-yl)methyl)tetrahydro-2H-pyran-4-ol (49)

[0227] A mixture of Int-28 (10 mg, 0.025 mmol), Int-48 (5.5 μL, 0.05 mmol) and DIPEA (17 μL, 0.1 mmol) in iPrOH (300 μL) was heated at 105 °C for 3 hours. The mixture was concentrated under reduced pressure. The product was purified by preparative TLC (CH2Cl2:MeOH, 95:5) to give 49 in 55% (7.0 mg) yield. HRMS (ESI-TOF), calculated value of C28H36FN5O3 [M + H]+: 510.2875, measured value: 510.2882. Specification 39 / 53 pages 53 CN 121866250 A

[0228] Bioactivity

[0229] General Methods and Materials

[0230] OPRKappa 1 Tango B-Inhibitor Protein Assay Protocol - Antagonist Mode. The purpose of this assay is to confirm the efficacy of the compounds of the present invention as OPRK1 antagonists. The assay uses Tango OPRK1-bla U2OS cells that express OPRK1 linked to the GAL4-VP16 transcription factor via the TEV protease site. The cells also express β-inhibitor protein / TEV protease fusion protein and β-lactamase (BLA) reporter gene under the control of UAS response elements. Stimulation of the OPRK1 receptor by an agonist leads to the migration of the β-repressor fusion protein to the GPCR, where it releases GAL4-VP16 via proteolysis. The released VP16-GAL4 migrates to the nucleus, where it induces transcription of the BLA gene. BLA expression is monitored by measuring the fluorescence resonance energy transfer (FRET) of cleavable, fluorescent, cell-permeable BLA substrates. As designed, the test compound, acting as an OPRK1 antagonist, inhibits the fusion protein...The agonist of white activates and migrates, thereby preventing the proteolysis of GAL4-VP16 and BLA transcription, resulting in no improvement in pore FRET. The compound was tested in quadruplicates using a 10-point, 1:3 dilution series starting at a nominal concentration of 10 μmol.

[0231] Tango OPRK1-U20S dividing cell lines were routinely cultured in 150 mm culture dishes at 37°C, 5% CO2, and 95% relative humidity (RH). The growth medium consisted of McCoys 5A medium supplemented with 10% v / v dialyzable fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin and streptomycin).

[0232] On day 1 of the assay, 16,000 cells were seeded into each well of a 384 Greiner 788092 black low-profile, clear-bottom, low-volume plate in 10 μL of assay medium (DMEM-Glutamax—containing sodium pyruvate, 10% fetal bovine serum deprived by activated charcoal-dextran (CDS), 25 mM HEPES, 0.1 mM non-essential amino acids, and an antibiotic mixture (penicillin-streptomycin)) and incubated at 37°C, 5% CO2, and 95% (RH) for 16 to 24 hours.

[0233] On day 2, 50 nL of the test compound in DMSO was added to the appropriate wells, and the plate was incubated at 37°C, 5% CO2, and 95% (RH) for 30 minutes. Next, 0.65 μL of commercially available U50488 OPRK1 agonist or DMSO in the assay medium was added: this EC80 challenge consisted of 0.6 μL of 111 nM U50488 to produce a final assay concentration of 6 nM. After incubation at 37 °C, 5% CO2, and 95% (RH) for 4 hours, 2.5 μL of LiveBLazer™ FRET B / G (CCF4-AM) mixture (solutions A, B, C, and D) was added to each well and incubated in the dark at room temperature for 2 hours. Well fluorescence was measured using an excitation filter at 409 nm, 460 nm, and 590 nm, with bottom readout, on a Perkin Elmer Envision.

[0234] The inhibition percentage was calculated from the median ratio as follows:

[0235] Wherein:

[0236] The test compound was defined as the well containing the test compound;

[0237] The low control was defined as the well containing U50488 excitation (6 nM final) = 0% inhibition; and

[0238] The high control was defined as the well containing DMSO = 100% inhibition.

[0239] Reagent list:

[0240] Tango™ OPRK1-blaU20S cells (Invitrogen K1576)

[0241] McCoy 5A medium (Invitrogen 16600-082)

[0242] Dialyzed fetal bovine serum (Invitrogen 26400-036)

[0243] Non-essential amino acids 100× (Invitrogen part 11140-050) Instruction manual 40 / 53 pages 54 CN 121866250 A

[0244] HEPES (pH 7.3) 1M (Invitrogen 15630-080)

[0245] Sodium pyruvate 100× (Invitrogen 11360-070)

[0246] Penicillin and streptomycin (Invitrogen 15640)

[0247] Trypsin 0.25% EDTA (Invitrogen 25200056)

[0248] Calcium / Magnesium-Free DPBS (Invitrogen 14190-136)

[0249] DMEM, High Glucose, GlutaMAX (Invitrogen 10569-010)

[0250] Fetal Bovine Serum, Activated Charcoal Deprivation (Invitrogen 12676-011)

[0251] Anhydrous DMSO (Sigma D2650)

[0252] U50488 OPRK1 Agonist MW410.29 (Tocris 67198-19-0)

[0253] GNTI Dihydrochloride OPRK1 Antagonist MW571.5 (Tocris 1282)

[0254] Nor-Binaltorphimine Dihydrochloride MW770.75 (Tocris 0347)

[0255] LiveBLAzer™-FRET / BG spiking mixture: (Invitrogen K1030 (5 mg)), consisting of solutions A, B, C, and D:

[0256] Solution A (6 μL): LiveBLAzer™-FRET / BG substrate (CCF4-AM)

[0257] Solution B (60 μL)

[0258] Solution C (904 μL)

[0259] Solution C (250 μL of 1 N NaOH must be added to 45 mL of Solution C before use)

[0260] Solution D (30 μL) [Probinicid] (Sigma P8161) prepared as a 200 mM stock solution in NaOH-H2O.

[0261] OPRMu1 Discover X-β-inhibitory protein assay – antagonist mode. The purpose of this assay is to determine the synthesis of X-β-inhibitory protein as an inhibitor of X-β-inhibitory protein.The efficacy and specificity of compounds acting as OPRK1 antagonists. This assay evaluated the activation of OPRMu1 in the membrane recruitment of β-repressor proteins. Additionally, this assay evaluated the proximity of GPCR-β-repressor proteins using low-affinity fragment complementation of β-galactosidase (β-gal). U20S cells expressing OPRMu1 fused to the complementary β-gal fragment (enzyme receptor) were used in the assay. As designed, compounds used as antagonists would prevent receptor activation, resulting in reduced pore luminescence. Compounds were tested in quadruplicate using a 10-point, 1:3 dilution series starting at a nominal concentration of 10 μmol.

[0262] Discover X OPRMu1-U20S cell lines were cultured in 150 mm dishes at 37°C, 5% CO2, and 95% relative humidity (RH). The growth medium consisted of DMEM / F12 1:1 medium supplemented with 10% (v / v) heat-inactivated fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin-streptomycin).

[0263] On day 1 of the assay, 5000 cells were seeded in 20 μL of assay buffer (Discover X Cell Plate Seeding Reagent 5) into each well of a 384 Corning 3570 standard white plate and incubated at 37°C, 5% CO2, and 95% RH for 16 to 24 hours.

[0264] On day 2, 100 nL of the test compound in DMSO was added to the appropriate wells, and the plate was then incubated at 37°C, 5% CO2, and 95% RH for 30 minutes. Next, 2.2 μL of DAMGO OPRMu1 agonist (commercially available) or DMSO in the assay medium was added. (EC80 excitation consisted of 1.8 μL of 3.7 μM DAMGO and 0.4 μL of assay buffer, with a final assay concentration of 303 nM). After incubation at 37°C, 5% CO2, and 95% RH for 3 hours, 10 μL of the Path Hunter assay mixture was added to each well, and the plate was then incubated in the dark at room temperature for 1 hour. The luminescence of the wells was measured on a Perkin Elmer Envision.

[0265] The inhibition percentage was calculated from the median ratio as follows: Specification 41 / 53 pages 55 CN 121866250 A

[0266] Wherein:

[0267] The test compound is defined as the well containing the test compound;

[0268] The low control is defined as the well containing DAMGO excitation (200 nM final) = 0% inhibition; and

[0269] The high control is defined as the well containing DMSO = 100% inhibition.

[0270] Reagent list:

[0271] DMEM medium (Invitrogen 11965)

[0272] F12 medium (Invitrogen 11765)

[0273] Heat-inactivated fetal bovine serum (Invitrogen 10082147)

[0274] 100× non-essential amino acids (Invitrogen 11140-050)

[0275] 1M HEPES (pH 7.3) (Invitrogen 15630-080)

[0276] 100× sodium pyruvate (Invitrogen 11360-070)

[0277] Penicillin and streptomycin (Invitrogen 15640)

[0278] Trypsin 0.25% EDTA (Invitrogen 25200056)

[0279] Calcium / magnesium-free DPBS (Invitrogen) 14190-136)

[0280] Anhydrous DMSO (Sigma D2650)

[0281] DAMGO OPRM1 agonist MW513.19 (Sigma E7384-5MG)

[0282] β-Funaltrexamine hydrochloride OPRM1 antagonist MW (SIGMA O003-2MG)

[0283] PathHunter cell plate seeding reagent 5 (Discover X 93-0563R5A)

[0284] Corning 3750 standard 384-well white plate with cap.

[0285] PathHunter assay mixture (Discover X 93-0001): 1 part Galacton Star / 5 parts Emerald II / 19 parts PH Cell Assay Buffer.

[0286] OPRDelta 1 Tango B-inhibitory protein assay protocol-antagonist mode. Tango OPRDelta1-U20S dividing cell lines were cultured in 150 mm culture dishes at 37°C, 5% CO2, and 95% relative humidity (RH). The growth medium consisted of McCoys 5A medium supplemented with 10% (v / v) dialyzable fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin-streptomycin).

[0287] On day 1 of the assay, 10 μL of assay medium (DMEM-Glutamax—containing sodium pyruvate, 10% CDS-depleted fetal bovine serum, 25 mM HEPES, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1× antibiotic mixture (penicillin-streptomycin)) was inoculated into each well of a 384 Greiner 788092 black low-profile, clear-bottom, low-volume plate.16,000 cells were in a mixture of mM non-essential amino acids and antibiotics (penicillin and streptomycin). 50 nL of the test compound in DMSO was added to the appropriate wells, and the plate was then incubated at 37°C, 5% CO2, and 95% RH for 30 min. Next, 1.1 μL of SNC80 OPRD1 agonist (commercially available) or DMSO (EC80 activation consists of 1.1 μL of 3.7 μM SNC80, final assay concentration = 370 nM) in assay medium was added to the appropriate wells, and the plate was incubated at 37°C, 5% CO2, and 95% RH for 16 to 24 h.

[0288] On day 2, 2.5 μL of LiveBLAzer™ FRET B / G (CCF4-AM) mixture (solutions A, B, C, and D) was added to each well, and the plate was then incubated at room temperature in the dark for 2 h. The fluorescence of the wells was measured using emission filters with excitation filters of 405 nm, 460 nm, and 590 nm on the Perkin Elmer Envision with bottom readout.

[0289] The inhibition percentage was calculated from the median ratio as follows: Specification 42 / 53 pages 56 CN 121866250 A

[0290] Wherein:

[0291] The test compound is defined as the well containing the test compound;

[0292] The low control is defined as the well containing SNC80 excitation (370 nM final) = 0% inhibition; and

[0293] The high control is defined as the well containing DMSO = 100% inhibition.

[0294] Reagent List:

[0295] Tango™ OPRD1-bla U20S (Invitrogen K1778)

[0296] McCoy 5A medium (Invitrogen 16600-082)

[0297] Dialyzed fetal bovine serum (Invitrogen 26400-036)

[0298] Non-essential amino acids 100× (Invitrogen 11140-050)

[0299] HEPES (pH 7.3) 1M (Invitrogen 15630-080)

[0300] Sodium pyruvate 100× (Invitrogen 11360-070)

[0301] Penicillin and streptomycin (Invitrogen 15640)

[0302] Trypsin 0.25% EDTA (Invitrogen) 25200056)

[0303] Calcium / magnesium-free DPBS (Invitrogen 14190-136)

[0304] DMEM, high glucose, GlutaMAX (Invitrogen 10569-010)

[0305] Fetal bovine serum, deprived by activated charcoal (Invitrogen 12676-011)

[0306] Anhydrous DMSO (Sigma D2650)

[0307] SNC80 OPRD1 agonist MW449.63 (Sigma S2812)

[0308] SDM25N hydrochloride OPRD1 antagonist MW468.98 (Tocris 1410)

[0309] LiveBLAzer™-FRET / BG spiking mixture: (Invitrogen K1030 (5 mg)), consisting of solutions A, B, C and D:

[0310] Solution A (6 μL): LiveBLAzer™-FRET / BG substrate (CCF4-AM)

[0311] Solution B (60 μL)

[0312] Solution C (904 μL)

[0313] Solution C (250 μL of 1 N must be added before use) Solution C) was added to 45 mL with NaOH.

[0314] Solution D (30 μL) [Probinicid] (Sigma P8161) was used to prepare a 200 mM stock solution in NaOH-H2O.

[0315] Biological Examples

[0316] The results of the determination are provided in Table 2 below. The activity of representative compounds is expressed as IC50 against κ opioid receptor (KOR) and μ opioid receptor (MOR). Table 2 also shows the selectivity of representative compounds against KOR.

[0317] Table 2. Activity Specifications of Representative Compounds 43 / 53 Pages 57 CN 121866250 A

[0318] Specifications 44 / 53 Pages 58 CN 121866250 A Specifications 45 / 53 Pages 59 CN 121866250 A Specifications 46 / 53 Pages 60 CN 121866250 A Specifications 47 / 53 Pages 61 CN 121866250 A Specifications 48 / 53 Pages 62 CN 121866250 A Specifications 49 / 53 Pages 63 CN 121866250 A Specifications 50 / 53 Pages 64 CN 121866250 A Specifications 51 / 53 Pages 65 CN 121866250 A Specifications 52 / 53 Pages 66 CN 121866250 A Specifications 53 / 53 Page 67 CN 121866250 A

Claims

1. Compounds of formula (I) or their pharmaceutically acceptable salts: Ar is (R) 3 ) n Substituted 5- or 6-membered heteroaryl groups (where 1 to 4 heteroaryl members are independently selected from N, O and S); n is 0, 1, or 2; Y is -N(R) 2 )-、-N(R 2 )C(=N-CN)NR 9 -or-N(R) 2 )C(O)-; R 1 and R 1a Independently selected from H, C1-C6 alkyl groups, and halogens; Optional, R 1 or R 1a Together with Y and the carbon atoms they are bonded to, they form fused 5- to 6-membered heterocyclic alkyl groups (where 1 to 4 ring members are independently selected from N, O, and S). Alternatively, R 1 and R 1a Together with the carbon atoms they are bonded to, they form fused C3-C8 cycloalkyl or 5- to 6-membered heterocycloalkyl groups (where 1 to 4 ring members are independently selected from N, O and S); R 2 and R 2a The C3-C8 cycloalkyl group independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl group optionally fused with a 3- to 6-membered heterocyclic alkyl group (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)C3-C8 cycloalkyl, 3- to 6-membered heterocyclic alkyl group (where 1 to 4 ring members are independently selected from N, O and S) and -(C1-C6 alkyl)(3- to 6-membered heterocyclic alkyl group (where 1 to 4 ring members are independently selected from N, O and S)); R 3 In each case, it is independently a C1-C6 alkyl or a C1-C6 haloalkyl; R 4 R 5 R 6 R 7 and R 8 Independently selected from H, CN, OH, halogen, NRR', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), -C(O)(C6-C 10 Aryl), -SO2(C1-C6 alkyl), -(C1-C6 alkyl)C(O)O(C1-C6 alkyl), -(C1-C6 alkyl)N(RR'), -CONRR', -COOR', -NRCOOR', -(C1-C6 alkyl)C(O)N(RR'), C6-C 10 Aryl, C3-C8 cycloalkyl, O(C3-C8 cycloalkyl), -(C1-C6 alkyl)(C6-C 10 Aryl), -(C1-C6 alkyl)(C3-C8 cycloalkyl), 3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S), -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)), 5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S), -(C1-C6 alkyl)(5 to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O and S)); R 9 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and -(C1-C6 alkyl)(C3-C8 cycloalkyl); R and R' are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; R 1 R 1a R 2 R 2a R 3 R 4 R 5 R 6 R 7 R 8 R 9 Any alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group in R and R' may optionally be substituted by 1 to 6 substituents independently selected from C1-C6 alkyl, halogen, NO2, OH, CN, and C1-C6 haloalkyl groups; And the compound mentioned therein is not: 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a 5-membered heteroaryl group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl, imidazole, ... azole group, iso azole group, diazole group, iso Diazole, thiazolyl, isothiazolyl, and thiadiazole.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazolyl and Diazole group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ar is... Diazole group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is -N(R) 2 )-.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 2 It's H.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2a It is optionally substituted -(C1-C6 alkyl)C3-C8 cycloalkyl or -(C1-C6 alkyl) (3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)).

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2a It is optionally substituted -(C1-C6 alkyl)(3 to 6-membered heterocyclic alkyl (where 1 to 4 ring members are independently selected from N, O and S)).

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2a Selected from those that are arbitrarily replaced: and .

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 2a yes or .

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 2a It is replaced by 1 to 3 halogens.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein n is 0.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein n is 1.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 1 and R 1a One of them is H and the other is a halogen.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 1 and R 1a One of them is H and the other is F.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 1 and R 1a Each of them is H.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 1 or R 1a Together with Y and the carbon atoms they bind to, they form fused 5- to 6-membered heterocyclic alkyl groups.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and 18, wherein R 1 or R 1a Together with Y and the carbon atoms they bind to, they form fused 5-membered heterocyclic alkyl groups.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the fused 5-membered heterocyclic alkyl group has the following formula: 。 21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 4 Selected from H, CN, halogens and C1-C6 alkyl groups.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 4 It is a C1-C6 alkyl group.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein R 5 and R 7 It is independently selected from H, halogens and CN.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein R 5 and R 7 At least one of them is H.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R 5 and R 7 Each of them is H.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R 6 It is selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl and C3-C8 cycloalkyl.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein R 6 It is a C1-C6 alkyl group.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O and S) and -CONRR'.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein R 8 It is a halogen or a 5 to 10-membered heteroaryl group (of which 1 to 4 heteroaryl members are independently selected from N, O and S).

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein R 8 It is F.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ar is a pyrazole group or Diazole group; n is 0 or 1; Y is NH; R 1 and R 1a Each of them is H; R 2a It is an optionally substituted 3- to 6-membered heterocyclic alkyl group (where one ring member is O); R 4 Selected from H, CN, halogens, and C1-C6 alkyl groups; R 5 and R 7 Independently selected from H, halogens, and CN, wherein R 5 and R 7 At least one of them is H; R 6 Selected from halogens, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C8 cycloalkyl; and R 8 Selected from H, CN, halogens, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 5 to 10 heteroaryl (of which 1 to 4 heteroaryl members are independently selected from N, O and S) and -CONRR'.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following table: 。 33. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, and a pharmaceutically acceptable carrier.

34. A method for treating a disorder in a subject suffering from a disorder, wherein the disorder is a disorder that is therapeutically applicable to κ-opioid receptor (KOR) antagonism, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32.

35. A method for treating a disorder in a subject suffering from the disorder, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein the disorder is selected from substance abuse or addiction, mental disorders, obesity and eating disorders, migraines, postpartum depression, neurodegenerative diseases or disorders, epilepsy, status epilepticus, seizures, and sleep disruption associated with the drug treatment of pain, mental disorders, or mental disorders.

36. The method of claim 35, wherein the obstacle is substance abuse or addiction.

37. The method of claim 36, wherein substance abuse or addiction is selected from gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, and substance-induced depression or mood disorder.

38. The method of claim 35, wherein the disorder is a mental disorder.

39. The method of claim 38, wherein the mental disorder is selected from anxiety disorders, depressive disorders, mood disorders, schizophrenia spectrum disorders, stress-related disorders, obsessive-compulsive disorders, social phobia, generalized anxiety disorder (GAD), social anxiety disorder, post-traumatic stress disorder (PTSD), personality disorders, and autism spectrum disorders (ASD).

40. The method of claim 35, wherein the condition is sleep disruption related to pain, mental disorder, or drug treatment for mental disorder.

41. The method of claim 35 or 40, wherein the pain is chronic pain or neuropathic pain.

42. The method according to any one of claims 35, 40 and 41, wherein the sleep is REM sleep.

43. The method according to any one of claims 35 and 40 to 42, wherein the sleep interruption is a sleep disorder, sleep deprivation, or a combination thereof.