Compositions and methods for treating diseases or conditions associated with sleep

Abstract

Methods of preventing, ameliorating, slowing the progression of, or treating diseases, disorders, and / or conditions associated with sleep in human subjects, by administering an activator of sirtuin 6 (SIRT6).

Description

Attorney Docket No. 1512.13.WOCOMPOSITIONS AND METHODS FOR TREATING DISEASES OR CONDITIONS ASSOCIATED WITH SLEEPSTATEMENT OF PRIORITY

[0001] The application claims the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No. 63 / 696,008, filed on September 18, 2024, the entire contents of which are incorporated by reference herein.FIELD OF THE INVENTION

[0002] The present invention relates to methods of preventing, ameliorating, slowing the progression of, or treating diseases, disorders, and / or conditions associated with sleep in human subjects, by administering an activator of sirtuin 6 (SIRT6).BACKGROUND OF THE INVENTION

[0003] Tryptophan is an essential amino acid whose metabolism plays a key role in brain homeostasis. Impaired or altered tryptophan metabolism has been associated with aging and neurodegeneration, in diseases such as Huntington’s, Parkinson’s, and Alzheimer’s. Further, serotonin and melatonin production, derived from tryptophan metabolism, are reduced with age and neurodegeneration, affecting mood and sleep cycles. Moreover, impaired tryptophan metabolism perturbs sleep quality and circadian rhythms.

[0004] Millions of individuals are affected with diseases, disorders, and / or conditions associated with sleep. There is a need in the art for effective therapeutics for sleep-associated diseases, disorders, and / or conditions.SUMMARY OF THE INVENTION

[0005] Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylase / deacylase. SIRT6 plays a key role in regulating tryptophan metabolism. SIRT6 deficiency leads to a switch in gene expression, stimulating the kynurenine pathway and its metabolites and decreasing serotonin and melatonin production. This switch leads to the accumulation of toxic byproducts, leading to circadian rhythm and sleep disruption, accelerating neurodegeneration.

[0006] Accordingly, the present invention is based on the determination that SIRT6 activators provide a significant therapeutic effect for diseases, disorders, and / or conditions associated with sleep.Attorney Docket No. 1512.13. WO

[0007] Thus, one aspect of the invention relates to a method of treating, preventing, ameliorating, or slowing the progression of a disease, disorder, and / or condition associated with sleep in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating, preventing, ameliorating, or slowing the progression of the disease, disorder, and / or condition associated with sleep. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating a disease, disorder, and / or condition associated with sleep.

[0008] Another aspect of the invention relates to a method of increasing tryptophan metabolism in a subject in need thereof, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing tryptophan metabolism. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may increase tryptophan metabolism.

[0009] Another aspect of the invention relates to a method of increasing serotonin and melatonin production in a subject in need thereof, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing serotonin and melatonin production. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may increase serotonin and melatonin production.

[0010] Another aspect of the invention relates to a method of increasing sleep quality in a subject in need thereof, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing sleep. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may increase serotonin and melatonin production.

[0011] These and other aspects of the invention are set forth in more detail in the description of the invention below.DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0012] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instantAttorney Docket No. 1512.13. WO disclosure which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.

[0013] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0014] 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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0015] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety.Definitions

[0016] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0017] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0018] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0019] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount.

[0020] As used herein, the transitional phrase “consisting essentially of’ is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basicAttorney Docket No. 1512.13. WO and novel characteristic(s) of the claimed invention. Thus, the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”

[0021] The term “enhance,” “promote,” or “increase” refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10- fold, twelve-fold, or even fifteen-fold.

[0022] The term “inhibit” or “reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity of at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).

[0023] A “therapeutically effective” or “treatment effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a “therapeutically effective” or “treatment effective” amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e.g., in the case of diseases, disorders, and / or conditions associated with sleep). Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0024] By the term “treat,” “treating,” or “treatment of’ (or grammatically equivalent terms) is meant to reduce or to at least partially improve or ameliorate (e.g., alleviate) the severity of the subject’s condition and / or to alleviate, mitigate or decrease in at least one clinical symptom and / or to delay the progression of the condition.

[0025] As used herein, the term “prevent,” “prevents,” or “prevention” (and grammatical equivalents thereof) means to delay or inhibit the onset of a disease. The terms are not meant to require complete abolition of disease, and encompass any type of prophylactic treatment to reduce the incidence of the condition or delays the onset of the condition.

[0026] A “prevention effective” amount as used herein is an amount that is sufficient to prevent and / or delay the onset of a disease, disorder and / or clinical symptoms in a subject and / or to reduce and / or delay the severity of the onset of a disease, disorder and / or clinical symptoms in a subject relative to what would occur in the absence of the methods of the invention. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0027] A “subject” of the invention may include any animal in need thereof. In some embodiments, a subject may be, for example, a mammal, a reptile, a bird, an amphibian, or a fish. A mammalian subject may include, but is not limited to, a laboratory animal (e.g., a rat,Attorney Docket No. 1512.13. WO mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., cattle, pig, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, gerbil, hamster, etc.). In some embodiments, a mammalian subject may be a primate, or a non-human primate (e.g., a chimpanzee, baboon, macaque (e.g., rhesus macaque, crab-eating macaque, stump-tailed macaque, pig-tailed macaque), monkey (e.g., squirrel monkey, owl monkey, etc.), marmoset, gorilla, etc.). In some embodiments, a mammalian subject may be a human.

[0028] A “subject in need” of the methods of the invention can be any subject known or suspected of having increased risk of developing a disease, disorder, and / or condition associated with sleep to which administering a compound as described herein may provide beneficial health effects.

[0029] By “effective amount” it is meant an amount sufficient that, when administered to the subject, an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of diseases, disorders, and / or conditions associated with sleep. Therefore, the “effective amount” may be a “therapeutically effective amount”. By “therapeutically effective amount” it is meant an amount sufficient that when administered to the subject an amount of active ingredient is provided to treat the disease or a symptom of the disease.

[0030] “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, z. e. , the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 21sted. 2005). Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution.

[0031] As used herein, the term “sleep disease,” “sleep condition,” “sleep disorder,” or “disease, disorder, and / or condition associated with sleep” means a disease, ailment, or condition which damages or alters the normal function of sleep. Non-limiting examples include: dyssomnias, parasomnias, or sleep disorders associated with medical and / or psychiatric disorders.

[0032] In some embodiments, dyssomnias comprise intrinsic sleep disorders. In some embodiments, the intrinsic sleep disorders include, but are not limited to, psychophysiologicalAttorney Docket No. 1512.13.WO insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless legs syndrome, or sleep disorders secondary to other disorders such as depression (e.g., major depressive disorder).

[0033] In other embodiments, dyssomnias comprise extrinsic sleep disorders. In some embodiments, the extrinsic sleep disorders include, but are not limited to, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep onset association disorder, nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, or toxin-induced sleep disorder.

[0034] In other embodiments, dyssomnias comprise circadian rhythm sleep disorders. In some embodiments, the circadian rhythm sleep disorders include, but are not limited to, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep- wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or on-24-hour sleep-wake disorder.

[0035] In some embodiments, parasomnias comprise arousal disorders. In some embodiments, the arousal disorders include, but are not limited to, confusional arousals, sleepwalking, or sleep terrors.

[0036] In other embodiments, parasomnias comprise sleep-wake transition disorders. In some embodiments, the sleep-wake transition disorders include, but are not limited to, rhythmic movement disorder, sleep starts, sleep talking, or nocturnal leg cramps.

[0037] In some embodiments, sleep disorders are associated with medical and / or psychiatric disorders. In some embodiments, sleep disorders associated with medical disorders include, but are not limited to, neurodevelopmental disorders, neurodegenerative disorders, and genetic conditions that cause insomnia. In some embodiments, sleep disorders associated with psychiatric disorders include, but are not limited to, mental illnesses and mental health disorders. In some embodiments, sleep disorders associated with medical and / or psychiatric disorders include, but are not limited to, psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, Parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, or sleep-related headaches.

[0038] As used herein, the term “sleep quality” refers to the ability to sleep without persistent interruptions or extended periods of wakefulness and / or sleep without difficulty falling asleep. In some embodiments, sleep quality refers to both the subjective assessment given by an individual of how restorative and undisturbed sleep has been (via a standardized questionnaire)Attorney Docket No. 1512.13. WO and to a series of objective measures derived from polysomnography. Examples of standardized sleep questionnaires, include but are not limited to the Pittsburgh Sleep Quality Index (Buysse et al., Psychiatry Research (1989), 28(2), 193-213). Examples of objective measures of sleep quality include, but are not limited to, the amount and depth of nonREM sleep, the amount of REM sleep and the temporal organization of nonREM and REM stages. Subjective and objective measures of sleep quality are not necessarily concordant.Methods of Use

[0039] A first aspect of the invention relates to a method of treating, preventing, ameliorating, or slowing the progression of a disease, disorder, and / or condition associated with sleep in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating, preventing, ameliorating, or slowing the progression of the disease, disorder, and / or condition associated with sleep. In some embodiments, the disease, disorder, and / or condition associated with sleep is characterized by decreased levels and / or activity of SIRT6 (e.g., the subject in need thereof has 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decreased levels and / or activity of SIRT6 relative to a control subject that does not have the disease, disorder, and / or condition associated with sleep). In some embodiments, the disease, disorder, and / or condition associated with sleep is a dyssomnia, parasomnia, or sleep disorder associated with a medical and / or psychiatric disorder.

[0040] In some embodiments, the method of treating, preventing, ameliorating, or slowing the progression of a disease, disorder, and / or condition associated with sleep further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating, preventing, ameliorating, or slowing the disease, disorder, and / or condition associated with sleep. In some embodiments, the additional therapeutic agent includes, but is not limited to, doxepin, estazolam, eszopiclone, ramelteon, suvorexant, temazepam, triazolam, trazodone, zaleplon, zolpidem, daridorexant, lemborexant, AMBIEN, amitriptyline, quetiapine, LUNESTA, mirtazapine, ANTIVAN, RESTRORIL, clonazepam, gabapentin, flurazepam, BELSOMBRA, HALCION, diphenhydramine, ROZEREM, SILENOR, quazepam, SONATA, ADVIL PM, doxylamine, EDLUAR, DORAL, olanzapine, TYLENOL PM, melatonin, pyridoxine, MIDOL PM, MOTRIN PM, SLEEPINAL, or any combination thereof.Attorney Docket No. 1512.13. WO

[0041] Assessment of sleep (e.g., sleep quality or other sleep-related issues) can be performed by one or more conventional tests known in the art e.g., Polysomnography (PSG), Electroencephalogram (EEG), Multiple sleep latency test (MSLT), etc.).

[0042] In some embodiments, the disease, disorder, and / or condition associated with sleep comprises a dyssomnia, parasomnia, or sleep disorder associated with a medical and / or psychiatric disorder.

[0043] In some embodiments, the dyssomnia comprises intrinsic sleep disorders, extrinsic sleep disorders, or circadian rhythm sleep disorders.

[0044] In some embodiments, the intrinsic sleep disorder comprises psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless legs syndrome, or sleep disorders secondary to other disorders such as depression (e.g., major depressive disorder).

[0045] In some embodiments, the extrinsic sleep disorder comprises inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep onset association disorder, nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, or toxin-induced sleep disorder.

[0046] In some embodiments, the circadian rhythm sleep disorder comprises time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep- wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or on-24-hour sleep- wake disorder.

[0047] In some embodiments, the parasomnia comprises arousal disorders or sleep-wake transition disorders. In some embodiments, the arousal disorder comprises confusional arousals, sleepwalking, or sleep terrors. In some embodiments, the sleep-wake transition disorder comprises rhythmic movement disorder, sleep starts, sleep talking, or nocturnal leg cramps.

[0048] In some embodiments, the medical and / or psychiatric disorder comprises psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, Parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, or sleep-related headaches.

[0049] In some embodiments, a method of increasing tryptophan metabolism in a subject in need thereof is provided, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing tryptophan metabolism. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator mayAttorney Docket No. 1512.13. WO increase tryptophan metabolism. In some embodiments, the SIRT6 activator may increase tryptophan metabolism in a subject in need thereof by 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% relative to levels in the subject absent or without administration of the SIRT6 activator.

[0050] In some embodiments, a method of increasing serotonin and melatonin production in a subject in need thereof is provided, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing serotonin and melatonin production. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may increase serotonin and melatonin production. In some embodiments, the SIRT6 activator may increase serotonin and melatonin production in a subject in need thereof by 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% relative to levels in the subject absent administration of the SIRT6 activator.

[0051] In some embodiments, a method of increasing sleep quality in a subject in need thereof is provided, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing sleep. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may increase serotonin and melatonin production.

[0052] In some embodiments, the methods of the invention may further include administering NAD+ or an NAD+ precursor. The NAD+ or NAD+ precursor may be administered at the same time as the SIRT6 activator or at different time, e.g., on a different administration schedule. The NAD+ or NAD+ precursor may be administered in the same composition as the SIRT6 activator or in a separate composition.

[0053] The methods of the invention may be carried out with any NAD+ precursor known in the art or later developed. The term “NAD+ precursor” is intended to mean compounds that are known to increase the level of NAD+ in a subject after administration. Example NAD+ precursors useful to the present invention include, but are not limited to, nicotinamide riboside, nicotinic acid riboside, nicotinic acid, nicotinamide, nicotinamide mononucleotide, niacin, and tryptophan. NAD+ precursors may be converted into NAD+ by any pathway, reaction, or synthesis method known to those in the art. Example synthesis pathways of NAD+ from NAD+ precursors include, but are not limited to, the Kynurenine pathway, the Preiss-Handler pathway, the NAD+ salvage pathway, and / or the NRH salvage pathway. The methods of the invention may be carried out with NAD+ by itself or in addition to a NAD+ precursor.CompoundsAttorney Docket No. 1512.13. WO

[0054] The methods of the invention may be carried out with any SIRT6 activator known in the art or later developed. Examples of SIRT6 activators include, without limitation, quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N- acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800, MDL-811, UBCS038 (You et al., Angew. Chem. Int. Ed. 56:1007 (2017)), UBCS039, UBCS040, UBCS058, UBCS060, UBCS068, myristic acid, OEA, CL5D, 10b, 5-C1-PZA, BHJH-TM3, 15f, 17a (catechin gallate), 19b (OSS 128167), 20b, 21b, 22a (A127-(CONHPr)-B178), 23, and forvisirvat (SP- 624). The compounds are described in more detail in Fiorentino et al., J. Med. Chem. 64:9732 (2021) and Akter et al., Int. J. Mol. Sci. 22:4180 (2021), each incorporated by reference herein in its entirety.

[0055] A further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof:(D wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,A is a 5-membered aromatic heterocyclic ring,Attorney Docket No. 1512.13. WO a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R3and R3’ do not exist,R3and R3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C 1 -C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,Attorney Docket No. 1512.13. WO an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a Cl- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl)Attorney Docket No. 1512.13.WO amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0056] In some embodiments, the compound of Formula 1 is any compound selected from the following group:(2S , 5 ’ R)-7-chloro-6-(5 -ethyl- 1 ,3 ,4-oxadiazol-2-yl)-3 ’ ,4-dimethoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6- [5-( 1 -methyl-4-piperidyl)- 1 ,3 ,4-oxadiazol-2- yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S ,5 ’ R)-7-chl oro-6- [5 -(4-fluoro- 1 -methyl-4-piperidyl)- 1 ,3 ,4-oxadiazol-2-y 1] -3 ’ ,4- dimethoxy-5’ -methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(lS)-l-methoxyethyl]-l,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol- 2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(l-methoxyethyl)-l,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4 ’-cyclohex-2-ene]-I ’, 3-dione;(2 S ,5 ’ R)-7-chloro-6- [3 -( 1 -hydroxy- 1 -methy 1-ethyl)- 1 ,2,4-oxadiazol-5 -yl] -3 ’ ,4-dimethoxy-5 ’ - methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2 S , 5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-( 1 H-pyrazol-5 -y 1) spiro [benzofuran-2,4 ’ - cyclohex-2-ene]- 1 ’ ,3 -dione;Attorney Docket No. 1512.13. WO(2S ,5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-6- [ 1 -(2-methoxy ethyl) pyrazol-3 -yl] -5 ’ -methyl-spiro[benzofuran-2,4 ’ -cy clohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’ -methylspiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran- 2, 4’-cyclohex-2-ene]-l ’,3-dione; or(2 S ,5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-(3 -pyridyl) spiro [benzofuran-2,4 ’ -cyclohex - 2-ene]-l ’,3-dione.

[0057] In some embodiments, the compound of Formula 1 is a compound of Formula 1 ’ or a pharmacologically acceptable salt thereof:d’) wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group XR2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, orAttorney Docket No. 1512.13. WO a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X.A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R3and R3’ is not present,R3and R3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,Attorney Docket No. 1512.13. WO a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a Cl- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group,Attorney Docket No. 1512.13. WO a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0058] In some embodiments of the compound of Formula 1 or Formula 1 ’, R1is a C1-C6 alkyl group, R2is a C1-C6 alkyl group, A is a 5-membered aromatic heterocyclic ring, and R3and R3’ are each independently a hydrogen or a C1-C6 alkyl group.

[0059] In some embodiments of the compound of Formula 1 or Formula 1 ’, R1is a methyl group, an ethyl group, or a hydroxyethyl group.

[0060] In some embodiments of the compound of Formula 1 or Formula 1’, R2is a methyl group.

[0061] In some embodiments of the compound of Formula 1 or Formula 1 ’, A is a 5-membered aromatic heterocyclic ring, R3is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, and R3’ is a hydrogen atom.

[0062] In some embodiments, the compound of Formula 1 is a compound of a Formula 1 ” or a pharmacologically acceptable salt thereof:Attorney Docket No. 1512.13. WOwherein R1is a methyl group or an ethyl group;R2is a methyl group;

[0063] A is any ring selected from the following group:indicates a binding group; andR3is a methyl group or an ethyl group.

[0064] In some embodiments, the compound of Formula 1’ is any compound selected from the following group:(2 S ,5 ’ R)-7-chloro-6-(2-hydroxyethoxy)-3 ’ ,4-dimethoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ - cyclohex-2-ene]-l ’,3-dione;(2S ,5 ’ R)-7-chloro-3 ’ , 4-dimethoxy-6-(2 -methoxy ethoxy)-5 ’ -methyl-spiro [benzofuran-2,4 ’ - cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(l-methylpyrazol-3-yl) spiro [benzofuran- 2,4’ -cy clohex-2-ene] - 1 ’ , 3 -dione;(2S,5’R)-7-chloro-6-(l-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4 ’- cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-methyl-l,2,4-oxadiazol-5-yl) spiro[benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-l,2,4-oxadiazol-3-yl) spiro[benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3-dione;(2S,5’R)-7-chloro-6-[5-(l -hydroxy-1 -methyl-ethyl)-l, 3, 4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;Attorney Docket No. 1512.13. WO(2S,5’R)-7-chloro-6-[5-[(lS)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-[5-[(lR)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-ethoxy-6-[5-(l-hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3’- methoxy-5 ’ -methy 1-spiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-4-ethoxy-6-[5-[(lS)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’-methoxy- 5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxyethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(3-methyl-l,2,4-oxadiazol-5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’, 3-dione;(2S,5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6- [5-( 1 -methyl-4-piperidyl)- 1 ,3 ,4-oxadiazol-2- yl] spiro [benzo furan-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(lS)-l-methoxyethyl]-l,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(l-methoxyethyl)-l,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -di one;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;Attorney Docket No. 1512.13. WO(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(lH-pyrazol-5-yl) spiro [benzofuran-2,4 ’- cyclohex-2-ene]-l’, 3-dione;(2 S ,5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-6- [ 1 -(2-methoxy ethyl) pyrazol-3 -yl] -5 ’ -methyl-spiro[benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5 ’-methylspiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2 S , 5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-6-(2-methoxypyrimidin-5 -yl)-5 ’ -methyl-spiro [benzofuran-2,4 ’-cyclohex-2-ene]-! ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran- 2, 4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’ -cyclohex - 2-ene]-l’, 3-dione; or(2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3- dione.

[0065] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(l-ethylpyrazol-3-yl)-3’,4- dimethoxy-5 ’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione or a pharmacologically acceptable salt thereof.

[0066] In one embodiment, the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6- (5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

[0067] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2- yl)-3’,4-dimethoxy-5’ -methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.

[0068] In one embodiment, the compound is (2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl- ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2- ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.

[0069] In one embodiment, the compound is (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’- methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.

[0070] In certain embodiments, the 5-membered aromatic heterocyclic ring for A is the same as described above, but more preferably, it represents the following 5-membered ring. It should be noted that in this case, R3’ is not present.Attorney Docket No. 1512.13. WOwherein * indicates a binding group.

[0071] In the present specification, the “5 -membered aromatic heterocyclic ring” is a monocyclic 5-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0072] In the present specification, the “6-membered aromatic heterocyclic ring” is a monocyclic 6-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0073] In the present specification, the “8- 10 membered condensed aromatic heterocyclic ring” is an 8-10 membered condensed aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.Attorney Docket No. 1512.13. WO

[0074] In the present specification, the “5-7 membered unsaturated heterocyclic ring” is a ring in which a monocyclic 5-7 membered saturated heterocyclic ring is partially oxidized or a ring in which an aromatic heterocyclic ring is partially reduced containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.Attorney Docket No. 1512.13. WO

[0075] In the present specification, the “4-7 membered saturated heterocyclic ring” is a monocyclic 4-7 membered saturated heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0076] The “halogen atom” in the present specification is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

[0077] The “C 1 -C6 alkyl group” in the present specification is a linear or branched alkyl group having one to six carbon atoms. Examples thereof include a methyl group, an ethyl group, a 1- propyl group, an isopropyl group, a 1 -butyl group, a 2 -butyl group, a 2-methyl-l -propyl group, a 2-methyl-2-propyl group, a 1 -pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl- 2 -butyl group, a 3 -methyl -2-butyl group, a 1 -hexyl group, a 2-hexyl group, a 3 -hexyl group, a 2-methyl-l -pentyl group, a 3-methyl-l -pentyl group, a 2-ethyl-l -butyl group, a 2,2-dimethyl- 1 -butyl group, and a 2,3 -dimethyl- 1 -butyl group, and it is preferably a methyl group or an ethyl group.Attorney Docket No. 1512.13. WO

[0078] The “C2-C6 alkenyl group” in the present specification is a linear or branched alkenyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon double bonds. For example, it is a vinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenyl group, a 3-methyl-2-butenyl group, a 2-hexenyl group, or a 3-methyl-2-pentenyl group, and preferably, it is a vinyl group or an allyl group.

[0079] The “C2-C6 alkynyl group” in the present specification is a linear or branched alkynyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon triple bonds. For example, it is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1 -pentynyl group, a 2-pentynyl group, or 1 -hexynyl group, and it is preferably an ethynyl group or a 1-propynyl group.

[0080] The “C1-C6 alkoxy group” in the present specification is a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include a methoxy group, an ethoxy group, a 1 -propoxy group, a 2-propoxy group, a 1 -butoxy group, a 2-butoxy group, a 2-methyl-1 -propoxy group, a 2-methyl-2-propoxy group, a 1 -pentyloxy group, a 2-pentyloxy group, a 3- pentyloxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group, a 1 -hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-l -pentyloxy group, and a 3-methyl-l- pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1 -propoxy group, or a2-propoxy group.

[0081] The “C3-C6 cycloalkyl group” in the present specification is a cyclic alkyl group having three to six carbon atoms, and it is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0082] The “hydroxy C1-C6 alkyl group” in the present specification is a group in which a hydroxyl group is bonded to a C1-C6 alkyl group. For example, it is a hydroxymethyl group or a hydroxy ethyl group.

[0083] The “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.

[0084] The “C1-C6 haloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2-iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3 -fluoropropyl group, a 3 -chloropropyl group, and a 4-fluorobutyl group. It is preferably a trifluoromethyl group.Attorney Docket No. 1512.13. WO

[0085] The “C3-C6 halocycloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.

[0086] The “C1-C6 haloalkoxy group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxy group, a 2- bromoethoxy group, a 2-chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a trichloroethoxy group, a pentafluoroethoxy group, a 3- fluoropropoxy group, a 3 -chloropropoxy group, and a 4-fluorobutoxy group. It is preferably a trifluoromethoxy group.

[0087] The “C3-C6 cycloalkoxy group” in the present specification is a group in which a C3- C6 cycloalkyl group is bonded to an oxygen atom, and it is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

[0088] The “C3-C6 halocycloalkoxy group” in the present specification is a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.

[0089] The “5 -membered aromatic heterocyclic oxy group” in the present specification is a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0090] The “6-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0091] The “4-7 membered saturated heterocyclic oxy group” in the present specification is a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom.

[0092] The “C1-C6 alkoxycarbonyl group” in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

[0093] The “C3-C6 cycloalkoxycarbonyl group” in the present specification is a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and it is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.Attorney Docket No. 1512.13. WO

[0094] The “C1-C6 alkyl carbonyl group” in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methyl carbonyl group, an ethyl carbonyl group, or a propyl carbonyl group.

[0095] The “mono (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and it is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.

[0096] The “di (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminocarbonyl group, and it is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.

[0097] The “mono (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminosulfonyl group, and it is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group, or a propylaminosulfonyl group

[0098] The “di (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

[0099] The “mono (C1-C6 alkyl) amino group” in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, and it is preferably a methylamino group, an ethylamino group, or a propylamino group.

[0100] The “di (C1-C6 alkyl) amino group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to an amino group, and it is preferably a dimethylamino group, a diethylamino group, or a dipropyl amino group.

[0101] The “C1-C6 alkoxycarbonylamino group” in the present specification is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, and for example, it is a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.

[0102] The “mono (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a mono (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.Attorney Docket No. 1512.13.WO

[0103] The “di (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0104] The “5-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 5 -membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0105] The “6-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0106] The “C1-C6 alkylsulfonylamino group” in the present specification is a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and it is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.Pharmaceutical compositions

[0107] The term “pharmaceutically acceptable salt” indicates a salt of the compounds that can be used as a pharmaceutical. When the compounds have an acidic group or a basic group it can be converted to a basic salt or an acidic salt by reacting with a base or an acid to form a salt thereof.

[0108] The pharmaceutically acceptable “basic salt” of the compounds preferably includes an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; organic base salts such as an N-methyl morpholine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, and a picoline salt; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is preferably an alkali metal salt.

[0109] The pharmaceutically acceptable “acidic salt” of the compounds preferably includes an inorganic acid salt such as a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide, and a hydroiodide, a nitrate, a perchlorate, a sulfate, and a phosphate; an organic salt such as a lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, an aryl sulfonate such as a benzenesulfonates, and a p-toluene sulfonate, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, a tartrate, an oxalate, a maleate, and the like; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt,Attorney Docket No. 1512.13.WO an ornithine salt, a glutamate, and an aspartate, and it is most preferably a hydrohalide (in particular, a hydrochloride).

[0110] The compounds of the present invention or the pharmaceutically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate by leaving in the air or recrystallization. The present invention also encompasses compounds of such various hydrates, solvates, and crystalline polymorphs.

[0111] The compounds of the present invention, their pharmaceutically acceptable salts or solvates thereof, depending on the type and combination of substituents, may have various isomers such as geometric isomers such as a cis isomer and a trans isomer, tautomers, or optical isomers such as a d isomer and an 1 isomer, while the compounds include those all isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Mixtures of these isomers may be resolved by known resolution means.

[0112] The compounds of the present invention also include labels, that is, a compound in which one or more atoms of the compounds are substituted with an isotope (for example,2H,3H,13C,14C,35S, and the like).

[0113] In addition, the present invention also encompasses a prodrug of the described compounds. The prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, it is a group described in Prog. Med., Vol. 5, pp. 2157 to 2161 (1985) or the like. As the prodrug, more specifically, when an amino group is present in the compound, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, it is a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butylated, or the like) and the like are included, and when a hydroxyl group is present in the compound, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, it is a compound in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethyl carbonylated, or the like) and the like are included. In addition, when a carboxy group is present in the compound, a compound in which the carboxy group is esterified or amidated (for example, it is a compound in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, or the like.), and the like are included.Attorney Docket No. 1512.13. WO

[0114] The SIRT6 activator compounds of the present invention may be produced by synthetic methods known in the art and as described in WO 2017 / 170623 and WO 2019 / 065928, incorporated by reference herein in their entirety.Administration methods

[0115] Administration of the compounds of the present invention may be carried out by any form of oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, or the like, or by any form of parenteral administration by an injection for intra-ocular, subretinal, transvitreal, suprachoroidal, intra-articular, intravenous, intramuscular, or the like, a suppository, an eye drop, an eye ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant, or the like.

[0116] In some embodiments, a solid composition for oral administration, a tablet, a powder, a granule, and the like are used. Such a solid composition is composed of one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate, and / or the like. The solid composition may contain, according to a conventional method, one or more of an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizer. The tablet or pill may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary.

[0117] In some embodiments, a liquid composition for oral administration, a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like is used. To such a liquid composition, it is possible to add a generally used inert diluent such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, one or more of a solubilizer, an adjuvant such as a wetting agent, a sweetening agent, a flavoring agent, a fragrance, and a preservative.

[0118] In some embodiments, an injection for parenteral administration, a sterile aqueous or non-aqueous solution, a suspension or an emulsion, and the like are used. The aqueous solvent includes, for example, distilled water for injection, physiological saline, and the like. The nonaqueous solvents include, for example, propylene glycol, polyethylene glycol, and vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80, and the like. Such an injection composition may further contain a one or more of a tonicity agent, a preservative, a wetting agent, an emulsion, a dispersing agent, a stabilizer, or a solubilizer. These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter,Attorney Docket No. 1512.13. WO application of a bactericide, or irradiation. In addition, these injection compositions may be used by producing a sterile solid composition and dissolved or suspended in sterile water or a sterile solvent for injection prior to use.

[0119] In some embodiments, an external preparation, an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, an eye drop, an eye ointment, and the like are used. These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like are used.

[0120] A transmucosal agent such as an inhalant and a transnasal agent are used in solid, liquid, or semisolid form, and it may be produced according to a conventionally known method. For example, a known excipient, and furthermore, one or more of a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be added as appropriate. With these transmucosal agents, devices appropriate for inhalation or insufflation may be used as the method of administration. For example, the compound may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. A dry powder inhaler or the like may be for single or multiple administration, and a dry powder or powder containing capsule may be also used. Alternatively, an appropriate ejector may be used. For example, it may be in the form of a pressurized aerosol spray or the like using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

[0121] In the case of normal oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg of body weight. In some embodiments, the appropriate daily dose is about 1 to 500 mg, e.g., about 5 to 200 mg, e.g., about 10-100 mg, e.g., about 15-30 mg. This is administered in one dose or separated into two or more doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg of body weight, which is administered once or separated into several times a day. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg of body weight is administered once or separated into several times a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like. In some embodiments, the administration occurs about 1 hour before going to sleep. In someAttorney Docket No. 1512.13. WO embodiments, the administration occurs about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, or about 5 minutes before going to sleep.

[0122] In the methods of the present invention, the compound may be administered in combination with additional various therapeutic agents or preventive agents for diseases that are considered to exhibit the efficacy thereof. The combination may be administered simultaneously, separately, concurrently, and continuously or at desired time intervals. The coadministered agents may be blended or formulated separately. The therapeutic agent may be, for example, one that is known to treat the targeted, or another, sleep disease or condition. In an embodiment, the therapeutic agent is one that treats a dyssomnia, parasomnia, or sleep disorder associated with a medical and / or psychiatric disorder.

[0123] In some embodiments, dyssomnias comprise intrinsic sleep disorders. In some embodiments, the intrinsic sleep disorders include, but are not limited to, psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless legs syndrome, or sleep disorders secondary to other disorders such as depression (e.g., major depressive disorder).

[0124] In other embodiments, dyssomnias comprise extrinsic sleep disorders. In some embodiments, the extrinsic sleep disorders include, but are not limited to inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep onset association disorder, nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, or toxin-induced sleep disorder.

[0125] In other embodiments, dyssomnias comprise circadian rhythm sleep disorders. In some embodiments, the circadian rhythm sleep disorders include, but are not limited to, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep- wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or on-24-hour sleep-wake disorder.

[0126] In some embodiments, parasomnias comprise arousal disorders. In some embodiments, the arousal disorders include, but are not limited to, confusional arousals, sleepwalking, or sleep terrors.

[0127] In other embodiments, parasomnias comprise sleep-wake transition disorders. In some embodiments, the sleep-wake transition disorders include, but are not limited to, rhythmic movement disorder, sleep starts, sleep talking, or nocturnal leg cramps.

[0128] The methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals. TheAttorney Docket No. 1512.13. WO term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. Optionally, the subject is “in need of’ the methods of the present invention, e.g., because the subject has or is believed at risk for a disease, disorder, and / or condition associated with sleep, e.g., a dyssomnia, parasomnia, or sleep disorder associated with a medical and / or psychiatric disorder, or that would benefit from the delivery of a compound as described herein. As a further option, the subject can be a laboratory animal and / or an animal model of disease. Preferably, the subject is a human.

[0129] The foregoing examples are illustrative of the present invention and are not to be construed as limiting thereof. Although the invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.

Claims

Attorney Docket No. 1512.

13. WOWhat is Claimed:

1. A method of treating, preventing, ameliorating, or slowing the progression of a disease, disorder, and / or condition associated with sleep in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sirtuin 6 (SIRT6) activator, thereby treating, preventing, ameliorating or slowing the progression of the disease, disorder, and / or condition associated with sleep.

2. The method of claim 1 , wherein the disease, disorder, and / or condition associated with sleep comprises a dyssomnia, parasomnia, or sleep disorder associated with a medical and / or psychiatric disorder.

3. The method of claim 2, wherein the dyssomnia comprises intrinsic sleep disorders, extrinsic sleep disorders, or circadian rhythm sleep disorders.

4. The method of claim 3, wherein the intrinsic sleep disorder comprises psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless legs syndrome, or sleep disorders secondary to other disorders such as depression (e.g., major depressive disorder).

5. The method of claim 3, wherein the extrinsic sleep disorder comprises inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep onset association disorder, nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, or toxin-induced sleep disorder.

6. The method of claim 3, wherein the circadian rhythm sleep disorder comprises time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep- wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or on-24-hour sleep-wake disorder.

7. The method of claim 2, wherein the parasomnia comprises arousal disorders or sleepwake transition disorders.Attorney Docket No. 1512.

13. WO8. The method of claim 7, wherein the arousal disorder comprises confusional arousals, sleepwalking, or sleep terrors.

9. The method of claim 7, wherein the sleep-wake transition disorder comprises rhythmic movement disorder, sleep starts, sleep talking, or nocturnal leg cramps.

10. The method of claim 2, wherein the medical and / or psychiatric disorder comprises psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, Parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, or sleep-related headaches.

11. A method of increasing tryptophan metabolism in a subject in need thereof, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing tryptophan metabolism.

12. A method of increasing serotonin and melatonin production in a subject in need thereof, comprising administering to the subject an effective amount of a SIRT6 activator, thereby increasing serotonin and melatonin production.

13. A method of increasing sleep quality in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby increasing sleep.

14. The method of any one of claims 1-13, further comprising administering to the subject a therapeutically effective amount of nicotinamide adenine dinucleotide (NAD+) and / or an NAD+ precursor.

15. The method of claim 14, wherein the SIRT6 activator and the NAD+ and / or NAD+ precursor are administered in the same composition.

16. The method of claim 14, wherein the SIRT6 activator and the NAD+ and / or NAD+ precursor are administered in separate compositions.Attorney Docket No. 1512.

13. WO17. The method of any one of claims 14-16, wherein the NAD+ precursor is nicotinamide riboside, nicotinic acid riboside, nicotinic acid, nicotinamide, nicotinamide mononucleotide, tryptophan, or any combination thereof.

18. The method of any one of claims 1-17, wherein the SIRT6 activator is quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N- acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-81 1 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (l-(4,5-Dihydropyrrolo[l,2-6z]quinoxalin-4-yl)naphthalen-2- ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[l,2-<7] quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5- dihydropyrrolofl ,2-a] quinoxaline), UBCS068 (1 -(5-((3-(Trifhioromethyl)phenyl)sulfonyl)- 4,5-dihydropyrrolo[l ,2-a |quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide, CL5D (CAS No. 2488745-53-3), 10b (2-(l -benzo furan-2-yl)- V- (diphenylmethyl) quinoline-4-carboxamide), or forvisirvat (SP-624).

19. The method of any one of claims 1-17, wherein the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof:wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X,Attorney Docket No. 1512.

13. WO a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R3and R3’ do not exist,R3and R3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,Attorney Docket No. 1512.13.WO a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or R3and R3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y,Attorney Docket No. 1512.

13. WO a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a Cl- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

20. The method of claim 19, wherein the 5-membered aromatic heterocyclic ring or the 5- membered aromatic heterocyclic group in A, R3, or R3’ is any one selected from the group:

21. The method of claim 19 or 20, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R3, or R3’ is any one selected from the group:Attorney Docket No. 1512.

13. WO22. The method of any one of claims 19-21, wherein the 8-10 membered condensed aromatic heterocyclic ring or the 8-10 membered condensed aromatic heterocyclic group in A, R3, or R3’ is any one selected from the group:

23. The method of any one of claims 19-22, wherein the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group in A, R3, or R3’ is any one selected from the group:Attorney Docket No. 1512.

13. WO24. The method of any one of claims 19-23, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R1, R2, or R3is any one selected from the group:

25. The method any one of claims 19-24, wherein the compound of Formula 1 is any compound selected from the following group:(2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-(5-tetrahydropyran-4-yl- 1 ,3 ,4- oxadiazol-2-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’,3-dione;(2S,5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6- [5-( 1 -methyl-4-piperidyl)- 1,3,4- oxadiazol-2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;Attorney Docket No. 1512.

13. WO(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-6- [5 - [( 1 S)- 1 -methoxy ethyl] -1,3 ,4-oxadiazol-2- yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-r,3-dione;(2S,5 ’R)-7-chloro-4-ethoxy-3 ’-methoxy-5 ’-methyl-6-(5 -methyl- 1 ,3,4-oxadiazol-2- yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-4-(difhroromethoxy)-3 ’-methoxy-5 ’-methyl-6-(5-methyl-l, 3, 4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(l-methoxyethyl)-l,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-r,3-dione;(2 S ,5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-( 1 H-pyrazol-5 -yl) spiro [benzo furan- 2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S, 5 ’R)-7-chloro-3 ’,4-dimethoxy-6-[l -(2 -methoxyethyl) pyrazol-3-yl]-5 ’ -methylspiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-T, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro[benzofuran-2,4 ’ -cy clohex-2-ene] - 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-r,3-dione; or(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]- 1 ’ ,3 -dione.

26. The method of any one of claims 19-25, wherein the compound of Formula 1 is a compound of Formula 1 ’ or a pharmacologically acceptable salt thereof:Attorney Docket No. 1512.

13. WOwherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group XR2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X.A is a 5 -membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R3andR3’ is not present,R3and R3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X,Attorney Docket No. 1512.

13. WO a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted yvith the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y,Attorney Docket No. 1512.13.WO a 5 -membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a Cl- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxy carbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, andAttorney Docket No. 1512.

13. WO substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

27. The method of claim 26, wherein R1is a methyl group, an ethyl group, or a hydroxyethyl group.

28. The method of claim 26 or 27, wherein R2is a methyl group.

29. The method of any one of claims 26-28, wherein the 5-membered aromatic heterocyclic ring or the 5 -membered aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

30. The method of any one of claims 26-29, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R3, or R3’ is any one selected from the group:

31. The method of any one of claims 26-30, wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7 membered unsaturated heterocyclic group in A, R3, or R3’ is any one selected from the group:Attorney Docket No. 1512.

13. WO32. The method of any one of claims 26-31 , wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R1, R2, or R3is any one selected from the group:

33. The method of any one of claims 26-32, wherein A is a 5-membered aromatic heterocyclic ring, R3is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, and R3’ is a hydrogen atom.

34. The method of any one of claims 26-33, wherein A is any ring selected from the following group, and in the case of two binding groups, R3’ is not present:Attorney Docket No. 1512.

13. WOwherein * indicates a binding group.

35. The method of any one of claims 26-28, wherein the compound of Formula 1 is a compound of a Formula 1 ” or a pharmacologically acceptable salt thereof:wherein R1is a methyl group or an ethyl group;R2is a methyl group;A is any ring selected from the following group:* indicates a binding group; andR3is a methyl group or an ethyl group.

36. The method of any one of claims 26-34, wherein the compound of Formula 1 ’ is any compound selected from the following group:(2S,5 ’R)-7-chloro-6-(2-hydroxyethoxy)-3 ’ ,4-dimethoxy-5 ’-methyl-spiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1 ’ ,3 -dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(2 -methoxy ethoxy)-5’ -methyl-spiro[benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;Attorney Docket No. 1512.

13. WO(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(l-methylpyrazol-3-yl) spiro [benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-(l-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2 S , 5 ’ R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-(3 -methyl- 1 ,2,4-oxadiazol-5 -yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-l,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-6-[5-(l-hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-[5-[(lS)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’,4-dimethoxy- 5 ’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5 ’R)-7-chloro-6-[5 -[( 1 R)- 1 -hydroxy ethyl] - 1 ,3 ,4-oxadiazol-2-yl]-3 ’ ,4- dimethoxy-5’ -methyl-spiro [benzofuran-2,4 ’-cyclohex-2-ene]-! ’, 3-dione;(2S,5’R)-7-chloro-4-ethoxy-6-[5-(l-hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3 ’ -methoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-4-ethoxy-6-[5-[(lS)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’- methoxy-5 ’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S ,5 ’ R)-7-chloro-6- [3 -(1 -hydroxy ethyl)- 1 ,2,4-oxadiazol-5 -yl] -3 ’ ,4-dimethoxy-5 ’ - methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(3-methyl-l,2,4- oxadiazol-5-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,2,4- oxadiazol-3-yl) spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-l,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(l-methyl-4-piperidyl)-l,3,4- oxadiazol-2-yl] spiro [benzofuran-2,4 ’-cyclohex-2-ene]-l ’,3 -dione;Attorney Docket No. 1512.13.WO(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(lS)-l-methoxyethyl]-l,3,4-oxadiazol-2- yl]-5 ’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2- yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5 ’R)-7-chloro-4-(difluoromethoxy)-3 ’-methoxy-5 ’-methyl-6-(5-methyl- 1 ,3 ,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(l-methoxyethyl)-l,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4- dimethoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene]- 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(lH-pyrazol-5-yl) spiro [benzofuran- 2,4’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[l-(2-methoxyethyl) pyrazol-3-yl] -5 ’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran-2,4 ’-cyclohex-2-ene]- 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 -di one;(2S,5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-(3 -pyridyl) spiro [benzofuran-2,4 ’ - cyclohex-2-ene]-l ’,3-dione; or(2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2- ene]-l ’,3-dione.

37. The method of claim 36, wherein the compound is (2S,5’R)-7-chloro-6-(l- ethylpyrazol-3 -y l)-3 ’ ,4-dimethoxy-5 ’ -methyl-spiro [benzofuran-2,4 ’ -cyclohex-2-ene] - 1 ’ ,3 - dione or a pharmacologically acceptable salt thereof.Attorney Docket No. 1512.

13. WO38. The method of claim 36, wherein the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy- 5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3- dione or a pharmacologically acceptable salt thereof.

39. The method of claim 36, wherein the compound is (2S,5’R)-7-chloro-6-(5-ethyl- l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1 ’,3-dione or a pharmacologically acceptable salt thereof.

40. The method of claim 36, wherein the compound is (2S,5’R)-7-chloro-6-[3-(l- hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.41 . The method of claim 36, wherein the compound is (2S,5’R)-7-chloro-4-ethoxy-3’- methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2- ene]-l ’, 3-dione or a pharmacologically acceptable salt thereof.

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