3-(4-(11H-dibenzo[b,e][1,4]azepin-6-yl)piperazin-1-yl)-propanoic acid derivatives and 3-(4-(dibenzo[b,f][1,4]oxazepine / thiazepine / diazepine-11-yl)piperazin-1-yl)-propanoic acid derivatives as H1 and 5-HT2A receptor modulators for the treatment of sleep disorders

Abstract

The present disclosure relates to 3-(4-(11H-dibenzo[b,e][1,4]azepin-6-yl)piperazin-1-yl)-propanoic acid derivatives, 3-(4-(dibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)-propanoic acid derivatives, 3-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-propanoic acid derivatives, and 3-(4-(dibenzo[b,f][1,4]diazepin-11-yl)piperazin-1-yl)-propanoic acid derivatives of formula (I), (III), and (II), where X is CR7R8, O, S, or NR7, as well as pharmaceutically acceptable salts thereof, pharmaceutical compositions, methods for their preparation, and to compounds for use in methods of medical treatment. The compounds disclosed herein are useful for modulating H1 and 5-HT2A receptors and are used to treat sleep disorders, such as sleep fragmentation, disturbed sleep / wake, and arousal threshold. This specification discloses the synthesis and characterization of exemplary compounds and their pharmacological data (e.g., pages 143-224; Examples 1-33; Compounds 1-39; Tables A-R). An exemplary compound is, for example, 3-(4-(7-chloro-3-methyldibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid (Example 1, Compound 1). TIFF2023501000000256.tif70128

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Patent Application No. 62 / 923,762, filed on October 21, 2019, and U.S. Patent Application No. 63 / 002,096, filed on March 30, 2020, the entire contents of each of which are hereby incorporated by reference.

[0002] Field of Disclosure The present disclosure relates to piperazine-substituted azepine derivatives, prodrugs thereof, and pharmaceutically acceptable salts, which can have dual-action H1 inverse agonist and 5-HT 2A antagonist (H1 / 5-HT 2A ) activity and are thus useful in methods of treating the human or animal body. The present disclosure also relates to processes for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of sleep disorders such as sleep fragmentation, disrupted sleep / wakefulness, and arousal thresholds.

Background Art

[0003] Background Epoch-making progress in the field of sleep disorder research has broadened the scientific and general understanding of the health benefits of peaceful and restorative sleep. Sleep is now recognized as one of the three pillars of good health, along with diet and exercise. The overall prevalence of current or past sleep disorders in adults is estimated to be 52.4% of the population. Almost two-thirds of the population (i.e., 64%) report having trouble sleeping at least a few times a week (National Sleep Foundation, "2012 Sleep in America" Poll, 2012 (Non-Patent Document 1)). In the International Classification of Sleep Disorders, more than 80 different disorders are distinguished, each of which can have a significant impact on health and the economy. Daytime dysfunction due to sleep deprivation has long been recognized, but sleep deprivation also has a cascading negative impact on a wide range of co-existing health conditions, including attention, cognition, learning and memory, alertness, performance, and acute and chronic pain and pain disorders, mental state, neurodegenerative diseases, developmental disorders, metabolic diseases and diabetes, obesity, cardiovascular diseases, immune disorders, and many other medical conditions.

[0004] Sleep disorder subjects are now readily classified into a broader category and spectrum of sleep disorders that are expected to benefit from new and tailored treatments that result in better outcomes. Objective measurement of sleep can play an important role in understanding sleep deprivation and its improvement. Subjects whose sleep is frequently interrupted or "fragmented," despite getting 7 - 8 hours or more of sleep, suffer from all the effects of sleep fragmentation. In fact, sleep consolidation is necessary to achieve the restorative physiological effects of sleep and for co-existing diseases.

[0005] Pharmacological options for treating sleep fragmentation are limited. There is an urgent and as yet unaddressed clinical need to develop new treatment methods for treating sleep fragmentation, including pharmacological treatment methods, to address this lack of pharmacological options.

Prior Art Documents

Non-Patent Documents

[0006] [Non-Patent Document 1] National Sleep Foundation, "2012 Sleep in America" Poll, 2012 [Summary of the Invention]

[0007] Summary In one aspect, the present disclosure provides, inter alia, a compound of formula (I), (II), or (II'): TIFF0007696354000001.tif89128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0008] In one aspect, the present disclosure provides a compound obtainable by or obtained by a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-3).

[0009] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0010] In one aspect, the present disclosure provides an intermediate as described herein (e.g., the intermediate is selected from the intermediates described in the synthesis of Examples 1-24) suitable for use in a method for preparing a compound as described herein.

[0011] In one aspect, the present disclosure provides a method for modulating H1 / 5-HT 2A activity (e.g., in vitro or in vivo) comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need thereof by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure to the subject.

[0012] In one aspect, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0013] In one aspect, the present disclosure relates to H1 / 5-HT 2A The present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating H1 / 5-HT activity (e.g., in vitro or in vivo). In one aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0014] In one aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0015] In one aspect, the present disclosure relates to H1 / 5-HT 2A The present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating H1 / 5-HT activity (e.g., in vitro or in vivo).

[0016] In one aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0017] In one aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0018] In one aspect, the disease or disorder to be treated is a sleep disorder.

[0019] In some embodiments, a sleep disorder is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold.

[0020] In some embodiments, a sleep disorder is caused by or coexists with a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0021] In some embodiments, a sleep disorder is caused by a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0022] In some embodiments, a sleep disorder coexists with a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0023] In one aspect, the present disclosure provides a method for preparing a compound of the present disclosure.

[0024] In one aspect, the present disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. The references cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. If there is a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0026] [The present invention 1001] A compound of formula (I), TIFF0007696354000002.tif43128 wherein, R 1 is C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; R 2 is C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; or R 1 and R 2 together with the atom to which they are attached form a C 3 ~C 6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R 3 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 4 is H, halogen, -S(C 1~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 7 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; R 8 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; and R 9 is H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, or C 3 ~C 6 cycloalkyl, provided that at least one of R 3 、R 4 、R 5 and R 6 is H, said compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [The present invention 1002] A compound of formula (II), TIFF0007696354000003.tif35128 wherein, X is CR 7 R 8 , O, S, or NR 7 ; R 1 is C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; R 2 is C 1 ~C 6 alkyl, C 2 ~C 6alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; or R 1 and R 2 together with the atoms to which they are attached form a C 3 ~C 6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R 3 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 4 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2, -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 7 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; R 8 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; and R 9 is H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, or C 3~C 6 cycloalkyl, provided that however, (a) when R 5 is H, X is CR 7 R 8 or S; (b) when R 5 is halogen and R 4 is H, R 3 is not methyl, not methoxyl, and not Br, and X is CR 7 R 8 or S; and (c) when R 5 is methoxyl or methyl, R 4 is not H, the compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. [Invention 1003] A compound of formula (II'), wherein TIFF0007696354000004.tif43128 in the formula, X is CR 7 R 8 , O, S, or NR 7 ; R 1 is C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; R 2 is C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, or C 3 ~C 6 cycloalkyl; or R 1 and R 2 together with the atoms to which they are attached form a C 3 ~C 6 forms a saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R 3is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 4 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C6 cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 7 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; R 8 is H, deuterium, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, or C 2 ~C 6 alkynyl; R 9 is H, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, or C 3 ~C 6 cycloalkyl; and R 10 is H or halogen, provided that however, (a)(i) when R 5 is H, X is CR 7 R 8 or S, or (ii) when R 5 is H and X is O, R 10 is halogen; (b) when R5 is halogen and R 4 is H, R 3 is not methyl, methoxyl, or Br, and X is CR 7 R 8 or S; and (c) when R 5 is methoxyl or methyl, R 4 is not H, the compound, or its prodrug, solvate, or pharmaceutically acceptable salt. [Invention 1004] A compound of Invention 1002, wherein X is O or CR 7 R 8 . [Invention 1005] R 1 Any compound of the present invention, wherein 1 ~C 6 is C [Invention 1006] R 2 Any compound of the present invention, wherein 1 ~C 6 is C [Invention 1007] R 1 and R 2 , together with the atoms to which they are attached, form C 3 ~C 6 Any compound of the present invention that forms a saturated or partially unsaturated cycloalkyl or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S. [Invention 1008] R 3 wherein R 1 ~C 6 is H, halogen, C 1 ~C 6 alkyl, or C [Invention 1009] R 4 wherein R 1 ~C 6 is H, halogen, C 1 ~C 6 alkyl, or C [Invention 1010] R 5 wherein R 1 ~C 6 is H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, S(C 1 ~C 6 alkyl), or C [Invention 1011] R 6wherein R 1 ~C 6 is H, C 1 ~C 6 alkyl, or C [Invention 1012] R 7 wherein R is H. R 8 [Invention 1013] wherein R R 9 is H. [Invention 1014] R 10 wherein R is F. A compound of formula (Ia) or (Ib) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000005.tif43128 wherein R 3 、R 4 、R 5 , and R 6 are as described herein. [Invention 1017] A compound of formula (IIa), (IIa-1), or (IIa-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000006.tif35143 wherein X, R 1 、R 2 、R 4 、R 5 , and R 9 are as described herein. [Invention 1018] A compound of formula (IIb), (IIb-1), or (IIb-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000007.tif35155 wherein X, R 1 、R 2 、R 3 、R 5 , and R 9 are as described herein. [Invention 1019] A compound of formula (IIc), (IIc-1), or (IIc-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000008.tif32157 wherein X, R 1 、R 2 、R 3、R 6 , and R 9 are as described herein. [Invention 1020] A compound of formula (II'a) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000009.tif39128 wherein X, R 1 、R 2 、R 9 , and R 10 are as described herein. [Invention 1021] A compound according to any one of the present invention 1001 to 1020, selected from compound numbers 1 to 39, their prodrugs, and pharmaceutically acceptable salts. [The present invention 1022] Obtainable or obtained by the method described herein, Optionally, the method includes one or more steps described in Schemes 1 to 3, Compound. [The present invention 1023] A pharmaceutical composition comprising a compound according to any one of the present invention 1001 to 1022 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [The present invention 1024] The pharmaceutical composition of the present invention 1023, wherein the compound is selected from compound numbers 1 to 36. [The present invention 1025] A method for alleviating symptoms of sleep disorder, treating sleep disorder, or preventing sleep disorder in a subject by administering to the subject in need thereof a compound according to any one of the present invention 1001 to 1022 or a pharmaceutical composition of the present invention 1023 or 1024. [The present invention 1026] A compound according to any one of the present invention 1001 to 1022 or a pharmaceutical composition of the present invention 1023 or 1024 for use in alleviating symptoms of sleep disorder, treating sleep disorder, or preventing sleep disorder. [The present invention 1027] Use of a compound according to any one of the present invention 1001 to 1022 or a pharmaceutical composition of the present invention 1023 or 1024 in the manufacture of a medicament for alleviating symptoms of sleep disorder, treating sleep disorder, or preventing sleep disorder. [The present invention 1028] Use of a compound according to any one of the present invention 1001 to 1022 or a pharmaceutical composition of the present invention 1023 or 1024 for alleviating symptoms of sleep disorder, treating sleep disorder, or preventing sleep disorder. [The present invention 1029] Any method, compound, pharmaceutical composition, or use according to the present invention 1025 to 1028, wherein the sleep disorder is an increase in sleep fragmentation. [The present invention 1030] The compound is H1 / 5-HT 2A A receptor modulator, any method, compound, pharmaceutical composition, or use according to the present invention 1025 to 1028. [The present invention 1031] The method, compound, pharmaceutical composition, or use according to any one of 1025 - 1028 of the present invention, wherein the sleep disorder is caused by or coexists with sleep apnea, restless legs syndrome, high respiratory disturbance index (RDI), neurological disorders, circadian rhythm disorders, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related fragmented sleep, postmenopausal sleep disorder, drug abuse, drug withdrawal symptoms, narcolepsy, mental disorders, increased sensitivity to pain, cardiovascular diseases, hypertension, non-restorative sleep, stroke, metabolic disorders, or cognitive disorders. [The present invention 1032] The method, compound, pharmaceutical composition, or use according to the present invention 1031, wherein the sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an increase in respiratory effort-related arousals (RERA), regardless of whether apnea, hypopnea, or acute hemoglobin desaturation is associated. [The present invention 1033] The method, compound, pharmaceutical composition, or use according to any one of 1025 - 1032 of the present invention, wherein the compound is administered in combination with an additional active agent. [The present invention 1034] The method, compound, pharmaceutical composition, or use according to any one of 1025 - 1033 of the present invention, wherein the compound, and any additional active agent if present, are administered either before sleep (hora somni), i.e., h.s. (at bedtime), or about 0 - 4 hours before bedtime. Other features and advantages of the disclosure will become apparent from the following detailed description and claims.

Brief Description of the Drawings

[0027] [Figure 1] Shows the average hourly aligned sleep episodes after administration of Compound 8. The thin line indicates administration of Compound 8 at 10 mg / kg PO (CT-18, n = 9), and the thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-18, n = 10). [Figure 2] Shows the number of transitions to wakefulness per hour after administration of Compound 8. The thin line indicates administration of Compound 8 at 10 mg / kg PO (CT-5, n = 11), and the thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-5, n = 11). [Figure 3] Shows the normalized EEG delta power after administration of Compound 8. The thin line indicates administration of Compound 8 at 3 mg / kg PO (CT-18, n = 10), and the thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-18, n = 10). [Figure 4] The cumulative hourly total sleep time (non-REM + REM sleep) after administration of Compound 8 was measured from the time of administration (0 hour on the horizontal axis) compared to the quiet baseline 24 hours before treatment. The thin line indicates administration of Compound 8 at 30 mg / kg PO (CT-18, n = 12). The thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-18, n = 15). The dotted line indicates an increase in total sleep time of approximately 70 minutes. [Figure 5] Shows the average hourly aligned sleep episodes after administration of Compound 7. The thin line indicates administration of Compound 7 at 30 mg / kg PO (CT-18, n = 10), and the thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-18, n = 10). [Figure 6]Shows the number of transitions to wakefulness per hour after administration of Compound 7. The thin line indicates administration of Compound 7 at 30 mg / kg PO (CT-5, n = 8), and the thick line indicates administration of control 2HPβCD 20% at 2 mL / kg PO (CT-5, n = 10). [Figure 7] Shows the normalized EEG delta power after administration of Compound 7. The thin line indicates administration of Compound 7 at 30 mg / kg PO (CT-18, n = 10), and the thick line indicates administration of control methylcellulose at 1 mL / kg PO (CT-18, n = 10). [Figure 8] Shows the average hourly consolidated sleep episodes after administration of Compound 15. The thin line indicates administration of Compound 15 at 30 mg / kg PO (CT-18, n = 11), and the thick line indicates administration of control 20% 2HPβCD at 2 mL / kg PO (CT-18, n = 11). [Figure 9] Shows the number of transitions to wakefulness per hour after administration of Compound 15. The thin line indicates administration of Compound 15 at 30 mg / kg PO (CT-5, n = 10), and the thick line indicates administration of control 20% 2HPβCD at 2 mL / kg PO (CT-5, n = 20). [Figure 10] Shows the normalized EEG delta power after administration of Compound 15. The thin line indicates administration of Compound 15 at 30 mg / kg PO (CT-18, n = 11), and the thick line indicates administration of control 20% 2HPβCD at 2 mL / kg PO (CT-18, n = 11).

Mode for Carrying Out the Invention

[0028] Detailed Description The compounds described herein are generally designed to modulate the H1 / 5-HT 2A function, and thus act as H1 / 5-HT 2A receptor antagonists for the treatment and prevention of sleep disorders in a subject. As used herein, modulation refers to dual-action H1 inverse agonist and 5-HT 2A antagonist activity.

[0029] The compounds described herein, in certain embodiments, act as dual - acting H1 inverse agonists and 5 - HT 2A antagonists to provide, for example, H1 / 5 - HT 2A receptors in either a positive or negative manner.

[0030] The 5 - HT2 receptor is a subclass of the serotonin receptor, a group of G - protein - coupled receptors and ligand - gated ion channels. 5 - HT 2A receptors found in the central nervous system mediate excitatory neurotransmission. 5 - HT 2A antagonists block excitatory neurotransmission. Without wishing to be bound by theory, blocking excitatory neurotransmission may be associated with promoting better sleep (e.g., treating sleep disorders). The H1 receptor, which is a G - protein - coupled receptor, is known to induce wakefulness upon receptor activation. Without wishing to be bound by theory, H1 inverse agonists may induce drowsiness (e.g., treat sleep disorders).

[0031] The present disclosure is directed to compounds that are particularly well - suited for treating sleep disorders characterized in whole or in part by fragmentation of sleep.

[0032] Accordingly, the compounds and pharmaceutical compositions provided herein are useful as therapeutic agents for preventing or treating sleep disorders in subjects such as mammals, including humans and non - human mammals. The compounds and pharmaceutical compositions provided herein are useful as therapeutic agents for treating sleep disorders in subjects such as mammals, including humans and non - human mammals. The present disclosure includes within its scope and extends to the described therapeutic methods, and compounds for such methods, and the use of such compounds for the preparation of medicaments useful for such methods.

[0033] The present disclosure relates to compounds useful for the modulation of H1 / 5 - HT 2A In particular, existing H1 / 5 - HT 2ACompounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to the modulating compounds are desired.

[0034] In some embodiments, the disclosure includes the step of contacting a cell with an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity). In some embodiments, the disclosure provides a method of modulating a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure to a subject in need thereof to alleviate the symptoms of a disease or disorder disclosed herein, treat the disease or disorder, or prevent the disease or disorder.

[0035] Definitions Unless otherwise specified, the following terms used in this specification and claims have the following meanings as set forth below.

[0036] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight (linear) saturated aliphatic hydrocarbon groups and C2, C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include moieties having from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, the straight or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chains and C3-C6 for branched chains), and in another embodiment, the straight or branched alkyl has 4 or fewer carbon atoms.

[0037] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having one or more designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may contain an aromatic or heteroaromatic moiety.

[0038] As used herein, the term "alkenyl" includes unsaturated aliphatic groups having a length similar to and optionally substituted as described above for alkyl, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, the straight-chain or branched alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain and C3-C6 for branched-chain). The term "C2-C6" includes alkenyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3-6 carbon atoms.

[0039] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having one or more designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or may include an aromatic or heteroaromatic moiety.

[0040] As used herein, the term "alkynyl" includes an unsaturated aliphatic group having a similar length and may be substituted with the alkyl described above, and containing at least one triple bond. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, the linear or branched alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for linear and C3-C6 for branched). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.

[0041] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl having one or more specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may contain an aromatic or heteroaromatic moiety.

[0042] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc.) include both unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups such as 2,2,6,6 - tetramethyl - piperidinyl and 2,2,6,6 - tetramethyl - 1,2,3,6 - tetrahydropyridinyl.

[0043] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3 - C 12 、C3 - C 10refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro ring) system having 3 to 8 carbon atoms (e.g., C3~C8). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl, without limitation. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0044] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic 3- to 8-membered ring, 7- to 12-membered bicyclic (fused, bridged, or spiro ring), or 11- to 14-membered tricyclic system (fused, bridged, or spiro ring) having one or more heteroatoms (such as O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms, unless otherwise specified.Examples of heterocycloalkyl groups include, without limitation, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridine]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of polycyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0045] As used herein, the term "aryl" includes groups having aromaticity including "conjugation" or polycyclic systems having one or more aromatic rings, and contains no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. For simplicity, aryl is phenyl.

[0046] As used herein, the term "heteroaryl" includes a stable 5-membered, 6-membered, or 7-membered monocyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic aromatic heterocyclic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may be oxidized (i.e., N→O and S(O) p , where p = 1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. The heteroaryl group may also be condensed or bridged with an alicyclic or heterocyclic ring that is not aromatic to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0047] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic, e.g., tricyclic, bicyclic aryl and heteroaryl groups, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0048] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., ring-forming carbon or heteroatom, e.g., N) with substituents such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may be substituted with an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups may also be fused or bridged to an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., methylenedioxyphenyl such as tetralin, benzo[d][1,3]dioxol-5-yl).

[0049] As used herein, the term "substituted" means that any one or more of the hydrogen atoms on a designated atom are replaced with those selected from the indicated groups, provided that the normal valence of the designated atom is not exceeded and the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. The keto substituent is not present in the aromatic moiety. The ring double bond used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). "Stable compound" and "stable structure" mean compounds that are robust enough to withstand isolation from the reaction mixture to useful purity and formulation into effective therapeutic agents.

[0050] When the bond to a substituent is shown to cross a bond connecting two atoms within the ring, such a substituent may be attached to any atom within the ring. When a substituent is described without indicating the atom to which such a substituent is attached to the remainder of the compound of a given formula, such a substituent may be attached via any atom in such a formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0051] When any component of a compound or any variable (e.g., R) in a formula appears more than once, its definition at each occurrence is independent of its definition at other occurrences. Thus, for example, if a group is shown to be substituted with from 0 to 2 R moieties, the group may be substituted with up to 2 R moieties, and each occurrence of R is independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0052] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - thereof.

[0053] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo and iodo.

[0054] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having a designated substituent that replaces one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents are, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may contain an aromatic or heteroaromatic moiety.

[0055] As used herein, expressions such as "one or more of A, B, or C", "one or more of A, B, or C", "one or more of A, B, and C", "one or more of A, B, and C", "selected from the group consisting of A, B, and C", "selected from A, B, and C", etc. are used interchangeably, unless otherwise indicated, and all refer to those selected from the group consisting of A, B, and / or C, i.e., one or more of A, one or more of B, one or more of C, or any combination thereof.

[0056] It should be understood that the present disclosure provides methods for the synthesis of any of the compounds of the formulas described herein. The present disclosure also provides the synthesis of various disclosed compounds according to the following schemes, as well as detailed methods for the synthesis of those shown in the examples.

[0057] Throughout the specification, when a composition is described as having, including, or comprising certain components, it should be understood that the composition is also contemplated to consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of or consists of the recited process steps. Also, it should be understood that the order of the steps or the order for performing certain acts is not critical as long as the invention is practicable. Further, two or more steps or acts may be carried out simultaneously.

[0058] It should be understood that since the disclosed synthetic processes are tolerant of a variety of functional groups, various substituted starting materials can be used. The process generally provides the desired final compound at or near the end of the overall process, although in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0059] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, intermediates known in the literature or readily prepared, by employing standard synthetic methods and procedures known to those skilled in the art or that will become apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for the conversion and manipulation of functional groups can be obtained from the relevant scientific literature or standard textbooks in the art. Without limitation to any one or more sources, the classic textbooks such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and recognized references for organic synthesis known to those skilled in the art.

[0060] One of ordinary skill in the art will recognize that, in the reaction sequences and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may be changed. One of ordinary skill in the art will recognize that certain groups may need to be protected from reaction conditions via the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups within a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0061] Unless otherwise specified, any description of a method of treatment is to be understood to include the use of a compound for providing a treatment or prophylaxis as described herein, and the use of a compound for the preparation of a medicament for treating or preventing such a condition. Unless otherwise specified, any description of a method of treatment is to be understood to include the use of a compound for providing a treatment or prophylaxis as described herein, and the use of a compound for the preparation of a medicament for treating such a condition. Treatment includes the treatment of humans or non-human animals, including murine and other disease models.

[0062] As used herein, the term "subject" is interchangeable with the term "subject in need thereof", and both refer to a subject having a disease or disorder or being at high risk of developing a disease or disorder. In some embodiments, the subject has a sleep disorder or is at high risk of developing a sleep disorder. "Subjects" include mammals. Mammals can be, for example, humans, or suitable non-human mammals such as primates, mice, rats, dogs, cats, cows, horses, goats, camels, sheep or pigs. The subject can also be a bird or poultry. In one embodiment, the mammal is a human. The subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. The subject in need thereof can also be a subject affected by a disease or disorder disclosed herein. Alternatively, the subject in need thereof can be a subject at high risk of developing such a disease or disorder (i.e., a subject having a predisposition to develop such a disorder as compared to the population as a whole). The subject in need thereof can have a refractory or resistant disease or disorder (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, the subject in need thereof has received all known effective treatments for the disease or disorder disclosed herein and they have not been successful. In some embodiments, the subject in need thereof has received at least one prior treatment.

[0063] As used herein, the terms "treating" or "treatment" describe the management and care of a subject for the purpose of combating a disease, condition, or disorder, and include the administration of a compound of the disclosure or a pharmaceutically acceptable salt, polymorph, or solvate thereof to reduce the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treatment" can also include in vitro treatment of cells, or animal models.

[0064] References to "treating" or "treatment" are to be understood to include alleviation of established symptoms of a condition. "Treating" or "treatment" of a condition, disorder or state thus includes (1) delaying the onset of clinical symptoms of a condition, disorder or state that may afflict or have a predisposition to afflict a human who has not yet experienced or exhibited clinical or preclinical symptoms of the condition, disorder or state, (2) inhibiting a condition, disorder or state, i.e., preventing, reducing or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one of its clinical or preclinical symptoms, or (3) reducing or attenuating a disease, i.e., causing regression of at least one of the condition, disorder or state or its clinical or preclinical symptoms.

[0065] It should be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can also be used or may be used to prevent a related disease, condition or disorder or to identify suitable candidates for such purposes.

[0066] As used herein, the terms "preventing", "prevention" or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such disease, condition or disorder.

[0067] One of ordinary skill in the art may refer to general references for a detailed description of the known or equivalent techniques discussed herein. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th including the 18th edition (1990). Of course, these documents may be referred to when preparing or using aspects of the disclosure.

[0068] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0069] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be, for example, any of a variety of forms including capsules, IV bags, tablets, a single pump on an aerosol inhaler, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dosage composition is an effective amount and varies depending on the specific treatment involved. One of ordinary skill in the art will recognize that in some cases it may be necessary to make routine modifications to the dosage depending on the age and condition of the subject. The dosage is also expected to vary depending on the route of administration. A variety of routes are contemplated including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal mucosa, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one aspect, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a compound, anion, cation, substance, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and that has a reasonable benefit / risk ratio.

[0071] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and that is useful for preparing a pharmaceutical composition, and includes excipients acceptable for veterinary use and pharmaceutical use in humans. As used in this specification and the claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0072] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate, and agents for adjustment of isotonicity such as sodium chloride or dextrose. The pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be placed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0073] It should be understood that the disclosed compounds or pharmaceutical compositions can be administered to a subject in many well-known ways. As non-limiting examples, the disclosed compounds may be administered orally, as an injection, or applied through the skin using a patch. The selected dosage should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The condition of the medical condition (e.g., the diseases or disorders disclosed herein) and the health of the subject are preferably closely monitored during and for a reasonable period after treatment.

[0074] As used herein, the term "effective amount" refers to the amount of an agent to treat, ameliorate, or prevent an identified disease, disorder, or condition, or to effect a detectable therapeutic or inhibitory effect. The effect can be detected by any of the assays known in the art. The exact effective amount for a subject will vary depending on the subject's weight, size, health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0075] As used herein, the term "therapeutically effective amount" refers to the amount of an agent to treat or ameliorate an identified disease, disorder, or condition, or to effect a detectable therapeutic or inhibitory effect. The effect can be detected by any of the assays known in the art. The exact effective amount for a subject will vary depending on the subject's weight, size, and health; the nature and extent of the symptoms; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. A "therapeutically effective amount" may be administered to a subject to treat a disease or disorder. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.

[0076] It should be understood that for any given compound, the therapeutically effective amount can first be estimated in cell culture assays, e.g., in neonatal cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Appropriate concentration ranges and routes of administration may also be determined using animal models. Such information can then be used to determine useful dosages and routes of administration in humans. The effectiveness and toxicity of treatment / prevention can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (the therapeutically effective dose in 50% of the population) and LD 50It may also be determined by (the dose lethal to 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which can be expressed as the ratio of LD 50 / ED 50 . A pharmaceutical composition showing a large therapeutic index is preferred. The dosage may vary within this range depending on the dosage form employed, the sensitivity of the subject, and the route of administration.

[0077] The dosage and the method of administration are adjusted to provide a sufficient level of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the medical condition of the disease or disorder, the general health of the subject, the age, weight, and gender of the subject, diet, the time and frequency of administration, drug combinations, responsiveness, and tolerance / response to treatment.

[0078] The pharmaceutical compositions containing the active compounds of the present disclosure may be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, tablet coating, pulverizing, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and / or auxiliaries that facilitate the processing of the active compounds into preparations that can be pharmaceutically used. Naturally, the appropriate formulation varies depending on the selected route of administration.

[0079] A pharmaceutical composition suitable for injectable use includes a sterile aqueous solution (when water-soluble), a dispersion, and a sterile powder for the immediate preparation of a sterile injectable solution or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, N.J.), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycols, etc.), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include in the composition isotonic agents such as sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride. An agent that delays absorption, for example, aluminum monostearate and gelatin, can be included in the composition to provide sustained absorption of the injectable composition.

[0080] A sterile injectable solution can be prepared by incorporating the required amount of the active compound into a suitable solvent containing, as required, one or a combination of the ingredients enumerated above, followed by filtration sterilization. Generally, a dispersion is prepared by incorporating the active compound into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of a sterile powder for the preparation of a sterile injectable solution, the method of preparation is vacuum drying and freeze-drying from which a powder of the active ingredient plus any additional desired ingredients is obtained from a previously sterile-filtered solution.

[0081] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. They can be encapsulated in gelatin capsules or tableted. For the purpose of oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, and the compounds in the fluid carrier are applied orally, gargled, and either spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0082] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas like carbon dioxide, or in the form of a nebulizer.

[0083] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, suitable penetration enhancers are used in the formulation for the barrier to be penetrated. Such penetration enhancers are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved through the use of nasal drops or suppositories. For transdermal administration, the active compounds are formulated into an ointment, salve, gel, or cream as generally known in the art.

[0084] The active compounds can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as in a controlled release formulation including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for the preparation of such formulations will be apparent to those skilled in the art. The substances can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions, including liposomes that target infected cells having monoclonal antibodies against viral antigens, can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, as described, for example, in U.S. Pat. No. 4,522,811.

[0085] It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as a single dosage for the subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the disclosed unit dosage forms will vary directly according to the particular properties of the active compound and the particular therapeutic effect to be achieved.

[0086] For therapeutic use, the dosage of the pharmaceutical composition used in accordance with the disclosure will vary depending among other factors affecting the selected dosage, on the agent, the age, weight, and clinical condition of the subject who is the recipient, as well as the experience and judgment of the clinician or practitioner performing the treatment. Generally, the dosage should be sufficient to retard, preferably reverse, and more preferably cause complete regression of the symptoms of the disease or disorder disclosed herein. An effective amount of an agent is an amount that produces an objectively discernible improvement as noted by a clinician or other qualified observer. Improvement in disrupted sleep, sleep fragmentation, arousal, or arousal threshold represents regression. As used herein, the term "in a therapeutically effective manner" refers to the amount of the active compound to produce the desired biological effect in a subject or cell.

[0087] It should be understood that the pharmaceutical composition can be contained in a container, pack, or dispenser together with instructions for administration.

[0088] It should be understood that if the compounds of the present disclosure are further capable of forming salts, any of those forms are contemplated within the scope of the claimed disclosure.

[0089] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts are 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, dicarboxylic acid, carboxylic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic, and those derived from inorganic and organic acids selected from naturally occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc., including but not limited to.

[0090] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonia salt, arginine salt, or lysine salt.

[0091] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also includes salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, the ratio of the compound to the cation or anion of the salt can be understood to be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0092] Any reference to a pharmaceutically acceptable salt is to be understood to include the solvate (solvent addition form) or crystalline form (polymorph) of the salt as defined herein.

[0093] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, by inhalation, intranasally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecal, and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of a particular route of administration.

[0094] For example, salts can be formed between a positively charged group (e.g., amino) on the substituted compounds disclosed herein and anions. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0095] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a negatively charged group (e.g., carboxylate) on the substituted compounds disclosed herein and cations. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those containing a quaternary nitrogen atom.

[0096] It should be understood that the compounds of the present disclosure, e.g., salts of the compounds, can exist in either a hydrated or non-hydrated (anhydrous) form, or as a solvate with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, etc. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0097] As used herein, the term "solvate" means a solvate addition form containing any stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one molecule of a substance, where water retains its molecular state as H2O.

[0098] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but has a slightly different composition (when one atom is replaced by an atom of another element or when a particular functional group is present, or when one functional group is replaced by another functional group). Thus, an analog is a compound whose function and appearance are similar or equivalent, but whose structure or origin is neither similar nor equivalent to the reference compound.

[0099] As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups described herein.

[0100] As used herein, the term "biological equivalent" refers to a compound resulting from the exchange of an atom or atomic group with another broadly similar atom or atomic group. The purpose of replacing with a biological equivalent is to create a new compound having biological properties similar to the parent compound. The replacement with a biological equivalent may be based on physical chemistry or morphology. Examples of carboxylic acid biological equivalents include, without limitation, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0101] As used herein, "2HPβCD" refers to (2-hydroxypropyl)-β-cyclodextrin.

[0102] As used herein, "REM" refers to the REM sleep stage.

[0103] As used herein, "SEM" refers to the standard error of the mean.

[0104] As used herein, "CT" refers to the circadian time.

[0105] As used herein, "sleep continuity" refers to a measure of the length of a sleep episode.

[0106] As used herein, the "depth" of sleep is characterized by EEG slow-wave activity and can promote sleep continuity or sleep consolidation, which are some of the determinants of sleep quality.

[0107] As used herein, "SWA" refers to slow-wave activity and can be exemplified as EEG delta power using Fourier analysis.

[0108] As used herein, the terms "rat" and "laboratory rat" are used interchangeably.

[0109] As used herein, the expression "compounds of the disclosure" refers to the compounds disclosed herein, both generally and specifically.

[0110] An "uninterrupted sleep episode" (average sleep episode duration) is defined herein as the average duration of all episodes of uninterrupted sleep occurring at each time, measured in minutes. An "interruption" is defined as a period of wakefulness of 10 seconds or more in two or more consecutive instances. The value of the length of an episode that extends to a subsequent time is assigned to the time at which it begins. Similar quantification can be performed for episodes of wakefulness. The length of a sleep episode can reflect the tendency of a human to wake regularly throughout the night (such awakenings are usually not remembered), which in turn can be an important factor in determining the restorative value of sleep in humans, and is thus of particular interest. Preclinical measurements of sleep episode duration are also powerful predictors of hypnotic effects in humans.

[0111] The "number of awakenings transitions" (number of transitions from sleep to wakefulness) is the count of the number of times that wakefulness (including any objectively determined stage of wakefulness) followed sleep (including any objectively determined stage of sleep) at each time. In this definition, a 10-second period of wakefulness immediately following sleep corresponds to a transition from sleep to wakefulness. One or more 10-second periods of sleep or one or more consecutive 10-second periods of wakefulness immediately following sleep are also counted as transitions from sleep to wakefulness. A 10-second period in which the proportion of wakefulness is at least 50% (determined by EEG and EMG within that period) can be classified as wakefulness for the entire period. The number of transitions to wakefulness is of interest because it provides a direct measure of the number of times of wakefulness (transitions from sleep to wakefulness) at each time. The number of awakenings is a useful measure of the fragmentation of sleep in animals and humans. Drugs that improve the fragmentation of sleep have been shown to enhance the restorative benefits of sleep.

[0112] "LMA intensity" is defined as the number of LMAs per minute of wakefulness as defined by EEG. This variable allows for the evaluation of LMAs independent of wakefulness time and can thus be used to quantify the specificity of wakefulness or sleep-promoting effects.

[0113] As used herein, "temporal proximity" means that the administration of one therapeutic agent occurs within a period before or after the administration of another therapeutic agent such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of another therapeutic agent. In some embodiments, "temporal proximity" means that the administration of one therapeutic agent occurs within a period before or after the administration of another therapeutic agent such that there is a synergistic effect between the one therapeutic agent and the other therapeutic agent. "Temporal proximity" can vary depending on various factors including, without limitation, the age, sex, weight, genetic background, medical condition, disorder, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease, disorder, or condition being treated or improved; the therapeutic result to be achieved; the dosage, frequency of administration, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be temporally proximate to a single administration of another therapeutic agent. In some embodiments, temporal proximity can be varied during a treatment cycle or dosing regimen.

[0114] Unless otherwise specified, the terms "about" and "approximate" are synonymous. In some embodiments, "about" and "approximate" refer to ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the recited amount, value, dosage, or duration. In another embodiment, "about" and "approximate" refer to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the recited amount or duration. In some embodiments, "about" and "approximate" refer to ±5% of the recited amount, value, dosage, or duration. In some embodiments, "about" and "approximate" refer to ±2% of the recited amount, value, dosage, or duration. In some embodiments, "about" and "approximate" refer to ±1% of the recited amount, value, dosage, or duration.

[0115] It should also be understood that any particular compound of any of the formulas disclosed herein may exist in solvated and unsolvated forms, such as, for example, a hydrated form. Suitable pharmaceutically acceptable solvates are hydrates such as, for example, hemihydrate, monohydrate, dihydrate, or trihydrate. The disclosure encompasses all such solvated forms having H1 / 5-HT 2A regulatory activity.

[0116] It should also be understood that any particular compound of any of the formulas disclosed herein may exhibit polymorphs, and that the disclosure encompasses all such forms or mixtures thereof having H1 / 5-HT 2A regulatory activity. Crystalline materials can generally be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline substances can be determined by Karl Fischer analysis.

[0117] Any one of the compounds of the formulas disclosed herein may exist in a number of different tautomeric forms, and references to the compounds of formulas (I), (II), and (II') include all such forms. To avoid misunderstanding, if a compound happens to exist in one of several tautomeric forms and only one is specifically described or shown, all others are still encompassed by formulas (I), (II), or (II'). Examples of tautomers include, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and forms of keto, enol, and enolate such as nitro / acyinitro. TIFF0007696354000010.tif18128

[0118] Any one of the compounds of the formulas disclosed herein that contain an amine functional group may also form an N-oxide. References herein to the compounds of formulas (I), (II), and (II') that contain an amine functional group include the N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of the nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514), where the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0119] Any one of the compounds of the formulas disclosed herein may be administered in the form of a prodrug that is decomposed in the human or animal body to release the disclosed compound. The prodrug may be used to alter the physical and / or pharmacokinetic properties of the disclosed compound. A prodrug can be formed when the disclosed compound contains a suitable group or substituent to which a group modifying the property can be attached. Examples of prodrugs include derivatives containing an alkyl or acyl substituent cleavable in vivo at an ester or amide group in any one of the formulas disclosed herein.

[0120] As used herein, the term "isomer" means compounds having the same molecular formula but different in the order of bonding of their atoms or the arrangement of those atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of the individual enantiomeric forms with opposite chirality is called a "racemic mixture".

[0121] As used herein, the term "chiral center" refers to an atom (e.g., a carbon atom) bonded to four non-identical substituents.

[0122] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center can exist either as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". When one chiral center is present, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold, and Prelog ranking rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0123] As used herein, the term "geometric isomer" means a diastereomer that exists due to restricted rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same side or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0124] It should be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the names of the compounds do not exclude any isomeric form, and that not all isomers have the same level of activity.

[0125] It is to be understood that the structures and other compounds contemplated in this disclosure include all of their atropisomeric forms. It is also to be understood that all atropisomeric forms do not necessarily have the same level of activity.

[0126] As used herein, the term "atropisomer" is a type of stereoisomer in which the atoms of two isomers are differently arranged in space. Atropisomers owe their existence to restricted rotation caused by hindrance to the rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible in certain cases to separate mixtures of two atropisomers.

[0127] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal shift of a hydrogen atom accompanied by a shift of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers is thought to be reached. The exact ratio of tautomers varies depending on several factors including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of an electron and a hydrogen atom occurs. Ring-chain tautomerism results when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving rise to a cyclic (ring-shaped) form as shown by glucose.

[0128] It should be understood that the compounds of the present disclosure can be depicted as different tautomers. When a compound has tautomeric forms, it is intended that all isomeric forms be included within the scope of the present disclosure, and it should also be understood that the names of the compounds do not exclude any particular tautomeric form. It will be understood that a particular tautomer may have a higher level of activity than others.

[0129] Compounds that have the same molecular formula but differ in the nature or order of bonding of atoms or in the arrangement of atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and those that are mirror images that cannot be superimposed on each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, either by the Cahn and Prelog R and S ranking rules or in the manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., the (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture".

[0130] The compounds of the present disclosure may have one or more asymmetric centers, and such compounds can thus be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise specified, the description or name of a particular compound in the specification and claims is intended to include both the individual enantiomers and mixtures such as racemates. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of the racemic form. Some of the disclosed compounds may have geometric isomer centers (E and Z isomers). The present disclosure is H1 / 5-HT 2A It is to be understood to include all optical, diastereoisomeric and geometric isomers and mixtures thereof having H1 / 5-HT

[0131] Accordingly, the present disclosure includes any one of the compounds of the formulas disclosed herein as defined above when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the present disclosure includes any one of the compounds of the formulas disclosed herein produced by organic synthetic means and also compounds produced in the body of a human or animal by metabolism of a precursor compound, i.e., any one of the compounds of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0132] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein are based on reasonable medical judgment that they are suitable for administration to a subject without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987。

[0133] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having a hydroxyl group is, for example, an ester or ether thereof cleavable in vivo. An ester or ether cleavable in vivo of any one of the compounds of the formulas disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in a subject to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidocyclic esters). Further, suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C 10 alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups, etc., C1-C 10 alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0134] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having a carboxy group is, for example, an amide cleavable in vivo thereof, for example, an amide formed by an amine such as ammonia, a C1-4 alkylamine such as methylamine, a (C1-C4 alkyl)2 amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine, and an amino acid such as glycine or an ester thereof.

[0135] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having an amino group is, for example, an amide derivative cleavable in vivo. Suitable pharmaceutically acceptable amides from an amino group include, for example, amides formed by C1-C 10 alkanoyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0136] The dosing regimen using the compounds is selected according to various factors including the type, species, age, weight, sex and medical condition of the subject; the severity of the condition being treated; the route of administration; the renal and hepatic function of the subject; the specific compound or its salt employed. A typical skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug necessary to prevent, counteract or arrest the progression of the condition. A typical skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug necessary to counteract or arrest the progression of the condition.

[0137] Techniques for the formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In one aspect, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0138] All percentages and ratios used herein are by weight, unless otherwise indicated. Other features and advantages of the disclosure will be apparent from different examples. The examples provided illustrate different components and methodologies useful for practicing the disclosure. The examples do not limit the claimed disclosure. Based on the disclosure, one of ordinary skill in the art can identify and adopt other components and methodologies useful for practicing the disclosure.

[0139] In the synthetic schemes described herein, for simplicity, compounds may be depicted in one particular configuration. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer or stereoisomer, nor excluding mixtures of isomers, tautomers, positional isomers or stereoisomers, but it will be understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer or stereoisomer.

[0140] All publications and patent documents cited herein are incorporated herein by reference as if each such individual publication or document was specifically and individually indicated to be incorporated by reference. The citation of publications and patent documents is not intended to admit that any of them are prior art relevant to the present invention, nor is any admission made as to their content or date. Although the invention has been described in literal terms heretofore, one of ordinary skill in the art will recognize that the invention can be practiced in various ways and that the above description and the following examples are for illustrative purposes and not limitations of the subsequent claims.

[0141] The compounds of the disclosure In some aspects, the disclosure is, inter alia, a compound of formula (I), TIFF0007696354000011.tif43128wherein, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; Is R2 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or Do R1 and R2, together with the atom to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, provided that at least one of R3, R4, R5, and R6 is H. There is provided a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0142] In some aspects, the disclosure provides, inter alia, a compound of formula (II) wherein TIFF0007696354000012.tif35128wherein X is CR7R8, O, S, or NR7; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or R1 and R2 together with the atom to which they are attached form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, provided that however, (a) when R5 is H, X is CR7R8 or S; (b) when R5 is halogen and R4 is H, R3 is not methyl, not methoxyl, and not Br, and X is CR7R8 or S; and (c) when R5 is methoxyl or methyl, R4 is not H, There is provided a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0143] In some aspects, the disclosure relates, inter alia, to a compound of formula (II') wherein In TIFF0007696354000013.tif43128, X is CR7R8, O, S, or NR7; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or R1 and R2, together with the atom to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; and R 10 is H or halogen, provided that however, (a) (i) when R5 is H, X is CR7R8 or S, or (ii) when R5 is H and X is O, R 10 is halogen; (b) when R5 is halogen and R4 is H, R3 is not methyl, not methoxyl, and not Br, and X is CR7R8 or S; and (c) when R5 is methoxyl or methyl, R4 is not H, There is provided a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0144] For the compounds of formulas (I), (II), and (II'), X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 can each be selected, where applicable, from the groups described herein, and any group described herein for any of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 is, where applicable, for the remaining X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10It is understood that it can be combined with any of the groups described herein for one or more of them.

[0145] For the compounds of formula (I), (II), and (II'), where applicable.

[0146] In some embodiments, X is CR7R8, O, S, or NR7. In some embodiments, X is CR7R8, O, or S. In some embodiments, X is CR7R8 or S. In some embodiments, X is CR7R8 or O. In some embodiments, X is CR7R8. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR7.

[0147] In some embodiments, X is CH2.

[0148] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0149] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0150] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is butyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is isobutyl. In some embodiments, R1 is sec-butyl. In some embodiments, R1 is tert-butyl. In some embodiments, R1 is pentyl. In some embodiments, R1 is isopentyl. In some embodiments, R1 is hexyl. In some embodiments, R1 is isohexyl.

[0151] In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, R1 is C2 alkenyl. In some embodiments, R1 is C3 alkenyl. In some embodiments, R1 is C4 alkenyl. In some embodiments, R1 is C5 alkenyl. In some embodiments, R1 is C6 alkenyl.

[0152] In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R1 is C2 alkynyl. In some embodiments, R1 is C3 alkynyl. In some embodiments, R1 is C4 alkynyl. In some embodiments, R1 is C5 alkynyl. In some embodiments, R1 is C6 alkynyl.

[0153] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0154] In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is cyclohexyl.

[0155] In some embodiments, R1 is C1-C6 haloalkyl. In some embodiments, R1 is halomethyl. In some embodiments, R1 is haloethyl. In some embodiments, R1 is halopropyl. In some embodiments, R1 is halobutyl. In some embodiments, R1 is halopentyl. In some embodiments, R1 is halohexyl.

[0156] In some embodiments, R1 is C1-C6 alkoxyl. In some embodiments, R1 is methoxyl. In some embodiments, R1 is ethoxyl. In some embodiments, R1 is propoxyl. In some embodiments, R1 is butoxyl. In some embodiments, R1 is pentoxyl. In some embodiments, R1 is hexyloxyl.

[0157] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0158] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is sec-butyl. In some embodiments, R2 is tert-butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is isohexyl.

[0159] In some embodiments, R2 is C2-C6 alkenyl. In some embodiments, R2 is C2 alkenyl. In some embodiments, R2 is C3 alkenyl. In some embodiments, R2 is C4 alkenyl. In some embodiments, R2 is C5 alkenyl. In some embodiments, R2 is C6 alkenyl.

[0160] In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is C2 alkynyl. In some embodiments, R2 is C3 alkynyl. In some embodiments, R2 is C4 alkynyl. In some embodiments, R2 is C5 alkynyl. In some embodiments, R2 is C6 alkynyl.

[0161] In some embodiments, R2 is C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0162] In some embodiments, R2 is C3-C6 cycloalkyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R2 is cyclohexyl.

[0163] In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is halomethyl. In some embodiments, R2 is haloethyl. In some embodiments, R2 is halopropyl. In some embodiments, R2 is halobutyl. In some embodiments, R2 is halopentyl. In some embodiments, R2 is halohexyl.

[0164] In some embodiments, R2 is C1-C6 alkoxyl. In some embodiments, R2 is methoxyl. In some embodiments, R2 is ethoxyl. In some embodiments, R2 is propoxyl. In some embodiments, R2 is butoxyl. In some embodiments, R2 is pentaoxyl. In some embodiments, R2 is hexaoxyl.

[0165] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0166] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl.

[0167] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C3 saturated or partially unsaturated cycloalkyl.

[0168] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C4 saturated or partially unsaturated cycloalkyl.

[0169] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C5 saturated or partially unsaturated cycloalkyl.

[0170] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C6 saturated or partially unsaturated cycloalkyl.

[0171] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C3-C6 saturated cycloalkyl.

[0172] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C3 saturated cycloalkyl.

[0173] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C4 saturated cycloalkyl.

[0174] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C5 saturated cycloalkyl.

[0175] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C6 saturated cycloalkyl.

[0176] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C3-C6 partially unsaturated cycloalkyl.

[0177] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C3 partially unsaturated cycloalkyl.

[0178] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C4 partially unsaturated cycloalkyl.

[0179] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C5 partially unsaturated cycloalkyl.

[0180] In some embodiments, R1 and R2 together with the atoms to which they are attached form a C6 partially unsaturated cycloalkyl.

[0181] In some embodiments, R1 and R2 together with the atoms to which they are attached form a cyclopropyl. In some embodiments, R1 and R2 together with the atoms to which they are attached form a cyclobutyl. In some embodiments, R1 and R2 together with the atoms to which they are attached form a cyclopentyl. In some embodiments, R1 and R2 together with the atoms to which they are attached form a cyclohexyl.

[0182] In some embodiments, R1 and R2 together with the atoms to which they are attached form a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0183] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0184] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 4-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0185] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 5-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0186] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 6-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0187] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 7-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0188] In some embodiments, R1 and R2, together with the atoms to which they are attached, form an 8-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0189] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 9-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0190] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 10-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0191] In some embodiments, R1 and R2, together with the atoms to which they are attached, form an 11-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0192] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 12-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0193] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 13-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0194] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0195] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0196] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0197] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 4-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0198] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 5-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0199] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 6-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0200] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 7-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0201] In some embodiments, R1 and R2, together with the atoms to which they are attached, form an 8-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0202] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 9-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0203] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 10-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0204] In some embodiments, R1 and R2, together with the atoms to which they are attached, form an 11-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0205] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 12-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0206] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 13-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0207] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 14-membered saturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0208] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0209] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0210] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 4-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0211] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 5-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0212] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 6-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0213] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 7-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0214] In some embodiments, R1 and R2, together with the atoms to which they are attached, form an 8-membered partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S.

[0215] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 9-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0216] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 10-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0217] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 11-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0218] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 12-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0219] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 13-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0220] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 14-membered partially unsaturated heterocyclic ring containing 1 to 5 heteroatoms selected from N, O, and S.

[0221] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated or partially unsaturated heterocyclic ring containing 1 heteroatom selected from N, O, and S.

[0222] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated or partially unsaturated heterocyclic ring containing 2 heteroatoms selected from N, O, and S.

[0223] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated or partially unsaturated heterocycle containing 3 heteroatoms selected from N, O, and S.

[0224] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated or partially unsaturated heterocycle containing 4 heteroatoms selected from N, O, and S.

[0225] In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 3- to 14-membered saturated or partially unsaturated heterocycle containing 5 heteroatoms selected from N, O, and S.

[0226] In some embodiments, R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0227] In some embodiments, R3 is H.

[0228] In some embodiments, R3 is halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0229] In some embodiments, R3 is a halogen. In some embodiments, R3 is F, Cl, Br, or I. In some embodiments, R3 is F, Cl, or Br. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I.

[0230] In some embodiments, R3 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0231] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is butyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is isobutyl. In some embodiments, R3 is sec-butyl. In some embodiments, R3 is tert-butyl. In some embodiments, R3 is pentyl. In some embodiments, R3 is isopentyl. In some embodiments, R3 is hexyl. In some embodiments, R3 is isohexyl.

[0232] In some embodiments, R3 is C2-C6 alkenyl. In some embodiments, R3 is C2 alkenyl. In some embodiments, R3 is C3 alkenyl. In some embodiments, R3 is C4 alkenyl. In some embodiments, R3 is C5 alkenyl. In some embodiments, R3 is C6 alkenyl.

[0233] In some embodiments, R3 is C2-C6 alkynyl. In some embodiments, R3 is C2 alkynyl. In some embodiments, R3 is C3 alkynyl. In some embodiments, R3 is C4 alkynyl. In some embodiments, R3 is C5 alkynyl. In some embodiments, R3 is C6 alkynyl.

[0234] In some embodiments, R3 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0235] In some embodiments, R3 is C1-C6 haloalkyl. In some embodiments, R3 is halomethyl. In some embodiments, R3 is haloethyl. In some embodiments, R3 is halopropyl. In some embodiments, R3 is halobutyl. In some embodiments, R3 is halopentyl. In some embodiments, R3 is halohexyl.

[0236] In some embodiments, R3 is C1-C6 alkoxyl. In some embodiments, R3 is methoxyl. In some embodiments, R3 is ethoxyl. In some embodiments, R3 is propoxyl. In some embodiments, R3 is butoxyl. In some embodiments, R3 is pentaoxyl. In some embodiments, R3 is hexaoxyl.

[0237] In some embodiments, R3 is C1-C6 haloalkoxyl. In some embodiments, R3 is halomethoxyl. In some embodiments, R3 is haloethoxyl. In some embodiments, R3 is halopropoxyl. In some embodiments, R3 is halobutoxyl. In some embodiments, R3 is halopentaoxyl. In some embodiments, R3 is halohexaoxyl.

[0238] In some embodiments, R3 is C3-C6 cycloalkyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is cyclobutyl. In some embodiments, R3 is cyclopentyl. In some embodiments, R3 is cyclohexyl.

[0239] In some embodiments, R3 is -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -NH(C1-C6 alkyl).

[0240] In some embodiments, R3 is -S(C1-C6 alkyl). In some embodiments, R3 is -S(methyl). In some embodiments, R3 is -S(ethyl). In some embodiments, R3 is -S(propyl). In some embodiments, R3 is -S(butyl). In some embodiments, R3 is -S(pentyl). In some embodiments, R3 is -S(hexyl).

[0241] In some embodiments, R3 is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), or -NH2.

[0242] In some embodiments, R3 is -NH2.

[0243] In some embodiments, R3 is -N(C1-C6 alkyl)2. In some embodiments, R3 is -N(methyl)2. In some embodiments, R3 is -N(ethyl)2. In some embodiments, R3 is -N(propyl)2. In some embodiments, R3 is -N(butyl)2. In some embodiments, R3 is -N(pentyl)2. In some embodiments, R3 is -N(hexyl)2.

[0244] In some embodiments, R3 is -NH(C1-C6 alkyl). In some embodiments, R3 is -NH(methyl). In some embodiments, R3 is -NH(ethyl). In some embodiments, R3 is -NH(propyl). In some embodiments, R3 is -NH(butyl). In some embodiments, R3 is -NH(pentyl). In some embodiments, R3 is -NH(hexyl).

[0245] In some embodiments, R3 is H, F, Cl, methyl, or methoxyl.

[0246] In some embodiments, R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0247] In some embodiments, R4 is H.

[0248] In some embodiments, R4 is halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0249] In some embodiments, R4 is halogen. In some embodiments, R4 is F, Cl, Br, or I. In some embodiments, R4 is F, Cl, or Br. In some embodiments, R4 is F or Cl. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Br. In some embodiments, R4 is I.

[0250] In some embodiments, R4 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is propyl. In some embodiments, R4 is butyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is isobutyl. In some embodiments, R4 is sec-butyl. In some embodiments, R4 is tert-butyl. In some embodiments, R4 is pentyl. In some embodiments, R4 is isopentyl. In some embodiments, R4 is hexyl. In some embodiments, R4 is isohexyl.

[0251] In some embodiments, R4 is C2-C6 alkenyl. In some embodiments, R4 is C2 alkenyl. In some embodiments, R4 is C3 alkenyl. In some embodiments, R4 is C4 alkenyl. In some embodiments, R4 is C5 alkenyl. In some embodiments, R4 is C6 alkenyl.

[0252] In some embodiments, R4 is C2-C6 alkynyl. In some embodiments, R4 is C2 alkynyl. In some embodiments, R4 is C3 alkynyl. In some embodiments, R4 is C4 alkynyl. In some embodiments, R4 is C5 alkynyl. In some embodiments, R4 is C6 alkynyl.

[0253] In some embodiments, R4 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0254] In some embodiments, R4 is C1-C6 haloalkyl. In some embodiments, R4 is halomethyl. In some embodiments, R4 is haloethyl. In some embodiments, R4 is halopropyl. In some embodiments, R4 is halobutyl. In some embodiments, R4 is halopentyl. In some embodiments, R4 is halohexyl.

[0255] In some embodiments, R4 is C1-C6 alkoxyl. In some embodiments, R4 is methoxyl. In some embodiments, R4 is ethoxyl. In some embodiments, R4 is propoxyl. In some embodiments, R4 is butoxyl. In some embodiments, R4 is pentoxyl. In some embodiments, R4 is hexoxyl.

[0256] In some embodiments, R4 is C1-C6 haloalkoxyl. In some embodiments, R4 is halomethoxyl. In some embodiments, R4 is haloethoxyl. In some embodiments, R4 is halopropoxyl. In some embodiments, R4 is halobutoxyl. In some embodiments, R4 is halopentoxyl. In some embodiments, R4 is halohexoxyl.

[0257] In some embodiments, R4 is C3-C6 cycloalkyl. In some embodiments, R4 is cyclopropyl. In some embodiments, R4 is cyclobutyl. In some embodiments, R4 is cyclopentyl. In some embodiments, R4 is cyclohexyl.

[0258] In some embodiments, R4 is -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -NH(C1-C6 alkyl).

[0259] In some embodiments, R4 is -S(C1-C6 alkyl). In some embodiments, R4 is -S(methyl). In some embodiments, R4 is -S(ethyl). In some embodiments, R4 is -S(propyl). In some embodiments, R4 is -S(butyl). In some embodiments, R4 is -S(pentyl). In some embodiments, R4 is -S(hexyl).

[0260] In some embodiments, R4 is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), or -NH2.

[0261] In some embodiments, R4 is -NH2.

[0262] In some embodiments, R4 is -N(C1-C6 alkyl)2. In some embodiments, R4 is -N(methyl)2. In some embodiments, R4 is -N(ethyl)2. In some embodiments, R4 is -N(propyl)2. In some embodiments, R4 is -N(butyl)2. In some embodiments, R4 is -N(pentyl)2. In some embodiments, R4 is -N(hexyl)2.

[0263] In some embodiments, R4 is -NH(C1-C6 alkyl). In some embodiments, R4 is -NH(methyl). In some embodiments, R4 is -NH(ethyl). In some embodiments, R4 is -NH(propyl). In some embodiments, R4 is -NH(butyl). In some embodiments, R4 is -NH(pentyl). In some embodiments, R4 is -NH(hexyl).

[0264] In some embodiments, R4 is H, F, Cl, methyl, or CHF2.

[0265] In some embodiments, R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0266] In some embodiments, R5 is H.

[0267] In some embodiments, R5 is halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0268] In some embodiments, R5 is halogen. In some embodiments, R5 is F, Cl, Br, or I. In some embodiments, R5 is F, Cl, or Br. In some embodiments, R5 is F or Cl. In some embodiments, R5 is F. In some embodiments, R5 is Cl. In some embodiments, R5 is Br. In some embodiments, R5 is I.

[0269] In some embodiments, R5 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0270] In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is propyl. In some embodiments, R5 is butyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is isobutyl. In some embodiments, R5 is sec-butyl. In some embodiments, R5 is tert-butyl. In some embodiments, R5 is pentyl. In some embodiments, R5 is isopentyl. In some embodiments, R5 is hexyl. In some embodiments, R5 is isohexyl.

[0271] In some embodiments, R5 is C2-C6 alkenyl. In some embodiments, R5 is C2 alkenyl. In some embodiments, R5 is C3 alkenyl. In some embodiments, R5 is C4 alkenyl. In some embodiments, R5 is C5 alkenyl. In some embodiments, R5 is C6 alkenyl.

[0272] In some embodiments, R5 is C2-C6 alkynyl. In some embodiments, R5 is C2 alkynyl. In some embodiments, R5 is C3 alkynyl. In some embodiments, R5 is C4 alkynyl. In some embodiments, R5 is C5 alkynyl. In some embodiments, R5 is C6 alkynyl.

[0273] In some embodiments, R5 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0274] In some embodiments, R5 is C1-C6 haloalkyl. In some embodiments, R5 is halomethyl. In some embodiments, R5 is haloethyl. In some embodiments, R5 is halopropyl. In some embodiments, R5 is halobutyl. In some embodiments, R5 is halopentyl. In some embodiments, R5 is halohexyl.

[0275] In some embodiments, R5 is C1-C6 alkoxyl. In some embodiments, R5 is methoxyl. In some embodiments, R5 is ethoxyl. In some embodiments, R5 is propoxyl. In some embodiments, R5 is butoxyl. In some embodiments, R5 is pentyloxyl. In some embodiments, R5 is hexyloxyl.

[0276] In some embodiments, R5 is C1-C6 haloalkoxyl. In some embodiments, R5 is halomethoxyl. In some embodiments, R5 is haloethoxyl. In some embodiments, R5 is halopropoxyl. In some embodiments, R5 is halobutoxyl. In some embodiments, R5 is halopentyloxyl. In some embodiments, R5 is halohexyloxyl.

[0277] In some embodiments, R5 is C3-C6 cycloalkyl. In some embodiments, R5 is cyclopropyl. In some embodiments, R5 is cyclobutyl. In some embodiments, R5 is cyclopentyl. In some embodiments, R5 is cyclohexyl.

[0278] In some embodiments, R5 is -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -NH(C1-C6 alkyl).

[0279] In some embodiments, R5 is -S(C1-C6 alkyl). In some embodiments, R5 is -S(methyl). In some embodiments, R5 is -S(ethyl). In some embodiments, R5 is -S(propyl). In some embodiments, R5 is -S(butyl). In some embodiments, R5 is -S(pentyl). In some embodiments, R5 is -S(hexyl).

[0280] In some embodiments, R5 is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), or -NH2.

[0281] In some embodiments, R5 is -NH2.

[0282] In some embodiments, R5 is -N(C1-C6 alkyl)2. In some embodiments, R5 is -N(methyl)2. In some embodiments, R5 is -N(ethyl)2. In some embodiments, R5 is -N(propyl)2. In some embodiments, R5 is -N(butyl)2. In some embodiments, R5 is -N(pentyl)2. In some embodiments, R5 is -N(hexyl)2.

[0283] In some embodiments, R5 is -NH(C1-C6 alkyl). In some embodiments, R5 is -NH(methyl). In some embodiments, R5 is -NH(ethyl). In some embodiments, R5 is -NH(propyl). In some embodiments, R5 is -NH(butyl). In some embodiments, R5 is -NH(pentyl). In some embodiments, R5 is -NH(hexyl).

[0284] In some embodiments, R5 is H, F, Cl, methyl, ethyl, isopropyl, n-propyl, methoxyl, methylthio, or CHF2.

[0285] In some embodiments, R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0286] In some embodiments, R6 is H.

[0287] In some embodiments, R6 is halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0288] In some embodiments, R6 is halogen. In some embodiments, R6 is F, Cl, Br, or I. In some embodiments, R6 is F, Cl, or Br. In some embodiments, R6 is F or Cl. In some embodiments, R6 is F. In some embodiments, R6 is Cl. In some embodiments, R6 is Br. In some embodiments, R6 is I.

[0289] In some embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is propyl. In some embodiments, R6 is butyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is isobutyl. In some embodiments, R6 is sec-butyl. In some embodiments, R6 is tert-butyl. In some embodiments, R6 is pentyl. In some embodiments, R6 is isopentyl. In some embodiments, R6 is hexyl. In some embodiments, R6 is isohexyl.

[0290] In some embodiments, R6 is C2-C6 alkenyl. In some embodiments, R6 is C2 alkenyl. In some embodiments, R6 is C3 alkenyl. In some embodiments, R6 is C4 alkenyl. In some embodiments, R6 is C5 alkenyl. In some embodiments, R6 is C6 alkenyl.

[0291] In some embodiments, R6 is C2-C6 alkynyl. In some embodiments, R6 is C2 alkynyl. In some embodiments, R6 is C3 alkynyl. In some embodiments, R6 is C4 alkynyl. In some embodiments, R6 is C5 alkynyl. In some embodiments, R6 is C6 alkynyl.

[0292] In some embodiments, R6 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0293] In some embodiments, R6 is C1-C6 haloalkyl. In some embodiments, R6 is halomethyl. In some embodiments, R6 is haloethyl. In some embodiments, R6 is halopropyl. In some embodiments, R6 is halobutyl. In some embodiments, R6 is halopentyl. In some embodiments, R6 is halohexyl.

[0294] In some embodiments, R6 is C1-C6 alkoxyl. In some embodiments, R6 is methoxyl. In some embodiments, R6 is ethoxyl. In some embodiments, R6 is propoxyl. In some embodiments, R6 is butoxyl. In some embodiments, R6 is pentaoxyl. In some embodiments, R6 is hexaoxyl.

[0295] In some embodiments, R6 is C1-C6 haloalkoxyl. In some embodiments, R6 is halomethoxyl. In some embodiments, R6 is haloethoxyl. In some embodiments, R6 is halopropoxyl. In some embodiments, R6 is halobutoxyl. In some embodiments, R6 is halopentaoxyl. In some embodiments, R6 is halohexaoxyl.

[0296] In some embodiments, R6 is C3-C6 cycloalkyl. In some embodiments, R6 is cyclopropyl. In some embodiments, R6 is cyclobutyl. In some embodiments, R6 is cyclopentyl. In some embodiments, R6 is cyclohexyl.

[0297] In some embodiments, R6 is -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -NH(C1-C6 alkyl).

[0298] In some embodiments, R6 is -S(C1-C6 alkyl). In some embodiments, R6 is -S(methyl). In some embodiments, R6 is -S(ethyl). In some embodiments, R6 is -S(propyl). In some embodiments, R6 is -S(butyl). In some embodiments, R6 is -S(pentyl). In some embodiments, R6 is -S(hexyl).

[0299] In some embodiments, R6 is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), or -NH2.

[0300] In some embodiments, R6 is -NH2.

[0301] In some embodiments, R6 is -N(C1-C6 alkyl)2. In some embodiments, R6 is -N(methyl)2. In some embodiments, R6 is -N(ethyl)2. In some embodiments, R6 is -N(propyl)2. In some embodiments, R6 is -N(butyl)2. In some embodiments, R6 is -N(pentyl)2. In some embodiments, R6 is -N(hexyl)2.

[0302] In some embodiments, R6 is -NH(C1-C6 alkyl). In some embodiments, R6 is -NH(methyl). In some embodiments, R6 is -NH(ethyl). In some embodiments, R6 is -NH(propyl). In some embodiments, R6 is -NH(butyl). In some embodiments, R6 is -NH(pentyl). In some embodiments, R6 is -NH(hexyl).

[0303] In some embodiments, R6 is H, methyl, or methoxyl.

[0304] In some embodiments, R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0305] In some embodiments, R7 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0306] In some embodiments, R7 is H or deuterium.

[0307] In some embodiments, R7 is H. In some embodiments, R7 is deuterium.

[0308] In some embodiments, R7 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R7 is C1-C6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl. In some embodiments, R7 is propyl. In some embodiments, R7 is butyl. In some embodiments, R7 is isopropyl. In some embodiments, R7 is isobutyl. In some embodiments, R7 is sec-butyl. In some embodiments, R7 is tert-butyl. In some embodiments, R7 is pentyl. In some embodiments, R7 is isopentyl. In some embodiments, R7 is hexyl. In some embodiments, R7 is isohexyl.

[0309] In some embodiments, R7 is C2-C6 alkenyl. In some embodiments, R7 is C2 alkenyl. In some embodiments, R7 is C3 alkenyl. In some embodiments, R7 is C4 alkenyl. In some embodiments, R7 is C5 alkenyl. In some embodiments, R7 is C6 alkenyl.

[0310] In some embodiments, R7 is C2-C6 alkynyl. In some embodiments, R7 is C2 alkynyl. In some embodiments, R7 is C3 alkynyl. In some embodiments, R7 is C4 alkynyl. In some embodiments, R7 is C5 alkynyl. In some embodiments, R7 is C6 alkynyl.

[0311] In some embodiments, R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0312] In some embodiments, R8 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0313] In some embodiments, R8 is H or deuterium.

[0314] In some embodiments, R8 is H. In some embodiments, R8 is deuterium.

[0315] In some embodiments, R8 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R8 is C1-C6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R8 is ethyl. In some embodiments, R8 is propyl. In some embodiments, R8 is butyl. In some embodiments, R8 is isopropyl. In some embodiments, R8 is isobutyl. In some embodiments, R8 is sec-butyl. In some embodiments, R8 is tert-butyl. In some embodiments, R8 is pentyl. In some embodiments, R8 is isopentyl. In some embodiments, R8 is hexyl. In some embodiments, R8 is isohexyl.

[0316] In some embodiments, R8 is C2-C6 alkenyl. In some embodiments, R8 is C2 alkenyl. In some embodiments, R8 is C3 alkenyl. In some embodiments, R8 is C4 alkenyl. In some embodiments, R8 is C5 alkenyl. In some embodiments, R8 is C6 alkenyl.

[0317] In some embodiments, R8 is C2-C6 alkynyl. In some embodiments, R8 is C2 alkynyl. In some embodiments, R8 is C3 alkynyl. In some embodiments, R8 is C4 alkynyl. In some embodiments, R8 is C5 alkynyl. In some embodiments, R8 is C6 alkynyl.

[0318] In some embodiments, R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl.

[0319] In some embodiments, R9 is H.

[0320] In some embodiments, R9 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R9 is C1-C6 alkyl. In some embodiments, R9 is methyl. In some embodiments, R9 is ethyl. In some embodiments, R9 is propyl. In some embodiments, R9 is butyl. In some embodiments, R9 is isopropyl. In some embodiments, R9 is isobutyl. In some embodiments, R9 is sec-butyl. In some embodiments, R9 is tert-butyl. In some embodiments, R9 is pentyl. In some embodiments, R9 is isopentyl. In some embodiments, R9 is hexyl. In some embodiments, R9 is isohexyl.

[0321] In some embodiments, R9 is C2-C6 alkenyl. In some embodiments, R9 is C2 alkenyl. In some embodiments, R9 is C3 alkenyl. In some embodiments, R9 is C4 alkenyl. In some embodiments, R9 is C5 alkenyl. In some embodiments, R8 is C6 alkenyl.

[0322] In some embodiments, R9 is C2-C6 alkynyl. In some embodiments, R9 is C2 alkynyl. In some embodiments, R9 is C3 alkynyl. In some embodiments, R9 is C4 alkynyl. In some embodiments, R9 is C5 alkynyl. In some embodiments, R9 is C6 alkynyl.

[0323] In some embodiments, R9 is C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0324] In some embodiments, R9 is C1-C6 haloalkyl. In some embodiments, R9 is halomethyl. In some embodiments, R9 is haloethyl. In some embodiments, R9 is halopropyl. In some embodiments, R9 is halobutyl. In some embodiments, R9 is halopentyl. In some embodiments, R9 is halohexyl.

[0325] In some embodiments, R9 is C3-C6 cycloalkyl. In some embodiments, R9 is cyclopropyl. In some embodiments, R9 is cyclobutyl. In some embodiments, R9 is cyclopentyl. In some embodiments, R9 is cyclohexyl.

[0326] In some embodiments, at least one of R3, R4, R5, and R6 is H.

[0327] In some embodiments, at least one of R3, R4, R5, and R6 is not H.

[0328] In some embodiments, at least one of R3 and R4 is H.

[0329] In some embodiments, at least one of R5 and R6 is H.

[0330] In some embodiments, X is CR7R8 or S, and R5 is H.

[0331] In some embodiments, X is CR7R8, and R5 is H.

[0332] In some embodiments, X is CH2, and R5 is H.

[0333] In some embodiments, X is S, and R5 is H.

[0334] In some embodiments, when R5 is halogen and R4 is H, R3 is not methyl, not methoxyl, not Br, and X is CR7R8 or S.

[0335] In some embodiments, R5 is halogen, R4 is H, X is CR7R8 or S, and R3 is H, F, Cl, I, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0336] In some embodiments, when R5 is halogen and R4 is H, X is S, and R3 is not methyl, not methoxyl, and not Br.

[0337] In some embodiments, R5 is halogen, R4 is H, X is S, and R3 is H, F, Cl, I, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0338] In some embodiments, when R5 is halogen and R4 is H, X is CR7R8, and R3 is not methyl, not methoxyl, and not Br.

[0339] In some embodiments, R5 is halogen, R4 is H, X is CR7R8, and R3 is H, F, Cl, I, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0340] In some embodiments, when R5 is halogen and R4 is H, X is CH2, and R3 is not methyl, not methoxyl, and not Br.

[0341] In some embodiments, R5 is halogen, R4 is H, X is CH2, and R3 is H, F, Cl, I, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0342] In some embodiments, when R5 is halogen and R4 is H, X is not O, and R3 is not methyl, not methoxyl, and not Br.

[0343] In some embodiments, R5 is halogen, R4 is H, X is not O, and R3 is H, F, Cl, I, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0344] In some embodiments, R5 is halogen, R4 is H, X is CR7R8 or S, and R3 is H, F, or Cl.

[0345] In some embodiments, R5 is halogen, R4 is H, X is CR7R8, and R3 is H, F, or Cl.

[0346] In some embodiments, R5 is halogen, R4 is H, X is CH2, and R3 is H, F, or Cl.

[0347] In some embodiments, R5 is methoxyl or methyl, and R4 is not H.

[0348] In some embodiments, R5 is methoxyl, and R4 is not H.

[0349] In some embodiments, R5 is methyl and R4 is not H.

[0350] In some embodiments, R5 is methoxyl or methyl and R4 is halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0351] In some embodiments, R5 is methoxyl or methyl and R4 is F, Cl, methyl, or CHF2.

[0352] In some embodiments, R 10 is H or halogen. In some embodiments, R 10 is H. In some embodiments, R 10 is halogen. In some embodiments, R 10 is F, Cl, Br, or I. In some embodiments, R 10 is F, Cl, or Br. In some embodiments, R 10 is F or Cl. In some embodiments, R 10 is F. In some embodiments, R 10 is Cl. In some embodiments, R 10 is Br. In some embodiments, R 10 is I.

[0353] In some embodiments, X is O and R9 is H.

[0354] In some embodiments, X is O, R9 is H, and R1 is C1-C6 alkyl.

[0355] In some embodiments, X is O, R9 is H, and R1 is methyl.

[0356] In some embodiments, X is O, R9 is H, R1 is methyl, and R2 is C1-C6 alkyl.

[0357] In some embodiments, X is O, R9 is H, R1 is methyl, and R2 is methyl.

[0358] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R3 is H.

[0359] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyl.

[0360] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R3 is F, Cl, methyl, CHF2, or methoxyl.

[0361] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R4 is H.

[0362] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R4 is halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0363] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R4 is F, Cl, methyl, or CHF2.

[0364] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R5 is H.

[0365] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R5 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or S(C1-C6 alkyl).

[0366] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R5 is F, Cl, methyl, ethyl, n-propyl, isopropyl, CHF2, methoxyl, or methylthio.

[0367] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R6 is H.

[0368] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R6 is C1-C6 alkyl or C1-C6 alkoxyl.

[0369] In some embodiments, X is O, R9 is H, R1 is methyl, R2 is methyl, and R6 is methyl or methoxyl.

[0370] In some embodiments, X is O, R9 is H, and R1 and R2 together with the atoms to which they are attached form a C3-C6 saturated or unsaturated cycloalkyl.

[0371] In some embodiments, X is O, R9 is H, and R1 and R2 together with the atoms to which they are attached form a C3-C6 saturated cycloalkyl.

[0372] In some embodiments, X is O, R9 is H, and R1 and R2 together with the atoms to which they are attached form cyclopropyl.

[0373] In some embodiments, X is O, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R3 is H.

[0374] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R4 is H.

[0375] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R4 is halogen or C1-C6 alkyl.

[0376] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R4 is F, Cl, or methyl.

[0377] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R5 is H.

[0378] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R5 is halogen or C1-C6 alkyl.

[0379] In some embodiments, X is O, R9 is H, R1 and R2 together with the atom to which they are attached form cyclopropyl, and R5 is F, methyl, or ethyl.

[0380] In some embodiments, X is CH2 and R9 is H.

[0381] In some embodiments, X is CH2, R9 is H, and R1 is methyl.

[0382] In some embodiments, X is CH2, R9 is H, R1 is methyl, and R2 is methyl.

[0383] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R3 is H.

[0384] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R4 is H.

[0385] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R4 is halogen or C1-C6 alkyl.

[0386] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R4 is Cl or methyl.

[0387] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R5 is H.

[0388] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R5 is halogen or C1-C6 alkyl.

[0389] In some embodiments, X is CH2, R9 is H, R1 is methyl, R2 is methyl, and R5 is F, Cl, or methyl.

[0390] In some embodiments, X is CH2, R9 is H, and R1 and R2 together with the atoms to which they are attached form a C3-C6 saturated or unsaturated cycloalkyl.

[0391] In some embodiments, X is CH2, R9 is H, and R1 and R2 together with the atoms to which they are attached form a C3-C6 saturated cycloalkyl.

[0392] In some embodiments, X is CH2, R9 is H, and R1 and R2 together with the atoms to which they are attached form cyclopropyl.

[0393] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R3 is H.

[0394] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R4 is H.

[0395] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R4 is halogen or C1-C6 alkyl.

[0396] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R4 is Cl or methyl.

[0397] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R5 is H.

[0398] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R5 is C1-C6 alkyl.

[0399] In some embodiments, X is CH2, R9 is H, R1 and R2 together with the atoms to which they are attached form cyclopropyl, and R5 is methyl.

[0400] In some embodiments, when R5 is H and X is O, R 10 is halogen.

[0401] In some embodiments, when R 10 is not H, X is O. In some embodiments, when R 10 is halogen, X is O.

[0402] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000014.tif43128 wherein R3, R4, R5, and R6 are as described herein for formula (I).

[0403] In some embodiments, the compound of formula (I) is a compound of formula (Ib) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000015.tif43128 wherein R3, R4, R5, and R6 are as described herein for formula (I).

[0404] In some embodiments, the compound of formula (II) is a compound of formula (IIa) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000016.tif35128 wherein X, R1, R2, R4, R5, and R9 are as described herein for formula (II).

[0405] In some embodiments, the compound of formula (II) is a compound of formula (IIa-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF0007696354000017.tif30128 wherein X, R4, and R5 are as described herein for formula (II).

[0406] In some embodiments, the compound of formula (II) is a compound of formula (IIa-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000018.tif, 28128, X, R4, and R5 are as described herein for formula (II).

[0407] In some embodiments, the compound of formula (II) is a compound of formula (IIb) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000019.tif, 35128, X, R1, R2, R3, R5, and R9 are as described herein for formula (II).

[0408] In some embodiments, the compound of formula (II) is a compound of formula (IIb-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000020.tif, 28128, X, R3, and R5 are as described herein for formula (II).

[0409] In some embodiments, the compound of formula (II) is a compound of formula (IIb-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000021.tif, 28128, X, R3, and R5 are as described herein for formula (II).

[0410] In some embodiments, the compound of formula (II) is a compound of formula (IIc) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000022.tif, 32128, X, R1, R2, R3, R6, and R9 are as described herein for formula (II).

[0411] In some embodiments, the compound of formula (II) is a compound of formula (IIc-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000023.tif28128, X, R3, and R6 are as described herein for formula (II).

[0412] In some embodiments, the compound of formula (II) is a compound of formula (IIc-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000024.tif28128, X, R3, and R6 are as described herein for formula (II).

[0413] In some embodiments, the compound of formula (II') is a compound of formula (II'a) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, In TIFF0007696354000025.tif39128, X, R1, R2, R9, and R 10 are as described herein for formula (II').

[0414] For any one of the compounds of the formulas described herein, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 can each be selected, where applicable, from the groups described herein, and any group described herein for any one of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 can, where applicable, be combined with any group described herein for one or more of the remaining X, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 It is understood that they can be combined.

[0415] In some embodiments, the compound is selected from the compounds described in Table 1 or 2 and their prodrugs and pharmaceutically acceptable salts.

[0416] In some embodiments, the compound is selected from the compounds described in Table 1 or 2 and their pharmaceutically acceptable salts.

[0417] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 or 2 and their pharmaceutically acceptable salts.

[0418] In some embodiments, the compound is selected from the compounds described in Table 1 or 2.

[0419] (Table 1) TIFF0007696354000026.tif156169TIFF0007696354000027.tif155169

[0420] (Table 2) TIFF0007696354000028.tif204155TIFF0007696354000029.tif199155TIFF0007696354000030.tif185155TIFF0007696354000031.tif195155TIFF0007696354000032.tif199155TIFF0007696354000033.tif199155TIFF0007696354000034.tif199155TIFF0007696354000035.tif201155TIFF0007696354000036.tif199155TIFF0007696354000037.tif147155

[0421] In some aspects, the disclosure provides a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds of the formulas disclosed herein.

[0422] In some embodiments, the compound from Table 1 or 2 is of formula (I).

[0423] In some embodiments, the compound from Table 1 or 2 is of formula (II).

[0424] In some embodiments, the compound from Table 1 or 2 is of formula (II').

[0425] In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 36, 37, 38, or 39, or a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 36, 37, or 38, or a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, or 36, or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, or 33, or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the compound is compound 7, 8, 15, or 17, or a pharmaceutically acceptable salt thereof.

[0430] In some embodiments, the compound is compound 7, 8, or 17, or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the compound is compound 7 or a pharmaceutically acceptable salt thereof.

[0432] In some embodiments, the compound is compound 8 or a pharmaceutically acceptable salt thereof.

[0433] In some embodiments, the compound is compound 15 or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the compound is compound 17 or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments, the compound is compound 30, 31, 34, or 35, or a pharmaceutically acceptable salt thereof.

[0436] In some embodiments, the compound is compound 30 or a pharmaceutically acceptable salt thereof.

[0437] In some embodiments, the compound is compound 31 or a pharmaceutically acceptable salt thereof.

[0438] In some embodiments, the compound is compound 34 or a pharmaceutically acceptable salt thereof.

[0439] In some embodiments, the compound is compound 35 or a pharmaceutically acceptable salt thereof.

[0440] In some embodiments, the compound is compound 36 or a pharmaceutically acceptable salt thereof.

[0441] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or 2 and their prodrugs and pharmaceutically acceptable salts.

[0442] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or 2 and their pharmaceutically acceptable salts.

[0443] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or 2 and the prodrugs of their pharmaceutically acceptable salts.

[0444] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 or 2.

[0445] It is understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can generally be prepared by substituting non-isotope labeled reagents with isotope labeled reagents and performing the procedures disclosed in the schemes and / or examples described herein.

[0446] In some embodiments, the isotope derivative is a deuterium labeled compound. In some embodiments, the compound is 18 an F-labeled compound. In some embodiments, the compound is 123 an I-labeled compound, 124 an I-labeled compound, 125 an I-labeled compound, 129 an I-labeled compound, 131 an I-labeled compound, 135 an I-labeled compound, or any combination thereof. In some embodiments, the compound is 33 an S-labeled compound, 34 an S-labeled compound, 35 an S-labeled compound, 36 an S-labeled compound, or any combination thereof.

[0447] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It is understood that S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium labeled compounds generally involve substituting non-isotope labeled reagents with 18 F, 123 I, 124 I, 125 I, 129 I, 131 I,135 I, 3 S, 34 S, 35 S, and / or 36 S-labeled reagents can be prepared by performing the procedures disclosed in the schemes and / or examples described herein.

[0448] Said 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the invention containing one or more of the S atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the invention. Further, substitution with isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced required dosage.

[0449] For the sake of avoiding misunderstanding, it should be noted that when a group meets the requirement of being "described herein" in this specification, the group is understood to include all of the broadest definition described first and all of the specific definitions for that group.

[0450] The various functional groups and substituents that make up the compounds of formulas (I), (II), and (II') are typically selected such that the molecular weight of the compound does not exceed 1000 daltons. In most cases, it is considered that the molecular weight of the compound is less than 900 daltons, for example, less than 800, or less than 750, or less than 700, or less than 650. More conveniently, the molecular weight is less than 600 daltons, for example, 550 daltons or less.

[0451] It will be understood that any one of the compounds of the formulas disclosed herein and any of their pharmaceutically acceptable salts include the stereoisomers of the compound, mixtures of stereoisomers, and polymorphs of all isomeric forms.

[0452] This disclosure also encompasses the disclosed compounds as defined herein that include one or more isotope substitutions.

[0453] It should be understood that any compound of any formula described herein includes the compound itself and, where applicable, its salts and its solvates.

[0454] The in vivo effect of any one of the compounds of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the body of a human or animal after administration of any one of the compounds of the formulas disclosed herein. As described above, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted through the metabolism of a precursor compound (prodrug).

[0455] Preferably, this disclosure excludes any individual compound that does not have the biological activity defined herein.

[0456] Synthetic methods In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0457] In some aspects, the present disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0458] In some aspects, the present disclosure provides a compound that can be obtained, or is obtained, or is directly obtained by a method for preparing a compound described herein.

[0459] In some aspects, the present disclosure provides an intermediate described herein that is suitable for use in a method for preparing a compound described herein.

[0460] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying examples.

[0461] It should be understood that in the description of the synthetic methods described herein, and in any of the referenced synthetic methods used to prepare starting materials, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by those skilled in the art.

[0462] Those skilled in the art of organic synthesis will understand that the functional groups present in the various parts of the molecule must be compatible with the reagents and reaction conditions used.

[0463] It will be recognized that in the synthesis of the disclosed compounds in the processes defined herein, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their unwanted reactions. A skilled chemist will recognize when such protection is necessary and how such protecting groups can be placed and later removed. For examples of protecting groups, see one of the many general documents on this subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). The protecting groups can be removed by any convenient method known to the skilled chemist as being described in the literature or appropriate for the removal of the protecting group in question, and such methods are selected to effect the removal of the protecting group while minimizing perturbation of groups at other positions within the molecule. Thus, when the reactants contain groups such as, for example, amino, carboxy or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0464] Examples of suitable protecting groups for amino or alkylamino groups include, for example, acyl groups such as alkanoyl groups like acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions of the above protecting groups necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as alkanoyl or an alkoxycarbonyl group or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed by hydrogenation on a catalyst such as palladium carbon or by treatment with a Lewis acid such as boron tris(trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with, for example, an alkylamine such as dimethylaminopropylamine or hydrazine.

[0465] Examples of suitable protecting groups for hydroxy groups include, for example, acyl groups such as alkanoyl groups like acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. It is considered that the deprotection conditions of the above protecting groups necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as alkanoyl or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed by hydrogenation on a catalyst such as palladium carbon.

[0466] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as methyl or ethyl groups, which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, tert-butyl groups, which may be removed, for example, by treatment with an acid such as an organic acid like trifluoroacetic acid, or, for example, benzyl groups, which may be removed, for example, by hydrogenation on a catalyst such as palladium on carbon.

[0467] When a compound of formula (I), (II), or (II') is synthesized by any one of the processes defined herein, the process may further include the following additional steps: (i) removing any protecting groups present; (ii) converting the compound of formula (I), (II), or (II') to another compound of formula (I), (II), or (II'); (iii) forming its pharmaceutically acceptable salt, hydrate or solvate; and / or (iv) forming its prodrug.

[0468] The obtained compounds of formula (I), (II), and (II') can be isolated and purified using techniques well known in the art.

[0469] For simplicity, the reactions of the compounds are preferably carried out in the presence of a suitable solvent that is inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of said solvents or mixtures with water, including but not limited to these.

[0470] Furthermore, by using the procedures described herein, additional compounds of the present disclosure can be readily prepared in conjunction with ordinary techniques in the art. One of ordinary skill in the art will readily understand that these compounds can be prepared using the conditions of the following preparation procedures and known variations of the processes.

[0471] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily accessible by a variety of synthetic routes, some of which are exemplified in the appended examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how they should be applied and adapted, if necessary or useful, in any particular case. Further, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions to a particular functional group present in a compound of the present disclosure or a suitable precursor molecule thereof; those methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or safeguarding) groups if necessary or useful; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0472] In some embodiments, the compounds of the present disclosure are prepared as described in Scheme 1, 2, or 3.

[0473] In some embodiments, the compounds of the present disclosure are prepared as described in Scheme 1.

[0474] In some embodiments, the compounds of the present disclosure are prepared as described in Scheme 2.

[0475] In some embodiments, the compounds of the present disclosure are prepared as described in Scheme 3.

[0476] TIFF0007696354000038.tif84128Scheme 1 describes the preparation of methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate (4), which can be coupled to intermediate 9 in Schemes 2 and 3 by substitution of the chloride to form compound 10.

[0477] TIFF0007696354000039.tif210141Schemes 2 and 3 describe the synthetic routes for preparing the dual H1 / 5HT2a antagonists exemplified herein. Intermediates 5 and 6 illustrated in Scheme 2 can be readily prepared by those skilled in the art according to the procedures in the literature. Intermediates 11 and 12 illustrated in Scheme 3 can be readily prepared by those skilled in the art according to the procedures in the literature.

[0478] Biological assays Compounds designed, selected, and / or optimized by the methods described above, once manufactured, can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays including, but not limited to, the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0479] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it becomes possible to rapidly screen the activities of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay technologies including, but not limited to, those described below.

[0480] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, gel shift assays, reporter gene assays, in vitro cell survival assays, and the assays described herein.

[0481] The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for H1 and 5-HT 2A 、5-HT 2C 、 or D2.

[0482] The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for H1 and 5-HT 2A 、5-HT 2C 、 or D2.

[0483] The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for H1 and 5-HT 2A for. The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for H1. The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for 5-HT 2A for. The binding assay may be for D2.

[0484] The compounds of the present disclosure may be analyzed in comparison to a reference standard (e.g., ketanserin or pyrilamine). The compounds of the present disclosure may be transferred to an assay plate for non-specific binding or total binding amount. The assay plate may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with buffer. The filter plate may be dried and sealed. The inhibition constant may be calculated using the following formula: TIFF0007696354000040.tif10128 may be used for calculation and the data may be analyzed. IC 50 may be calculated and converted to K i .

[0485] The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for 5-HT 2C . The compounds of the present disclosure may be analyzed in comparison to a reference standard, such as SB-206553 (i.e., 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole hydrochloride hydrate). The compounds of the present disclosure may be transferred to assay plates for non-specific binding or total binding amounts. The assay plates may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with buffer. The filter plates may be dried and sealed. The inhibition constant may be calculated using the following formula: TIFF0007696354000041.tif9128 and the data may be analyzed. IC 50 may be calculated and converted to K i .

[0486] The biological activity of the compounds of the present disclosure may be determined using a binding assay. The binding assay may be for D2. The compounds of the present disclosure may be analyzed in comparison to a reference standard, such as droperidol (i.e., 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]-3,6-dihydro-2H-pyridin-4-yl]-1H-benzimidazol-2-one). The compounds of the present disclosure may be transferred to assay plates for non-specific binding or total binding amounts. The assay plates may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with buffer. The filter plates may be dried and sealed. The inhibition constant may be calculated using the following formula: TIFF0007696354000042.tif9128 and the data may be analyzed. IC 50 may be calculated and converted to K i .

[0487] In some embodiments, the compounds of the present disclosure selectively target H1 / 5-HT2 A . In some embodiments, the compounds of the present disclosure are 5-HT2C does not selectively target. In some embodiments, the compounds of the present disclosure are 5-HT2 C compared to H1 / 5-HT2 A target to a greater extent (e.g., the compound is 5-HT2 C when compared, H1 / 5-HT2 at a percentage greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% A targets).

[0488] In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 150 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 125 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 100 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 75 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 50 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 40 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 30 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 20 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 10 nM. In some embodiments, 5-HT2 A The K i value is from about 1 nM to about 5 nM.

[0489] In some embodiments, 5-HT2 A The K iThe value is about 150 nM. In some embodiments, the K A value for 5-HT2 i is about 125 nM. In some embodiments, the K A value for 5-HT2 i is about 100 nM. In some embodiments, the K A value for 5-HT2 i is about 75 nM. In some embodiments, the K A value for 5-HT2 i is about 50 nM. In some embodiments, the K A value for 5-HT2 i is about 40 nM. In some embodiments, the K A value for 5-HT2 i is about 30 nM. In some embodiments, the K A value for 5-HT2 i is about 20 nM. In some embodiments, the K A value for 5-HT2 i is about 15 nM. In some embodiments, the K A value for 5-HT2 i is about 10 nM. In some embodiments, the K A value for 5-HT2 i is about 9 nM. In some embodiments, the K A value for 5-HT2 i is about 8 nM. In some embodiments, the K A value for 5-HT2 i is about 7 nM. In some embodiments, the K A value for 5-HT2 i is about 6 nM. In some embodiments, the K A value for 5-HT2 i is about 5 nM. In some embodiments, the K A value for 5-HT2 i is about 4 nM. In some embodiments, the K A value for 5-HT2 i is about 3 nM. In some embodiments, the K A value for 5-HT2 i is about 2 nM. In some embodiments, the K AK for i The value is about 1 nM.

[0490] In some embodiments, K for H1 i The value is from about 1 nM to about 150 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 125 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 100 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 75 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 50 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 40 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 30 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 20 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 10 nM. In some embodiments, K for H1 i The value is from about 1 nM to about 5 nM.

[0491] In some embodiments, K for H1 i The value is about 150 nM. In some embodiments, K for H1 i The value is about 125 nM. In some embodiments, K for H1 i The value is about 100 nM. In some embodiments, K for H1 i The value is about 90 nM. In some embodiments, K for H1 i The value is about 80 nM. In some embodiments, K for H1 i The value is about 70 nM. In some embodiments, K for H1 i The value is about 60 nM. In some embodiments, K for H1 i The value is about 50 nM. In some embodiments, K for H1 i The value is about 40 nM. In some embodiments, K for H1 i The value is about 30 nM. In some embodiments, K for H1i The value is about 20 nM. In some embodiments, K for H1 i The value is about 15 nM. In some embodiments, K for H1 i The value is about 10 nM.

[0492] In some embodiments, 5-HT2 C K for i The value is about 500 nM to about 10 μM. In some embodiments, 5-HT2 C K for i The value is about 500 nM. In some embodiments, 5-HT2 C K for i The value is about 750 nM. In some embodiments, 5-HT2 C K for i The value is about 1 μM. In some embodiments, 5-HT2 C K for i The value is about 2 μM. In some embodiments, 5-HT2 C K for i The value is about 3 μM. In some embodiments, 5-HT2 C K for i The value is about 4 μM. In some embodiments, 5-HT2 C K for i The value is about 5 μM. In some embodiments, 5-HT2 C K for i The value is about 6 μM. In some embodiments, 5-HT2 C K for i The value is about 7 μM. In some embodiments, 5-HT2 C K for i The value is about 8 μM. In some embodiments, 5-HT2 C K for i The value is about 9 μM. In some embodiments, 5-HT2 C K for i The value is about 10 μM.

[0493] In some embodiments, the compounds of the present disclosure are 5-HT2 Chaving low affinity for (e.g., K values exceeding about 100 nM, about 200 nM, about 500 nM, about 750 nM, about 1,000 nM, about 1,500 nM, or about 2,000 nM). In some embodiments, Compound No. 7 has low affinity for 5-HT2 (e.g., a K value of about 2,200 nM). i In some embodiments, the compounds of the present disclosure have affinity for 5-HT2 (e.g., K values of less than about 1,500 nM, about 1,000 nM, about 750 nM, about 500 nM, about 250 nM, or about 100 nM). In some embodiments, Compound No. 8 has affinity for 5-HT2 (e.g., a K value of about 87 nM). C having low affinity for (e.g., a K value of about 2,200 nM). i

[0494] In some embodiments, the compounds of the present disclosure have affinity for 5-HT2 A having low affinity for (e.g., K values exceeding about 100 nM, about 200 nM, about 500 nM, about 750 nM, about 1,000 nM, about 1,500 nM, or about 2,000 nM). In some embodiments, Compound No. 7 has low affinity for 5-HT2 (e.g., a K value of about 2,200 nM). i In some embodiments, the compounds of the present disclosure have affinity for 5-HT2 A having low affinity for (e.g., a K value of about 2,200 nM). i

[0495] In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i In some embodiments, the K value for D2 is greater than about 100 nM. In some embodiments, the K value for D2 is greater than about 500 nM. In some embodiments, the K value for D2 is greater than about 1,000 nM. In some embodiments, the K value for D2 is greater than about 10,000 nM. In some embodiments, the K value for D2 is greater than about 25,000 nM. In some embodiments, the K value for D2 is greater than about 50,000 nM. i

[0496] In some embodiments, the compounds of the present disclosure have low affinity for D2 (e.g., K values exceeding about 100 nM, about 200 nM, about 500 nM, about 750 nM, about 1,000 nM, about 1,500 nM, about 2,000 nM, about 10,000 nM, about 25,000 nM, or about 50,000 nM). In some embodiments, Compound No. 7 has low affinity for D2 (e.g., a K value exceeding about 50,000 nM). i In some embodiments, the compounds of the present disclosure have low affinity for D2 (e.g., K values exceeding about 100 nM, about 200 nM, about 500 nM, about 750 nM, about 1,000 nM, about 1,500 nM, about 2,000 nM, about 10,000 nM, about 25,000 nM, or about 50,000 nM). In some embodiments, Compound No. 7 has low affinity for D2 (e.g., a K value exceeding about 50,000 nM). i

[0497] ​​​​While not wishing to be bound by theory, non-selective 5-HT2 modulators (e.g., those targeting both 2A 5-HT and 2C ) neither alleviate, treat, nor prevent the symptoms of sleep disorders.

[0498] Furthermore, while not wishing to be bound by theory, modulating the function of 5-HT 2C neither alleviates, treats, nor prevents the symptoms of sleep disorders.

[0499] The biological activity of the compounds of the present disclosure may be determined using predicted human clearance (CL) and half-life in humans. Clearance was predicted using a relative growth scaling method with single-species scaling from monkey clearance. Human volume of distribution (V d ) was adjusted according to differences in plasma protein binding and predicted from animal V d assuming similar unbound V d across species. Human half-life (T 1 / 2 ) was calculated based on a one-compartment model using the relationship T 1 / 2 = 0.693 × (predicted V d / predicted CL).

[0500] In some embodiments, the predicted human half-life (t 1 / 2 ) is from about 10 hours to about 1 hour. In some embodiments, the predicted human half-life is about 10 hours. In some embodiments, the predicted human half-life is about 9 hours. In some embodiments, the predicted human half-life is about 8 hours. In some embodiments, the predicted human half-life is about 7 hours. In some embodiments, the predicted human half-life is about 6 hours. In some embodiments, the predicted human half-life is about 5 hours. In some embodiments, the predicted human half-life is about 4 hours. In some embodiments, the predicted human half-life is about 3 hours. In some embodiments, the predicted human half-life is about 2 hours. In some embodiments, the predicted human half-life is about 1 hour.

[0501] A patch-clamp electrophysiology system, e.g., SyncroPatch 384PE (Nanion), may be suitable for obtaining data related to ion currents in individual isolated cells.

[0502] SCORE™, a microcomputer-based sleep / wake and physiological monitoring system, may be suitable for determining sleep and wakefulness. The validation of the SCORE™ sleep stage discrimination algorithm in rodents and its utility in preclinical drug evaluation have been described previously (Van Gelder et al. 1991; Edgar et al., Psychopharmacology, 1991, 105: 374-380; Edgar et al., J Pharmacology & Experimental Therapeutics, 1997, 283: 757-769; Edgar et al., J. Pharmacol. Exp. Ther, 1997, 282: 420-429; Seidel et al., J Pharmacology & Experimental Therapeutics, 1995, 275: 263-273; Olive et al., J Pharmacology & Experimental Therapeutics, 1998, 285: 1073-1083).

[0503] The standard recording period for SCORE data may be 30 hours or more before and after treatment. Animals may be acclimated in the home / recording cage for at least 24 hours prior to the 30-hour pre-treatment baseline recording itself. Rats may be randomly assigned to treatment in parallel groups. Some rats may receive multiple active treatments, in which case at least a 7-day "washout period" elapses between each treatment.

[0504] Subjects are surgically prepared for EEG and EMG recording, analgesics are administered with antibiotics, and subsequent therapeutic delivery may follow via intraperitoneal or oral administration. Sleep and wakefulness may be determined using SCORE™.

[0505] Statistical significance between drugs and vehicle may be applied to data pooled every hour and screened using a post hoc Student's T test adjusted for repeated measures.

[0506] The compounds of the present disclosure may show improvement in sleep fragmentation, as confirmed by evaluating the sleep architecture and sleep quality endpoints of several dual acting H1 inverse agonist and 5-HT 2A antagonist compounds at this target.

[0507] In some aspects, sleep fragmentation is improved by either (i) decreasing the number of awakenings (measured by the number of transitions to wakefulness per hour) or (ii) increasing sleep consolidation (measured by the average sleep episode duration per hour). In some aspects, sleep fragmentation is improved by both (i) decreasing the number of awakenings (measured by the number of transitions to wakefulness per hour) and (ii) increasing sleep consolidation (measured by the average sleep episode duration per hour). In some aspects, sleep fragmentation is improved by decreasing the number of awakenings (measured by the number of transitions to wakefulness per hour). In some aspects, sleep fragmentation is improved by increasing sleep consolidation (measured by the average sleep episode duration per hour).

[0508] The usefulness of dual acting H1 inverse agonist and 5-HT 2A antagonist molecules for improving sleep fragmentation was confirmed by evaluating the sleep architecture and sleep quality endpoints of the compounds of the present disclosure.

[0509] H1 and 5-HT of the compounds of the present disclosure 2A The binding activity may be confirmed by using the assay of the present disclosure. In some embodiments, the H1 and 5-HT 2A binding activity of the compounds of the present disclosure is compared with another compound.

[0510] In some embodiments, the compound for comparison may be analyzed in comparison with a reference standard (e.g., ketanserin or pyrilamine). The compound for comparison may be transferred to the assay plate for non-specific binding or total binding amount. The assay plate may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with buffer. The filter plate may be dried and sealed. The inhibition constant may be calculated using the following formula: TIFF0007696354000043.tif9128 may be used for calculation and the data may be analyzed. IC 50 is calculated and K i may be converted.

[0511] The 5-HT 2C binding activity of the compounds of the present disclosure may be confirmed by using the assay of the present disclosure. In some embodiments, the 5-HT 2C binding activity of the compounds of the present disclosure is compared with another compound.

[0512] The biological activity of the compound for comparison may be determined using a binding assay. The binding assay may be for 5-HT 2C The compound for comparison may be analyzed in comparison with a reference standard, e.g., SB-206553 (i.e., 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole hydrochloride hydrate). The compound for comparison may be transferred to the assay plate for non-specific binding or total binding amount. The assay plate may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with buffer. The filter plate may be dried and sealed. The inhibition constant may be calculated using the following formula: It may be calculated using TIFF0007696354000044.tif10128, and the data was analyzed. IC 50 is calculated and K i may be converted to.

[0513] The D2 binding activity of the compounds of the present disclosure may be confirmed by using the assays of the present disclosure. In some embodiments, the D2 binding activity of the compounds of the present disclosure is compared to another compound.

[0514] The biological activity of the compound for comparison may be determined using a binding assay. The binding assay may be for D2. The compound for comparison may be analyzed compared to a reference standard, for example, droperidol (i.e., 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]-3,6-dihydro-2H-pyridin-4-yl]-1H-benzimidazol-2-one). The compound for comparison may be transferred to an assay plate for non-specific binding or total binding amount. The assay plate may be sealed and shaken. At the end of the assay, the reaction mixture may be filtered and washed with a buffer. The filter plate may be dried and sealed. The inhibition constant is given by the following formula: It may be calculated using TIFF0007696354000045.tif10128, and the data was analyzed. IC 50 is calculated and K i may be converted to.

[0515] Pharmaceutical compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure as active ingredients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0516] As used herein, the term "composition" is intended to encompass a product containing specific ingredients in specific amounts, as well as any product directly or indirectly resulting from a combination of specific amounts of specific ingredients.

[0517] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration using forms well known to those skilled in the pharmaceutical arts.

[0518] The formulations of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizers, chelating agents, preservatives, isotonic agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0519] Any suitable solubilizer can be used. Examples of solubilizers include cyclodextrins such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and those selected from the group consisting of mixtures thereof.

[0520] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0521] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropylbiguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0522] The aqueous vehicle may also contain an isotonic agent for adjusting isotonicity (osmotic pressure). The isotonic agent can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0523] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400, etc.), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers such as polymers of acrylic acid cross-linked with polyalkenyl ether or divinyl glycol (carbomers) (carbopol such as carbopol 934, carbopol 934P, carbopol 971, carbopol 974, and carbopol 974P), and those selected from the group consisting of mixtures thereof.

[0524] To adjust the formulation to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Thus, it may not be necessary to use both an acid and a base depending on the formulation, and the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0525] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffering agent is selected from the group consisting of phosphate buffering agents (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), boric acid buffering agents (such as boric acid or salts thereof containing disodium tetraborate), citric acid buffering agents (such as citric acid or salts thereof containing sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0526] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0527] According to a further aspect of the disclosure, there is provided a pharmaceutical composition comprising a compound of the disclosure as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0528] The disclosed compositions may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as micronized powders or liquid aerosols), administration by insufflation (e.g., as micronized powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0529] The disclosed compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may, for example, contain one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0530] An effective amount of the compound of the disclosure for use in therapy is an amount sufficient to treat or prevent a sleep disorder-related condition referred to herein, slow its progression, and / or reduce the symptoms associated with the condition.

[0531] An effective amount of a compound of the present disclosure for use in a method of treatment is an amount sufficient to treat a sleep disorder-related condition referred to herein, slow its progression, and / or reduce symptoms associated with the condition.

[0532] The magnitude of the dosage for therapeutic or prophylactic purposes of the compounds of formula (I), (II), and (II') will, of course, vary according to well-known medical principles depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration.

[0533] Method of Use Sleep fragmentation, a condition in humans characterized by insufficient sleep consolidation, includes frequent short awakenings or micro-awakenings (defined by the American Academy of Sleep Medicine as the manifestation of cortical EEG activation where sleep is interrupted, lasting at least 2 seconds up to a maximum of 16 seconds), as well as significant daytime dysfunction, significant secondary medical conditions, and, when sleep fragmentation is accompanied by pain, sleep disordered breathing, and other medical conditions, frequent transitions to lighter stages of sleep that can result in significant mortality. Daytime dysfunction can include decreased attention and concentration, excessive sleepiness, decreased judgment, decreased memory and learning, and increased risk of accidents. Subjects affected by sleep fragmentation typically are unaware of the hundreds of short awakenings that can occur during the night and mainly complain of severe daytime dysfunction. Subjects with sleep fragmentation often complain that sleep is neither beneficial nor refreshing.

[0534] The diagnosis of and method for treating sleep fragmentation are different from insomnia, which is a distinct and clearly different medical diagnosis. Insomnia is typically characterized by the subject's awareness of dissatisfaction with sleep. Most insomniacs have a hyperarousal disorder that makes it difficult to fall asleep and / or stay asleep, but can function well during the day. Insomnia is diagnosed by measuring the latency to persistent sleep (when LPS is ≥ 30 minutes, it meets the definition of insomnia with sleep onset disorder) and / or the length of wake time after sleep onset (WASO ≥ 50 minutes meets the definition of insomnia with sleep maintenance disorder). Insomniacs, especially the elderly, commonly wake up at night and are unable to return to sleep. Unlike subjects affected by sleep fragmentation, insomniacs are generally strongly aware that they can hardly fall asleep or stay asleep at night, complain about their nocturnal experiences, but typically do not complain about daytime dysfunction.

[0535] Aspects herein relate to the identification of classes of pharmacological compounds particularly suitable for treating sleep disorders characterized in whole or in part by sleep fragmentation. The compounds of the disclosure are dual H1 receptor inverse agonists and 5-HT receptor antagonists having activity as demonstrated by a decrease in the number of awakenings (measured as a decrease in the number of transitions to wakefulness per hour), an improvement in sleep continuity / consolidation (measured by the average sleep episode duration per hour), and an improvement in sleep depth (preclinically measured by electroencephalogram (EEG) spectral analysis to identify power in the EEG frequency band of 0.5 - 4.0 Hz (EEG "delta power")) to improve sleep fragmentation. 2A may be described as having antagonist activity.

[0536] The required H1 inverse agonist and 5-HT 2AMolecules with antagonist receptor pharmacological effects can be studied for their effects on EEG sleep-wakefulness, spontaneous motor activity, drinking and food-related activities, and body temperature in laboratory rats using an improved and extended version of the SCORE-2000® complex sleep-wake bioassay and analysis system, hereinafter referred to as "SCORE®".

[0537] The said technique is well-suited for the evaluation of effectiveness on sleep-wakefulness and physiological and behavioral side effects. A broad pharmacological database with standardized sleep-wakefulness, physiological, and behavioral data exists for over 500 distinct and different molecules related to this technique. The nature of the experimental design, data quality control, and data analysis methods are standardized, allowing for direct comparison between molecules.

[0538] Sleep in Rats and Humans The present disclosure provides preclinical drug evaluation using rats. Without wishing to be bound by theory, rat sleep and human sleep share all the essential similarities necessary to enable the use of rats as a preclinical model. Thus, a compound hypnotic in humans may have a hypnotic effect in rats, and a compound hypnotic in rats may have a hypnotic effect in humans. Both rats and humans exhibit a strong circadian modulation of the propensity for sleep and the architecture of sleep.

[0539] The "homeostatic" control of sleep is shared across mammalian species, including humans, in that sleep deprivation can be demonstrated by a decrease in sleep latency, an increase in the depth of sleep as reflected by the amount of slow-wave "delta" EEG during non-REM sleep ("EEG slow waves"), an improvement in the consolidation of sleep as measured by sleep episode duration, or an increase in total sleep time, which increases the homeostatic drive for sleep. Sleep deprivation in a subject can cause the subject to fall asleep earlier, sleep deeper, sleep more efficiently (e.g., further consolidation of sleep episodes), or sleep more (e.g., an increase in sleep time) until the homeostatic drive for sleep is fully depleted through the sleep process.

[0540] Sufficiently consolidated sleep without interruption can determine the quality of sleep in both rats and humans. Without wishing to be bound by theory, regardless of how much a subject sleeps or the frequency at which the EEG is dominant during sleep, it is necessary for the beneficial function of the sleep process that sleep is not disrupted (interrupted) by frequent awakenings.

[0541] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by reducing the latency to sleep onset, increasing the sleep time, improving the depth and / or consolidation of sleep, reducing awakenings, or a combination of the aforementioned effects, have the same effect in different subjects. Compounds of the present disclosure that affect non-REM sleep by reducing the effect on the latency to sleep onset in a subject may have the same effect on different species of subjects. Compounds of the present disclosure that affect non-REM sleep by reducing the effect on the latency to sleep onset in rats may have the same effect on different species of subjects. Compounds of the present disclosure that affect non-REM sleep by reducing the effect on the latency to sleep onset in rats may have the same effect on humans.

[0542] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by increasing the sleep time in a subject have the same effect on different subjects. Compounds of the present disclosure that affect non-REM sleep by increasing the sleep time in a subject may have the same effect on different species of subjects. Compounds of the present disclosure that affect non-REM sleep by increasing the sleep time in rats may have the same effect on different species of subjects. Compounds of the present disclosure that affect non-REM sleep by increasing the sleep time in rats may have the same effect on humans.

[0543] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by improving the depth and / or consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and / or consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and / or consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and / or consolidation of sleep in rats may have the same effect in humans.

[0544] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by improving the depth and consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth and consolidation of sleep in rats may have the same effect in humans.

[0545] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by improving the depth or consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth or consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth or consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth or consolidation of sleep in rats may have the same effect in humans.

[0546] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by improving the depth of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the depth of sleep in rats may have the same effect in humans.

[0547] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by improving the consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by improving the consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by improving the consolidation of sleep in rats may have the same effect in humans.

[0548] Without wishing to be bound by theory, the compounds of the present disclosure that affect non-REM sleep by reducing wakefulness in a subject have the same effect in different subjects. The compounds of the present disclosure that affect non-REM sleep by reducing wakefulness in a subject have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by reducing wakefulness in rats have the same effect in different species of subjects. The compounds of the present disclosure that affect non-REM sleep by reducing wakefulness in rats have the same effect in humans.

[0549] Without wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by decreasing the latency to sleep onset, increasing the sleep time, improving the depth and / or consolidation of sleep, reducing arousal, or a combination of the aforementioned effects in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by decreasing the effect on the latency to sleep onset in a subject may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by decreasing the effect on the latency to sleep onset in rats may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by decreasing the effect on the latency to sleep onset in rats may have the same effect on humans.

[0550] Without wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by increasing the sleep time in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by increasing the sleep time in a subject may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by increasing the sleep time in rats may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by increasing the sleep time in rats may have the same effect on humans.

[0551] Without wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by improving the depth and / or consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and / or consolidation of sleep in a subject may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and / or consolidation of sleep in rats may have the same effect on different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and / or consolidation of sleep in rats may have the same effect on humans.

[0552] While not wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by improving the depth and consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth and consolidation of sleep in rats may have the same effect in humans.

[0553] While not wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by improving the depth or consolidation of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by improving the depth or consolidation of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth or consolidation of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth or consolidation of sleep in rats may have the same effect in humans.

[0554] While not wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by improving the depth of sleep in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by improving the depth of sleep in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth of sleep in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving the depth of sleep in rats may have the same effect in humans.

[0555] While not wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by improving sleep consolidation in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by improving sleep consolidation in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving sleep consolidation in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by improving sleep consolidation in rats may have the same effect in humans.

[0556] While not wishing to be bound by theory, the compounds of the present disclosure that affect REM sleep by reducing wakefulness in a subject have the same effect in different subjects. The compounds of the present disclosure that affect REM sleep by reducing wakefulness in a subject may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by reducing wakefulness in rats may have the same effect in different species of subjects. The compounds of the present disclosure that affect REM sleep by reducing wakefulness in rats may have the same effect in humans.

[0557] While not wishing to be bound by theory, sleep duration can be measured as the duration of non-REM "episodes" or REM episodes, or the duration of non-REM + REM "episodes", and wakefulness, or wakefulness episodes, interrupt non-REM - REM cycles.

[0558] In some embodiments, a sleep episode can consist of non-REM, REM, or non-REM + REM.

[0559] In some embodiments, a sleep episode may consist of non-REM. In some embodiments, a sleep episode may consist of REM. In some embodiments, a sleep episode may consist of non-REM + REM.

[0560] In some aspects, non-REM and REM sleep occur alternately, sometimes referred to as the non-REM-REM cycle. In some aspects, non-REM precedes REM.

[0561] In some aspects, the ratio of the time spent in non-REM to REM is the same for different subjects. In some aspects, the ratio of the time spent in non-REM to REM is the same for different subjects of different species. In some aspects, the ratio of the time spent in non-REM to REM is the same for rats and subjects of different species. In some aspects, the ratio of the time spent in non-REM to REM is the same for rats and humans.

[0562] In some aspects, the ratio of the time spent in non-REM to REM is about 5:1. In some aspects, the ratio of the time spent in non-REM to REM is about 4:1. In some aspects, the ratio of the time spent in non-REM to REM is about 3:1. In some aspects, the ratio of the time spent in non-REM to REM is about 2:1.

[0563] In some embodiments, the ratio of time spent in non-REM to REM is from about 100:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 90:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 80:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 70:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 60:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 50:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 40:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 30:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 20:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 10:1 to about 1:1. In some embodiments, the ratio of time spent in non-REM to REM is from about 5:1 to about 1:1. In some embodiments, the species is a mouse. In some embodiments, the species is an ungulate. In some embodiments, the ungulate is a horse or a cow. In some embodiments, the species is not a laboratory rat. In some embodiments, the species is not a human.

[0564] In some embodiments, the sleep drug reduces REM sleep to some extent, and some classes of sleep disorder drugs can strongly suppress REM sleep. Without wishing to be bound by theory, suppression of REM sleep may be related to learning, memory, and / or psychiatric health.

[0565] Although not wishing to be bound by theory, the relative effects of some classes of drugs for sleep disorders, neuropsychiatric disorders, and cardiovascular diseases that inhibit or stimulate REM sleep can be transferred from one subject to another. The relative effects of some classes of drugs for sleep disorders, neuropsychiatric disorders, and cardiovascular diseases that inhibit or stimulate REM sleep can be transferred from one species of subject to another. The relative effects of some classes of drugs for sleep disorders, neuropsychiatric disorders, and cardiovascular diseases that inhibit or stimulate REM sleep can be transferred from rats to another species of subject. The relative effects of some classes of drugs for sleep disorders that inhibit or stimulate REM sleep can be transferred from laboratory rats to humans.

[0566] There are two differences that may exist between rat and human sleep. First, rats are nocturnal and humans are diurnal. This difference may not in itself be important for testing drug effects on sleep and wakefulness. When comparing rat and human sleep, the dosing timing with respect to the normal sleep period can vary depending on the time at which the drug effect on sleep-related variables (e.g., suppression of REM sleep) is to be evaluated. The difference between rats and humans is the length of the sleep episode, also called "sleep continuity". Further, humans consolidate sleep into one episode per day and may be interrupted only by short (e.g., less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute) wake episodes. In abnormal states, human sleep may be fragmented and the restorative effect of sleep may be diminished. Rats may have shorter sleep episodes throughout the 24-hour day (e.g., on average, rats complete a sleep-wake cycle every 20 minutes). At night (when rats are most active), sleep typically occupies about 1 / 3 of each 20-minute cycle and REM sleep is rare. During the day (when the lights are on), rats are typically asleep for about 2 / 3 of each 20-minute cycle. The polyphasic nature of sleep and the shorter duration of spontaneous sleep episodes in rats allow for a sensitive assessment of drug effects such as those that improve the consolidation of sleep (duration of the sleep episode) and reduce the number of awakenings (number of wake episodes), as well as various secondary but desirable measures of sleep quality, such as EEG slow-wave activity in non-REM sleep and a measure of wake maintenance measured by wake episode duration. The length of the sleep episode can also be a sensitive measure of physiological sleepiness and a preclinical predictor of hypnotic effects in humans.

[0567] Timing of treatment Empirical optimization can be performed by evaluating such compounds by administering a sleep-related compound at two circadian times, CT-18 and CT-5, defined as the start of lighting of CT-0. CT-18 is the midpoint of the active phase of the rat's circadian cycle at 6 hours after lights out, and may be susceptible to the hypnotic effect on the length of the sleep episode, but such effects can be observed at both CT-18 and CT-5. Since CT-5 starts at the peak of REM sleep over several hours, it is a time suitable for revealing drug-related inhibition of REM sleep. Both CT-18 and CT-5 are suitable times for evaluating the drug effect on sleep fragmentation measured by wakefulness (the number of wake episodes or the number of transitions to wakefulness), sleep consolidation (sleep episode duration), as well as maintaining wakefulness (the length of wake episodes) and evaluating drug-related side effects.

[0568] The preclinical effects observed at either CT-5 (treatment performed at a time corresponding to 5 hours after lighting) and / or CT-18 (treatment performed at a time corresponding to 18 hours after lighting or 6 hours after lights out when the animals are housed in a 24-hour light-dark cycle consisting of 12 hours of light period and 12 hours of dark period) are considered sufficient for the purpose of identifying compounds that can reduce sleep fragmentation.

[0569] Method of use In some embodiments, the disclosure provides a method of modulating an H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) comprising contacting a cell with an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method of alleviating the symptoms of a disease or disorder disclosed herein, treating the disease or disorder, or preventing the disease or disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the disclosure.

[0570] In some embodiments, H1 / 5-HT 2A modulating function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) alleviates the symptoms of a sleep disorder, treats a sleep disorder, or prevents a sleep disorder.

[0571] In some embodiments, H1 / 5-HT 2A modulating function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) alleviates the symptoms of a sleep disorder or treats a sleep disorder.

[0572] In some embodiments, H1 / 5-HT 2A modulating function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) treats a sleep disorder.

[0573] In some aspects, the present disclosure provides a method of alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0574] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0575] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0576] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating or preventing a disease or disorder.

[0577] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a disease or disorder.

[0578] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder.

[0579] In some embodiments, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder.

[0580] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder.

[0581] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder.

[0582] In some embodiments, the disease or disorder is a sleep disorder.

[0583] In some embodiments, the sleep disorder is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in the arousal threshold.

[0584] In some embodiments, the sleep fragmentation coexists with a medical condition.

[0585] In some embodiments, the sleep disorder is caused by or coexists with a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0586] In some aspects, the sleep disorder is caused by a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0587] In some aspects, the sleep disorder coexists with a medical condition, and the medical condition causes or exacerbates the sleep disorder.

[0588] In some aspects, the present disclosure provides a method of alleviating symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0589] In some aspects, the present disclosure provides a method of treating or preventing a sleep disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0590] In some aspects, the present disclosure provides a method of treating a sleep disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0591] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for alleviating symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0592] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for alleviating symptoms of a sleep disorder or treating a sleep disorder.

[0593] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a sleep disorder.

[0594] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0595] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating the symptoms of a sleep disorder or treating a sleep disorder.

[0596] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a sleep disorder.

[0597] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0598] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in alleviating the symptoms of a sleep disorder or treating a sleep disorder.

[0599] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a sleep disorder.

[0600] In some embodiments, H1 / 5-HT 2A modulating the function (e.g., in vitro or in vivo, dual acting H1 inverse agonist and 5-HT 2A antagonist activity) alleviates the symptoms of a sleep disorder, treats a sleep disorder, or prevents a sleep disorder.

[0601] In some embodiments, H1 / 5-HT 2A modulating the function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2AThe antagonist activity) alleviates the symptoms of sleep disorders or treats sleep disorders.

[0602] In some embodiments, H1 / 5-HT 2A modulating the function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) treats sleep disorders.

[0603] In some embodiments, the present disclosure provides a method of modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) by administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0604] In some embodiments, the present disclosure provides H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) for use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the present disclosure provides H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) for use in the manufacture of a medicament of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0606] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity).

[0607] In some embodiments, H1 / 5-HT 2A receptors regulate sleep. In some embodiments, H1 / 5-HT 2A regulation of function improves sleep disorders. In some embodiments, H1 / 5-HT 2A regulation of function improves disrupted sleep. In some embodiments, H1 / 5-HT 2A regulation of function improves sleep fragmentation. In some embodiments, H1 / 5-HT 2A regulation of function improves sleep-wakefulness. In some embodiments, H1 / 5-HT 2A regulation of function improves the arousal threshold. In some embodiments, H1 / 5-HT 2A receptors are upregulated. In some embodiments, H1 / 5-HT 2A receptors are downregulated.

[0608] In some embodiments, the present disclosure provides a method of modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) by administering to a subject a therapeutically effective amount of a compound of formula (I), (II), or (II') of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0609] In some embodiments, the present disclosure provides the use of a compound of formula (I), (II), or (II') of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof for modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity).

[0610] In some embodiments, the present disclosure provides H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2ATo provide the use of a compound of formula (I), (II), or (II') of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for modulating (antagonist activity).

[0611] In some embodiments, the present disclosure is H1 / 5-HT 2A Function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A To provide a compound of formula (I), (II), or (II') of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in modulating (antagonist activity).

[0612] In some embodiments, a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof is provided herein for treating sleep disorders. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided herein for treating sleep disorders. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided herein for treating sleep disorders. In some embodiments, a compound of formula (II') or a pharmaceutically acceptable salt thereof is provided herein for treating sleep disorders.

[0613] In some embodiments, a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof is provided for treating sleep disorders in a subject having a co-existing medical condition. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for treating sleep disorders in a subject having a co-existing medical condition. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided for treating sleep disorders in a subject having a co-existing medical condition. In some embodiments, a compound of formula (II') or a pharmaceutically acceptable salt thereof is provided for treating sleep disorders in a subject having a co-existing medical condition.

[0614] In some aspects, the present disclosure provides the use of a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (II') or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders.

[0615] In some aspects, the present disclosure provides the use of a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (II') or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders in a subject having a co-existing medical condition.

[0616] In some aspects, the present disclosure provides the use of a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders. In some aspects, the present disclosure provides the use of a compound of formula (II') or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders.

[0617] In some aspects, the present disclosure provides the use of a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides the use of a compound of formula (II') or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sleep disorders in a subject having a co-existing medical condition.

[0618] In some aspects, the present disclosure provides a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof for use in the treatment of sleep disorders. In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of sleep disorders. In some aspects, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof for use in the treatment of sleep disorders. In some aspects, the present disclosure provides a compound of formula (II') or a pharmaceutically acceptable salt thereof for use in the treatment of sleep disorders.

[0619] In some aspects, the present disclosure provides a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof for use in treating sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof for use in treating sleep disorders in a subject having a co-existing medical condition. In some aspects, the present disclosure provides a compound of formula (II') or a pharmaceutically acceptable salt thereof for use in treating sleep disorders in a subject having a co-existing medical condition.

[0620] In some aspects, the present disclosure provides a method of modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) by administering to a subject a therapeutically effective amount of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof.

[0621] In some aspects, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity).

[0622] In some aspects, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity).

[0623] In some aspects, the present disclosure is H1 / 5-HT 2A function (e.g., in vitro or in vivo, e.g., dual acting H1 inverse agonist and 5-HT 2A antagonist activity) for use in modulating the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof.

[0624] In some aspects, the present disclosure provides a method of alleviating symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder by administering to a subject a therapeutically effective amount of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof.

[0625] In some aspects, the present disclosure provides a method of alleviating symptoms of a sleep disorder or treating a sleep disorder by administering to a subject a therapeutically effective amount of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof.

[0626] In some aspects, the present disclosure provides a method of treating a sleep disorder by administering to a subject a therapeutically effective amount of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof.

[0627] In some aspects, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for alleviating symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0628] In some aspects, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for alleviating symptoms of a sleep disorder or treating a sleep disorder.

[0629] In some aspects, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for treating a sleep disorder.

[0630] In some embodiments, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0631] In some embodiments, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating the symptoms of a sleep disorder or treating a sleep disorder.

[0632] In some embodiments, the present disclosure provides the use of compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a sleep disorder.

[0633] In some embodiments, the present disclosure provides compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for use in alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder.

[0634] In some embodiments, the present disclosure provides compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for use in alleviating the symptoms of a sleep disorder or treating a sleep disorder.

[0635] In some embodiments, the present disclosure provides compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof for use in treating a sleep disorder.

[0636] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder is caused by or coexists with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance withdrawal symptoms, narcolepsy, a mental disorder, an increased sensitivity to pain, a cardiovascular disease, hypertension, non-restorative sleep, a stroke, a metabolic disorder, or a cognitive disorder.

[0637] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder is caused by sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance withdrawal symptoms, narcolepsy, a mental disorder, an increased sensitivity to pain, a cardiovascular disease, hypertension, non-restorative sleep, a stroke, a metabolic disorder, or a cognitive disorder.

[0638] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder coexists with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance withdrawal symptoms, narcolepsy, a mental disorder, an increased sensitivity to pain, a cardiovascular disease, hypertension, non-restorative sleep, a stroke, a metabolic disorder, or a cognitive disorder.

[0639] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder is caused by or coexists with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance abuse withdrawal symptoms, narcolepsy, a mental disorder, or non-restorative sleep.

[0640] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder is caused by sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance abuse withdrawal symptoms, narcolepsy, a mental disorder, or non-restorative sleep.

[0641] In some aspects, the present disclosure is directed to alleviating the symptoms of, treating, or preventing a sleep disorder, which is an increase in disrupted sleep, an increase in sleep fragmentation, an increase in awakenings, or a decrease in arousal threshold in a subject, and the sleep disorder coexists with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), a neurological disorder, a circadian rhythm disorder, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, substance abuse, substance abuse withdrawal symptoms, narcolepsy, a mental disorder, or non-restorative sleep.

[0642] In some embodiments, the sleep disorder is caused by or coexists with one or more types of pain.

[0643] In some embodiments, the sleep disorder is caused by one or more types of pain.

[0644] In some embodiments, the sleep disorder coexists with one or more types of pain.

[0645] In some embodiments, the pain is selected from inflammatory pain, nociceptive pain, neuropathic pain, a mixed nociceptive and neuropathic pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia, back pain, cancer pain, and osteoarthritic pain.

[0646] In some embodiments, the pain is chronic pain.

[0647] In some embodiments, the pain is arthritic pain.

[0648] In some embodiments, the pain is inflammatory pain.

[0649] In some embodiments, the inflammatory pain is arthritis. In some embodiments, the arthritis is rheumatoid arthritis. In some embodiments, the arthritis is osteoarthritis.

[0650] In some embodiments, the pain is nociceptive pain. In some embodiments, the nociceptive pain is acute. In some embodiments, the nociceptive pain is chronic. In some embodiments, the nociceptive pain is caused by cancer treatment. In some embodiments, the nociceptive pain is caused by surgery.

[0651] In some embodiments, the pain is neuropathic pain. In some embodiments, the neuropathic pain is chronic. In some embodiments, the neuropathic pain is acute. In some embodiments, the neuropathic pain is back pain. In some embodiments, the neuropathic pain is caused by spinal cord injury. In some embodiments, the neuropathic pain is caused by multiple sclerosis. In some embodiments, the neuropathic pain is caused by stroke. In some embodiments, the neuropathic pain is caused by diabetes. In some embodiments, the neuropathic pain is caused by metabolic conditions.

[0652] In some embodiments, the pain is a mixed pain of nociceptive and neuropathic.

[0653] In some embodiments, the pain is postoperative pain.

[0654] In some embodiments, the pain is postherpetic neuralgia.

[0655] In some embodiments, the pain is traumatic pain. In some embodiments, the trauma pain is caused by burning pain.

[0656] In some embodiments, the pain is phantom limb pain.

[0657] In some embodiments, the pain is fibromyalgia.

[0658] In some embodiments, the pain is back pain. In some embodiments, the pain is low back pain.

[0659] In some embodiments, the pain is cancer pain. In some embodiments, the cancer pain is cancer. In some embodiments, the cancer pain is caused by a tumor. In some embodiments, the cancer pain is caused by cancer treatment. In some embodiments, the cancer pain is caused by chemotherapy. In some embodiments, the cancer pain is radiation therapy. In some embodiments, the cancer pain is caused by surgery.

[0660] In some embodiments, the pain is osteoarthritic pain.

[0661] In some embodiments, the pain may be characterized by a mood change.

[0662] In some embodiments, the sleep disorder is caused by or coexists with sleep apnea.

[0663] In some embodiments, the sleep disorder is caused by sleep apnea.

[0664] In some embodiments, the sleep disorder coexists with sleep apnea.

[0665] In some embodiments, the sleep apnea is obstructive sleep apnea.

[0666] In some embodiments, the sleep apnea is obstructive sleep apnea, which is due to a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA), with or without associated apnea.

[0667] In some embodiments, the sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA), with associated apnea.

[0668] In some embodiments, the sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA), with or without associated hypopnea.

[0669] In some embodiments, the sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA), with associated hypopnea.

[0670] In some embodiments, sleep apnea is obstructive sleep apnea with a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA), with or without an accompanying acute hemoglobin desaturation.

[0671] In some embodiments, sleep apnea is obstructive sleep apnea with a high respiratory disturbance index (RDI) associated with an increase in respiratory effort related arousals (RERA) and an accompanying acute hemoglobin desaturation.

[0672] In some embodiments, obstructive sleep apnea may be characterized by excessive daytime sleepiness.

[0673] In some embodiments, obstructive sleep apnea may be characterized by the presence of cardiovascular biomarkers.

[0674] In some embodiments, sleep apnea is central sleep apnea.

[0675] In some embodiments, sleep apnea is hypopnea with a low arousal threshold.

[0676] In some embodiments, sleep apnea is hypopnea.

[0677] In some embodiments, a sleep disorder is caused by or coexists with restless legs syndrome.

[0678] In some embodiments, a sleep disorder is caused by restless legs syndrome.

[0679] In some embodiments, a sleep disorder coexists with restless legs syndrome.

[0680] In some embodiments, a sleep disorder is caused by or coexists with a high respiratory disturbance index (RDI).

[0681] In some embodiments, a sleep disorder is caused by a high respiratory disturbance index (RDI).

[0682] In some embodiments, the sleep disorder coexists with a high respiratory disturbance index (RDI).

[0683] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs), regardless of whether apnea is associated.

[0684] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs) that are associated with apnea.

[0685] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs), regardless of whether hypopnea is associated.

[0686] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs) that are associated with hypopnea.

[0687] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs), regardless of whether acute hemoglobin desaturation is associated.

[0688] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs) that are associated with acute hemoglobin desaturation.

[0689] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs), regardless of whether hemoglobin desaturation is associated.

[0690] In some embodiments, the RDI is associated with an increase in respiratory effort related arousals (RERAs) that are associated with hemoglobin desaturation.

[0691] In some embodiments, the sleep disorder is caused by or coexists with mental disorders.

[0692] In some embodiments, the sleep disorder is caused by mental disorders.

[0693] In some aspects, the sleep disorder coexists with a mental disorder.

[0694] In some aspects, the mental disorder is depression, major depressive disorder, post-traumatic stress disorder, anxiety disorder, bipolar disorder, or schizophrenia.

[0695] In some aspects, the mental disorder is depression. In some aspects, the mental disorder is major depressive disorder. In some aspects, the mental disorder is post-traumatic stress disorder. In some aspects, the mental disorder is anxiety disorder. In some aspects, the mental disorder is bipolar disorder. In some aspects, the mental disorder is schizophrenia.

[0696] In some aspects, post-traumatic stress disorder may be characterized by the occurrence of nightmares.

[0697] In some aspects, post-traumatic stress disorder may be characterized by a decrease in sleep quality.

[0698] In some aspects, post-traumatic stress disorder may be characterized by disruptive nocturnal behavior.

[0699] In some aspects, post-traumatic stress disorder may coexist with depression.

[0700] In some aspects, post-traumatic stress disorder may coexist with anxiety.

[0701] In some aspects, the sleep disorder is caused by or coexists with a neurological disorder.

[0702] In some aspects, the sleep disorder is caused by a neurological disorder.

[0703] In some aspects, the sleep disorder coexists with a neurological disorder.

[0704] In some aspects, the neurological disorder is a neurodegenerative disorder.

[0705] In some aspects, the neurodegenerative disease is Lewy body disease (i.e., Lewy body dementia). In some aspects, the Lewy body disease is diffuse.

[0706] In some aspects, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some aspects, the neurodegenerative disease is Huntington's disease. In some aspects, the neurodegenerative disease is Parkinson's disease. In some aspects, the neurodegenerative disease is Alzheimer's disease. In some aspects, the neurodegenerative disease is synucleinopathy.

[0707] In some aspects, the synucleinopathy is Alzheimer's disease, Parkinson's disease, or Lewy body dementia. In some aspects, the synucleinopathy is Alzheimer's disease. In some aspects, the synucleinopathy is Parkinson's disease. In some aspects, the synucleinopathy is Lewy body type dementia. In some aspects, the synucleinopathy is multiple system atrophy.

[0708] In some aspects, Parkinson's disease may be characterized by sleep disturbances associated with Parkinson's disease.

[0709] In some aspects, Parkinson's disease may be characterized by the occurrence of nightmares.

[0710] In some aspects, Parkinson's disease may be characterized by the occurrence of hallucinations.

[0711] In some aspects, Parkinson's disease may be characterized by excessive daytime sleepiness.

[0712] In some aspects, Alzheimer's disease may be characterized by a sleep disorder associated with Alzheimer's disease.

[0713] In some aspects, Alzheimer's disease may be characterized by nocturnal wandering.

[0714] In some embodiments, the neurological disorder is a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder is autism. In some embodiments, the neurological disorder is dystonia. In some embodiments, the dystonia is neuromuscular dystonia. In some embodiments, the neuromuscular dystonia is spasmodic torticollis.

[0715] In some embodiments, the neurological disorder is multiple sclerosis (MS).

[0716] In some embodiments, the sleep disorder is caused by or coexists with a circadian rhythm disorder.

[0717] In some embodiments, the sleep disorder is caused by a circadian rhythm disorder.

[0718] In some embodiments, the sleep disorder coexists with a circadian rhythm disorder.

[0719] In some embodiments, the circadian rhythm disorder is advanced sleep-wake phase disorder. In some embodiments, the circadian rhythm disorder is irregular sleep-wake rhythm disorder. In some embodiments, the circadian rhythm disorder is jet lag. In some embodiments, the circadian rhythm disorder is shift work sleep disorder. In some embodiments, the circadian rhythm disorder is delayed sleep phase syndrome. In some embodiments, the circadian rhythm disorder is non-24-hour rhythm disorder.

[0720] In some embodiments, the sleep disorder is caused by or coexists with fragmented sleep in the elderly.

[0721] In some embodiments, the sleep disorder is caused by fragmented sleep in the elderly.

[0722] In some embodiments, the sleep disorder coexists with fragmented sleep in the elderly.

[0723] In some embodiments, the sleep disorder is caused by or coexists with age-related fragmentation of sleep.

[0724] In some embodiments, the sleep disorder is caused by age-related fragmentation of sleep.

[0725] In some embodiments, the sleep disorder coexists with age-related fragmentation of sleep.

[0726] In some embodiments, the sleep disorder is caused by or coexists with postmenopausal sleep disorder.

[0727] In some embodiments, a sleep disorder caused by postmenopausal sleep disorder.

[0728] In some embodiments, the sleep disorder coexists with postmenopausal sleep disorder.

[0729] In some embodiments, the sleep disorder is caused by or coexists with substance abuse.

[0730] In some embodiments, the sleep disorder is caused by substance abuse.

[0731] In some embodiments, the sleep disorder coexists with substance abuse.

[0732] In some embodiments, the substance abuse is opioid abuse or alcohol dependence. In some embodiments, the substance abuse is opioid abuse. In some embodiments, the substance abuse is alcohol dependence.

[0733] In some embodiments, the sleep disorder is caused by or coexists with substance withdrawal symptoms.

[0734] In some embodiments, the sleep disorder is caused by substance withdrawal symptoms.

[0735] In some embodiments, the sleep disorder coexists with substance withdrawal symptoms.

[0736] In some embodiments, the substance use withdrawal symptoms are opioid withdrawal symptoms or alcohol withdrawal symptoms. In some embodiments, the substance use withdrawal symptoms are opioid withdrawal symptoms. In some embodiments, the substance use withdrawal symptoms are alcohol withdrawal symptoms.

[0737] In some embodiments, the sleep disorder is caused by or coexists with narcolepsy.

[0738] In some embodiments, the sleep disorder is caused by narcolepsy.

[0739] In some embodiments, the sleep disorder coexists with narcolepsy.

[0740] In some embodiments, the sleep disorder is caused by or coexists with periodic limb movement disorder (PLMD).

[0741] In some embodiments, the sleep disorder is caused by periodic limb movement disorder (PLMD).

[0742] In some embodiments, the sleep disorder coexists with periodic limb movement disorder (PLMD).

[0743] In some embodiments, the sleep disorder is caused by or coexists with REM sleep behavior disorder.

[0744] In some embodiments, the sleep disorder is caused by REM sleep behavior disorder.

[0745] In some embodiments, the sleep disorder coexists with REM sleep behavior disorder.

[0746] In some embodiments, the sleep disorder is caused by or coexists with fragmented sleep in the elderly.

[0747] In some embodiments, the sleep disorder is caused by fragmented sleep in the elderly.

[0748] In some embodiments, the sleep disorder coexists with fragmented sleep in the elderly.

[0749] In some embodiments, the sleep disorder is caused by or coexists with idiopathic hypersomnia.

[0750] In some embodiments, the sleep disorder is caused by idiopathic hypersomnia.

[0751] In some embodiments, the sleep disorder coexists with idiopathic hypersomnia.

[0752] In some embodiments, the sleep disorder is caused by or coexists with non-restorative sleep.

[0753] In some embodiments, the sleep disorder is caused by non-restorative sleep.

[0754] In some embodiments, the sleep disorder coexists with non-restorative sleep.

[0755] In some embodiments, the sleep disorder is caused by or coexists with snoring.

[0756] In some embodiments, the sleep disorder is caused by snoring.

[0757] In some embodiments, the sleep disorder coexists with snoring.

[0758] In some embodiments, the sleep disorder is caused by or coexists with increased sensitivity to pain.

[0759] In some embodiments, the sleep disorder is caused by increased sensitivity to pain.

[0760] In some embodiments, the sleep disorder coexists with increased sensitivity to pain.

[0761] In some aspects, sleep disorders are caused by or coexist with cardiovascular diseases.

[0762] In some aspects, sleep disorders are caused by cardiovascular diseases.

[0763] In some aspects, sleep disorders coexist with cardiovascular diseases.

[0764] In some aspects, sleep disorders are caused by or coexist with hypertension.

[0765] In some aspects, sleep disorders are caused by hypertension.

[0766] In some aspects, sleep disorders coexist with hypertension.

[0767] In some aspects, sleep disorders are caused by or coexist with stroke.

[0768] In some aspects, sleep disorders are caused by stroke.

[0769] In some aspects, sleep disorders coexist with stroke.

[0770] In some aspects, sleep disorders are caused by or coexist with metabolic diseases.

[0771] In some aspects, sleep disorders are caused by metabolic diseases.

[0772] In some aspects, sleep disorders coexist with metabolic diseases.

[0773] In some aspects, the metabolic disease is diabetes.

[0774] In some aspects, sleep disorders are caused by or coexist with cognitive impairment.

[0775] In some embodiments, the sleep disorder is caused by a cognitive disorder.

[0776] In some embodiments, the sleep disorder coexists with a cognitive disorder.

[0777] This disclosure provides compounds that function as modulators of H1 / 5-HT 2A function. Accordingly, this disclosure provides methods of modulating H1 inverse agonism and 5-HT 2A antagonism in vitro or in vivo. The methods include contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined herein.

[0778] The effectiveness of the disclosed compounds can be determined by standard practices for elucidating effectiveness as described in the art and by industry-accepted assays or disease models found in current general knowledge.

[0779] This disclosure also provides methods of treating a disease or disorder in a subject in need thereof in which H1 / 5-HT 2A function is involved, the method by administering to the subject a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0780] The compounds of this disclosure or pharmaceutically acceptable salts thereof may be administered alone as the sole therapy or may be administered with one or more other substances and / or treatments. In some embodiments, one or more other substances and / or treatments and the compounds of this disclosure or pharmaceutically acceptable salts thereof may be administered in temporal proximity. Such co-therapies may be achieved by simultaneous, sequential, or separate administration of the individual components of the therapy.

[0781] In some embodiments, the methods of the present disclosure involve administering the compounds of the present disclosure and an additional active agent. In some embodiments, the additional active agent may be, for example, a hypnotic sedative.

[0782] In some embodiments, the methods of the present disclosure include administering the compound of the present disclosure or a pharmaceutically acceptable derivative thereof alone.

[0783] In some embodiments, the methods of the present disclosure include administering the compound of the present disclosure or a pharmaceutically acceptable derivative thereof in combination with a single additional active agent.

[0784] In some embodiments, the methods of the present disclosure include administering the compound of the present disclosure or a pharmaceutically acceptable derivative thereof and a combination of active agents.

[0785] In some embodiments, the methods of the present disclosure involve administering the compound of the present disclosure, if present, at any time before sleep (hora somni), i.e., h.s. (at bedtime), or from 0 to about 4 hours before bedtime.

[0786] In some embodiments, the methods of the present disclosure involve administering the compound of the present disclosure, if present, at bedtime, i.e., h.s.

[0787] In some embodiments, the methods of the present disclosure involve administering the compound of the present disclosure and any additional active agent from 0 to about 4 hours before bedtime.

[0788] In some embodiments, the methods of the present disclosure involve administering the compound of the present disclosure and any additional active agent about 1 hour before bedtime.

[0789] In some embodiments, the methods of the present disclosure involve administering the compound of the present disclosure and any additional active agent about 2 hours before bedtime.

[0790] In some embodiments, the methods of the disclosure involve administering the compounds of the disclosure and any additional active agent about 3 hours before bedtime.

[0791] In some embodiments, the methods of the disclosure involve administering the compounds of the disclosure and any additional active agent about 4 hours before bedtime.

[0792] For example, the therapeutic effect can be enhanced by the administration of an adjuvant (i.e., the adjuvant alone may have minimal therapeutic effect, but when combined with other therapeutic agents, the overall therapeutic effect on the individual is enhanced). Alternatively, by way of mere illustration, the benefits experienced by an individual can be increased by administering a compound of formula (I), (II), or (II') together with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic advantage.

[0793] When the compounds of the disclosure are administered in combination with other therapeutic agents, the disclosed compounds need not be administered via the same route as the other therapeutic agents and may be administered via different routes due to their different physical and chemical properties. For example, the compounds of the disclosure may be administered orally to produce and maintain a good blood concentration thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be carried out according to established protocols known in the art, and then, based on the observed effects, the dosage, mode of administration, and administration time can be changed by a skilled clinician.

[0794] The specific selection of other therapeutic agents is thought to vary depending on the diagnosis of the attending physician and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination for use in the treatment of sleep disorders comprising a disclosed compound or a pharmaceutically acceptable salt thereof as defined above and another suitable agent.

[0795] According to a further aspect of the disclosure, there is provided a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0796] In addition to their use in therapeutic medicine, the compounds of formula (I), (II), or (II') and their pharmaceutically acceptable salts are, as part of the search for new therapeutic agents, H1 / 5-HT in experimental animals such as dogs, rabbits, monkeys, rats, and mice 2A They are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of function.

[0797] In some embodiments, the methods of the disclosure include administering the compounds of the disclosure or their pharmaceutically acceptable salts either alone or in combination with a single additional active agent.

[0798] In some embodiments, the methods of the disclosure include administering the compounds of the disclosure or their pharmaceutically acceptable salts in combination with a single additional active agent.

[0799] In some embodiments, the methods of the disclosure include administering the compounds of the disclosure or their pharmaceutically acceptable salts and a combination of active agents.

[0800] In some embodiments, the methods of the disclosure include administering the compounds of the disclosure or their pharmaceutically acceptable salts to a subject as combination therapy with a treatment based on a medical device.

[0801] In some embodiments, the methods of the disclosure include administering the compounds of the disclosure or their pharmaceutically acceptable salts to a subject as combination therapy with a treatment based on a medical device such as continuous positive airway pressure (CPAP) technology or transcranial magnetic stimulation or transcranial electromagnetic stimulation technology.

[0802] In some embodiments, the methods of the disclosure include administering the compounds of formula (I), (II), or (II') or their pharmaceutically acceptable salts either alone or in combination with a single additional active agent.

[0803] In some embodiments, the methods of the present disclosure include administering a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof in combination with a single additional active agent.

[0804] In some embodiments, the methods of the present disclosure include administering a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof and a combination of active agents.

[0805] In some embodiments, the methods of the present disclosure include administering a compound of formula (I), formula (II), or formula (II') or a pharmaceutically acceptable salt thereof as a combination therapy with a treatment based on a medical device.

[0806] In some embodiments, the methods of the present disclosure include administering a compound of formula (I), (II), or (II') or a pharmaceutically acceptable salt thereof as a combination therapy with a treatment based on a medical device such as continuous positive airway pressure (CPAP) technology or transcranial magnetic stimulation or transcranial electromagnetic stimulation technology.

[0807] In some embodiments, the methods of the present disclosure include administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof either alone or in combination with a single additional active agent.

[0808] In some embodiments, the methods of the present disclosure include administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in combination with a single additional active agent.

[0809] In some embodiments, the methods of the present disclosure include administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and a combination of active agents.

[0810] In some embodiments, the methods of the present disclosure include administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as a combination therapy with a treatment based on a medical device.

[0811] In some embodiments, the method of the present disclosure comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as combination therapy with a treatment based on a medical device such as continuous positive airway pressure (CPAP) technology or transcranial magnetic stimulation or transcranial electromagnetic stimulation technology.

[0812] In some embodiments, the method of the present disclosure comprises administering compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof either alone or in combination with a single additional active agent.

[0813] In some embodiments, the method of the present disclosure comprises administering compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof in combination with a single additional active agent.

[0814] In some embodiments, the method of the present disclosure comprises administering compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof and a combination of active agents.

[0815] In some embodiments, the method of the present disclosure comprises administering compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof as combination therapy with a treatment based on a medical device.

[0816] In some embodiments, the method of the present disclosure comprises administering compound 30, 31, 34, or 35 or a pharmaceutically acceptable salt thereof as combination therapy with a treatment based on a medical device such as continuous positive airway pressure (CPAP) technology or transcranial magnetic stimulation or transcranial electromagnetic stimulation technology.

[0817] In some embodiments, the treatment based on a medical device is continuous positive airway pressure (CPAP) technology, transcranial magnetic stimulation technology, or transcranial electromagnetic stimulation technology.

[0818] In some embodiments, the treatment based on a medical device is continuous positive airway pressure (CPAP) technology.

[0819] In some embodiments, the treatment based on the medical device is transcranial magnetic stimulation technology.

[0820] In some embodiments, the treatment based on the medical device is transcranial electrical stimulation technology.

[0821] In some embodiments, the method of the present disclosure includes administering a compound of formula (I) or formula (II) to a subject as a combination therapy with cognitive behavioral therapy (CBT).

[0822] In some embodiments, CBT is brief cognitive behavioral therapy (BCBT), cognitive emotional behavioral therapy (CEBT), structured cognitive behavioral training (SCBT), moral reconation therapy, stress inoculation training, or activity-based CBT.

[0823] In some embodiments, CBT is brief cognitive behavioral therapy (BCBT).

[0824] In some embodiments, CBT is cognitive emotional behavioral therapy (CEBT).

[0825] In some embodiments, CBT is structured cognitive behavioral training (SCBT).

[0826] In some embodiments, CBT is moral reconation therapy.

[0827] In some embodiments, CBT is stress inoculation training.

[0828] In some embodiments, CBT is activity-based CBT.

[0829] In some embodiments, the compounds of the present disclosure may improve sleep fragmentation.

[0830] Sleep fragmentation can be confirmed by evaluating the depth of sleep architecture and sleep endpoints obtained from a sleep polygraph, including the number of awakenings (measured by the number of transitions from sleep to wakefulness), sleep continuity / consolidation (measured by the average duration of sleep episodes), and the depth of sleep measured by EEG delta power (Fourier analysis-derived power in the 0.5 - 4.0 Hz band in cortical EEG during non-REM sleep).

[0831] Sleep fragmentation can be confirmed by evaluating the depth of sleep architecture and sleep endpoints obtained from a sleep polygraph, including the number of awakenings (measured by the number of transitions from sleep to wakefulness). Sleep fragmentation can be confirmed by evaluating the depth of sleep architecture and sleep endpoints obtained from a sleep polygraph, including sleep continuity / consolidation (measured by the average duration of sleep episodes). Sleep fragmentation can be confirmed by evaluating the depth of sleep architecture and sleep endpoints obtained from a sleep polygraph, including the depth of sleep measured by EEG delta power (Fourier analysis-derived power in the 0.5 - 4.0 Hz band in cortical EEG during non-REM sleep).

[0832] In some embodiments, the compounds of the present disclosure meet the minimal co-primary preclinical endpoints for identifying molecules that reduce sleep fragmentation.

[0833] In some embodiments, the compounds of the present disclosure may improve other measures of sleep quality indicative of molecules that promote sleep maintenance.

[0834] In some embodiments, the compounds of the present disclosure may improve other measures of sleep quality indicative of molecules that promote sleep maintenance, as demonstrated by an improvement in the depth of sleep measured by EEG or by indirectly using other behavioral parameters.

[0835] In some embodiments, the compounds of the present disclosure can improve sleep fragmentation without causing certain undesirable side effects. In some embodiments, the undesirable side effects are selected from muscle relaxation, motor dysfunction, absence of rebound insomnia, and significant changes in sleep stage architecture (e.g., percentage of sleep stages per unit time).

[0836] In some embodiments, the undesirable side effect is muscle relaxation.

[0837] In some embodiments, the undesirable side effect is motor dysfunction.

[0838] In some embodiments, the undesirable side effect is rebound insomnia.

[0839] In some embodiments, the undesirable side effect is a significant change in sleep stage architecture.

[0840] In any of the above pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features of the present disclosure, any of the alternative embodiments of the polymers of the present disclosure described herein are applicable.

[0841] Route of administration The disclosed compounds, or pharmaceutical compositions containing these compounds, can be administered to a subject by any convenient route of administration, whether systemic / peripheral or topical (i.e., at the site of the desired action).

[0842] The administration routes include oral (e.g., by ingestion); buccal; sublingual; transdermal (including those by patch, plaster, etc.); transmucosal (including those by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., via aerosol, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; including, for example, subcutaneous or intramuscular, non-limitingly including depot or reservoir implantation.

[0843] Exemplary embodiments Embodiment No. 1. A compound of formula (I), TIFF0007696354000046.tif43128 wherein, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or R1 and R2, together with the atom to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3-14 membered saturated or partially unsaturated heterocycle containing 1-5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, provided that at least one of R3, R4, R5, and R6 is H, a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. Embodiment No. 2. A compound of formula (II), wherein TIFF0007696354000047.tif35128 wherein X is CR7R8, O, S, or NR7; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or R1 and R2, together with the atoms to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, provided that however, (a) when R5 is H, X is CR7R8 or S; (b) when R5 is halogen and R4 is H, R3 is not methyl, not methoxyl, and not Br, and X is CR7R8 or S; and (c) when R5 is methoxyl or methyl, R4 is not H, a compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. Embodiment No. 3. A compound of formula (II'), TIFF0007696354000048.tif43128 wherein X is CR7R8, O, S, or NR7; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; or R1 and R2, together with the atom to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S; R3 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R4 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R5 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R6 is H, halogen, -S(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl; R7 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R8 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; and R 10 is H or halogen, but provided that (a) (i) when R5 is H, X is CR7R8 or S, or (ii) when R5 is H and X is O, R 10 is halogen; (b) when R5 is halogen and R4 is H, R3 is not methyl, not methoxyl, and not Br, and X is CR7R8 or S; and (c) when R5 is methoxyl or methyl, R4 is not H, A compound, or a prodrug, solvate, or pharmaceutically acceptable salt thereof. The compound of embodiment 2, wherein aspect number 4, X is O or CR7R8. The compound of embodiment 2, wherein aspect number 5, X is O. The compound of embodiment 2, wherein aspect number 6, X is CH2. The compound of any of the above aspects, wherein aspect number 7, R1 is C1-C6 alkyl. The compound of any of the above aspects, wherein aspect number 8, R1 is methyl. The compound of any one of the above aspects, wherein aspect number 9, R2 is C1-C6 alkyl. The compound of any of the above aspects, wherein aspect number 10, R2 is methyl. The compound of any of the above aspects, wherein aspect number 11, R1 and R2, together with the atom to which they are attached, form a C3-C6 saturated or partially unsaturated cycloalkyl, or a 3- to 14-membered saturated or partially unsaturated heterocycle containing 1 to 5 heteroatoms selected from N, O, and S. The compound of any of the above aspects, wherein aspect number 12, R1 and R2, together with the atom to which they are attached, form cyclopropyl. The compound of any of the above aspects, wherein aspect number 13, R3 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxyl. The compound of any one of the above aspects, wherein aspect number 14, R3 is H, F, Cl, methyl, or methoxyl. The compound of any of the above aspects, wherein aspect number 15, R3 is H. The compound of any of the above aspects, wherein aspect number 16, R3 is F. The compound of any of the above aspects, wherein aspect number 17, R3 is Cl. The compound of any of the above aspects, wherein aspect number 18, R3 is methyl. The compound of any of the above aspects, wherein aspect number 19, R3 is methoxyl. The compound of any of the above aspects, wherein aspect number 20, R4 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. A compound of any of the above aspects, wherein aspect number 21. R4 is H, F, Cl, methyl, or CHF2. A compound of any of the above aspects, wherein aspect number 22. R4 is H. A compound of any of the above aspects, wherein aspect number 23. R4 is F. A compound of any of the above aspects, wherein aspect number 24. R4 is Cl. A compound of any of the above aspects, wherein aspect number 25. R4 is methyl. A compound of any of the above aspects, wherein aspect number 26. R4 is CHF2. A compound of any of the above aspects, wherein aspect number 27. R5 is H, halogen, C1-C6 alkyl, C1-C6 alkoxyl, S(C1-C6 alkyl), or C1-C6 haloalkyl. A compound of any of the above aspects, wherein aspect number 28. R5 is H, F, Cl, methyl, ethyl, isopropyl, n-propyl, methoxyl, -SCH3, or CHF2. A compound of any of the above aspects, wherein aspect number 29. R5 is H. A compound of any of the above aspects, wherein aspect number 30. R5 is F. A compound of any of the above aspects, wherein aspect number 31. R5 is Cl. A compound of any of the above aspects, wherein aspect number 32. R5 is methyl. A compound of any of the above aspects, wherein aspect number 33. R5 is ethyl. A compound of any of the above aspects, wherein aspect number 34. R5 is isopropyl. A compound of any of the above aspects, wherein aspect number 35. R5 is n-propyl. A compound of any of the above aspects, wherein aspect number 36. R5 is methoxyl. A compound of any of the above aspects, wherein aspect number 37. R5 is methylthio. A compound of any of the above aspects, wherein aspect number 38. R5 is CHF2. A compound of any of the above aspects, wherein aspect number 39. R6 is H, C1-C6 alkyl, or C1-C6 alkoxyl. A compound of any of the above aspects, wherein aspect number 40, R6 is H, methyl, or methoxyl. A compound of any of the above aspects, wherein aspect number 41, R6 is H. A compound of any of the above aspects, wherein aspect number 42, R6 is methyl. A compound of any of the above aspects, wherein aspect number 43, R6 is methoxyl. A compound of any of the above aspects, wherein aspect number 44, R7 is H. A compound of any of the above aspects, wherein aspect number 45, R8 is H. A compound of any of the above aspects, wherein aspect number 46, R9 is H. Aspect number 47, R 10 is H, a compound of any of the above aspects. Aspect number 48, R 10 is F, a compound of any of the above aspects. Aspect number 49, a compound of formula (Ia) or its prodrug, solvate, or pharmaceutically acceptable salt, TIFF0007696354000049.tif43128 wherein R3, R4, R5, and R6 are as described herein, a compound of any of the above aspects. Aspect number 50, a compound of formula (Ib) or its prodrug, solvate, or pharmaceutically acceptable salt, TIFF0007696354000050.tif43128 wherein R3, R4, R5, and R6 are as described herein, a compound of any of the above aspects. Aspect number 51, a compound of formula (IIa) or its prodrug, solvate, or pharmaceutically acceptable salt, TIFF0007696354000051.tif35128 wherein X, R1...

Claims

1. A compound of formula (I), wherein, R 1 is C 1 - C 6 alkyl; R 2 is C 1 - C 6 alkyl or; or R 1 and R 2 together with the atom to which they are attached form a C 3 - C 6 saturated cycloalkyl; R 3 is H, halogen, - S(C 1 - C 6 alkyl), - N(C 1 - C 6 alkyl) 2 - NH(C 1 - C 6 alkyl), - NH 2 C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 - C 6 alkoxyl, C 1 - C 6 haloalkoxyl, or C 3 - C 6 cycloalkyl; R 4 is H, halogen, - S(C 1 - C 6 alkyl), - N(C 1 - C 6 alkyl) 2 - NH(C 1 - C 6 alkyl), - NH 2 C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 2~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 、-NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 、-NH(C 1 ~C 6 alkyl), -NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6Haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 7 is H; R 8 is H; and R 9 is H, but provided that R 3 , R 4 , R 5 , and R 6 at least one of is H, the compound, or a solvate thereof, or a pharmaceutically acceptable salt.

2. A compound of formula (II), wherein in the formula, X is CR 7 R 8 or O; R 1 is C 1 ~C 6 alkyl; R 2 is C 1 ~C 6 alkyl; or R 1 and R 2 together with the atom to which they are attached form a C 3 ~C 6 saturated cycloalkyl; R 3 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 is cycloalkyl; R 4 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 is cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 is cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 7 is H; R 8 is H; and R 9 is H, provided that however, (a) when R 5 is H, X is CR 7 R 8 ; (b) when R 5 is halogen and R 4 is H, R 3 is neither methyl nor methoxyl nor Br, and X is CR 7 R 8 ; and (c) when R 5 is methoxyl or methyl, R 4 is not H, the compound, or a solvate thereof, or a pharmaceutically acceptable salt.

3. A compound of formula (II'), wherein in the formula, X is CR 7 R 8or O; R 1 is C 1 ~ C 6 alkyl; R 2 is C 1 ~ C 6 alkyl; or R 1 and R 2 together with the atom to which they are attached form C 3 ~ C 6 saturated cycloalkyl; R 3 is H, halogen, -S(C 1 ~ C 6 alkyl), -N(C 1 ~ C 6 alkyl) 2 , -NH(C 1 ~ C 6 alkyl), -NH 2 C 1 ~ C 6 alkyl, C 2 ~ C 6 alkenyl, C 2 ~ C 6 alkynyl, C 1 ~ C 6 haloalkyl, C 1 ~ C 6 alkoxyl, C 1 ~ C 6 haloalkoxyl, or C 3 ~ C 6 cycloalkyl; R 4 is H, halogen, -S(C 1 ~ C 6 alkyl), -N(C 1 ~ C 6 alkyl) 2 , -NH(C 1 ~ C 6 alkyl), -NH 2 C 1 ~ C 6 alkyl, C 2 ~ C 6 alkenyl, C 2 ~ C 6 alkynyl, C 1 ~ C 6 Haloalkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkoxyl, or C 3 ~C 6 Cycloalkyl; R 5 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 cycloalkyl; R 6 is H, halogen, -S(C 1 ~C 6 alkyl), -N(C 1 ~C 6 alkyl) 2 , -NH(C 1 ~C 6 alkyl), -NH 2 , C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, or C 3 ~C 6 is cycloalkyl; R 7 is H; R 8 is H; R 9 is H; and R 10 is H or halogen, provided that however, (a)(i) when R 5 is H, X is CR 7 R 8 or (ii) when R 5 is H and X is O, R 10 is halogen; (b) when R 5 is halogen and R 4 is H, R 3 is not methyl, methoxyl or Br, and X is CR 7 R 8 and (c) when R 5 is methoxyl or methyl, R 4 is not H, said compound, or a solvate thereof, or a pharmaceutically acceptable salt.

4. R 1 is C 1 to C 6 alkyl, the compound according to any one of claims 1 to 3.

5. R 2 is C 1 to C 6 alkyl, the compound according to any one of claims 1 to 4.

6. R 1 and R 2 together with the atoms to which they are attached form a C 3 to C 6 saturated cycloalkyl, the compound according to any one of claims 1 to 3.

7. R 3 is H, halogen, C 1 ~C 6 alkyl, or C 1 ~C 6 is alkoxyl, the compound according to any one of claims 1 to 6.

8. R 4 is H, halogen, C 1 ~C 6 alkyl, or C 1 ~C 6 is alkoxyl, the compound according to any one of claims 1 to 7.

9. R 5 is H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, S(C 1 ~C 6 alkyl), or C 1 ~C 6 haloalkyl, the compound according to any one of claims 1 to 8.

10. R 6 is H, C 1 ~C 6 alkyl, or C 1 ~C 6 is alkoxyl, the compound according to any one of claims 1 to 9.

11. R 10 is F, the compound according to claim 3.

12. is a compound of formula (Ia) or (Ib) or a solvate thereof, or a pharmaceutically acceptable salt, wherein R 3 , R 4 , R 5 , and R 6 are as described in claim 1, the compound according to claim 1.

13. is a compound of formula (IIa), (IIa-1), or (IIa-2) or a solvate thereof, or a pharmaceutically acceptable salt, wherein X, R 1 , R 2 , R 4 , R 5 , and R 9 is as described in claim 2, the compound according to claim 2.

14. A compound of formula (IIb), (IIb-1), or (IIb-2) or a solvate thereof, or a pharmaceutically acceptable salt, wherein X, R 1 , R 2 , R 3 , R 5 , and R 9 is as described in claim 2, the compound according to claim 2.

15. A compound of formula (IIc), (IIc-1), or (IIc-2) or a solvate thereof, or a pharmaceutically acceptable salt, wherein X, R 1 , R 2 , R 3 , R 6 , and R 9 is as described in claim 2, the compound according to claim 2.

16. A compound of formula (II'a) or a solvate thereof, or a pharmaceutically acceptable salt, wherein X, R 1 , R 2 , R 9 , and R 10 is as described in claim 3, the compound according to claim 3.

17. The following compound numbers 1-39: , and a compound selected from their pharmaceutically acceptable salts.

18. A pharmaceutical composition comprising the compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

19. The pharmaceutical composition according to claim 18, wherein the compound is selected from the compounds of compound numbers 1-39 according to claim 17 or a pharmaceutically acceptable salt thereof. Claim 20 A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 for use in alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder. Claim 21 Use of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 or 19 in the manufacture of a medicament for alleviating the symptoms of a sleep disorder, treating a sleep disorder, or preventing a sleep disorder. Claim 22 The pharmaceutical composition according to claim 20, wherein the sleep disorder is an increase in sleep fragmentation. Claim 23 The pharmaceutical composition according to claim 20, wherein the compound is an H1 / 5-HT 2A receptor modulator. Claim 24 The pharmaceutical composition according to claim 20, wherein the sleep disorder is caused by or coexists with sleep apnea, restless legs syndrome, high respiratory disturbance index (RDI), neurological disorders, circadian rhythm disorders, pain, periodic limb movement disorder (PLMD), REM behavior disorder, fragmented sleep in the elderly, age-related sleep fragmentation, postmenopausal sleep disorder, drug abuse, drug withdrawal symptoms, narcolepsy, mental disorders, increased sensitivity to pain, cardiovascular diseases, hypertension, non-restorative sleep, stroke, metabolic disorders, or cognitive impairment. Claim 25 The pharmaceutical composition according to claim 24, wherein the sleep apnea is obstructive sleep apnea with a high respiratory disturbance index (RDI) associated with an increase in respiratory effort-related arousals (RERA), regardless of whether apnea, hypopnea, or acute hemoglobin saturation decrease is associated. Claim 26 The pharmaceutical composition according to claim 20, wherein the compound is administered in combination with an additional active agent. Claim 27 The pharmaceutical composition according to claim 20, wherein the compound and, if present, any additional active agent are administered either before sleep (hora somni), i.e., h.s. (at bedtime), or about 0 to 4 hours before bedtime.

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