WO2024168215A1

WO2024168215A1 - Compositions and methods for treating anhedonia

Info

Publication number: WO2024168215A1
Application number: PCT/US2024/015109
Authority: WO
Inventors: Michael Friedrich ACKERMANN; Stephen E. Butts
Original assignee: Sirtsei Pharaceuticals, Inc.
Priority date: 2023-02-10
Filing date: 2024-02-09
Publication date: 2024-08-15

Abstract

The present invention relates to methods of treating anhedonia in human subjects by administering a SIRT6 activator. The present invention also provides methods for treating anhedonia in human female subjects by administering a SIRT6 activator, wherein female subjects may be identified by, e.g., the presence of two X chromosomes or circulating female hormones.

Description

Attorney Docket No.1512.8.WO COMPOSITIONS AND METHODS FOR TREATING ANHEDONIA STATEMENT OF PRIORITY [0001] This application cliams the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No.63/484,277 , filed February 10, 2023, the entire contents of which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods of treating anhedonia in human subjects by administering an activator of SIRT6. BACKGROUND OF THE INVENTION [0003] Anhedonia, a reduced capacity for pleasure or loss of interest, is a common symptom for neuropsychiatric diseases, including major depressive disorder (MDD), anxiety, and schizophrenia. In the U.S. alone, approximately 16 million people or 7% of the adult population is afflicted with major depressive disorder. Anhedonia is a core symptom of major depressive disorder and affects functioning in patients with MDD. Additionally, anhedonia in MDD can be resistant to some antidepressants. Unfortunately, anhedonia can be a predictor of poor long-term outcomes in some neuropsychiatric diseases, including suicide, and poor treatment response. (Craske et al., ADAA Scientific Res. Symposium 33(10):927-938 (2016)). [0004] There is a need in the art for effective treatments for anhedonia. Attorney Docket No.1512.8.WO SUMMARY OF THE INVENTION [0005] The present invention is based on the determination that activators of Sirtuin 6 (SIRT6) provide a significant therapeutic effect for anhedonia. [0006] Thus, one aspect of the invention relates to a method of treating anhedonia in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia. [0007] Another aspect of the invention relates to a method of treating anhedonia in a human female subject in need thereof, comprising identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia. [0008] These and other aspects of the invention are set forth in more detail in the description of the invention below. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG.1. Graph of female change in anhedonia subscale score from baseline as measured by Montgomery-Asberg Depression Rating Scale (MADRS). MADRS score over time was determined for female treatment groups receiving example SIRT6 activator SP-624, or placebo. P-value, difference in Least Square Means (LSM) estimate and 95% CI based on Mixed Model for Repeated Measures (MMRM). Error bars represent standard error (SE) for LSM estimate. The model for the change at Week 5 analysis is different from the change through Week 4 (treatment period) analysis due to inclusion of data at Week 5 (off-treatment follow-up period). ** - Modified intent to treat (mITT) Population is defined as all subjects who were randomized, received at least Attorney Docket No.1512.8.WO one dose of study drug (SP-624 or placebo) and had a baseline and at least one post-dose efficacy assessment. [0010] FIGS.2A-2B. FIG.2A. Percent of patients with example neuropsychiatric diseases that suffer from anhedonia. FIG.2B. Week 4 difference between treatment with exemplary compound SP-624 and Placebo in individual MADRS items. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION [0011] 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 instant 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. [0012] 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. Attorney Docket No.1512.8.WO [0013] 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. [0014] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety. [0015] 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. [0016] 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”). [0017] 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. [0018] 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. [0019] 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 basic 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.” Attorney Docket No.1512.8.WO [0020] By the term “treat,” “treating,” or “treatment of” (or grammatically equivalent terms) is meant to reduce or to at least partially improve or ameliorate 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. [0021] 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. [0022] The term “administering” refers to providing a composition to a subject suffering from or at risk of the disease(s) and/or condition(s) to be treated. [0023] A “treatment effective” or “therapeutically effective” amount as used herein is an amount that is sufficient to provide some improvement or benefit to the subject. Alternatively stated, a “treatment effective” or “therapeutically effective” amount is an amount that will provide some alleviation, mitigation, decrease or stabilization in at least one clinical symptom in the subject. 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] A “prevention effective” or “prophylactically 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. Attorney Docket No.1512.8.WO [0025] The term “pharmaceutical composition” relates to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form. “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.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; 21^st ed. 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. [0026] Mammalian Sirtuin 6 (SIRT6) is an NAD⁺-dependent protein deacylase. SIRT6 deacetylates nucleosomal histones in vitro and nucleosomes as well as proteins involved in DNA repair in cells. In some aspects, SIRT6-activating compounds or “SIRT6 activators” increase the cellular function of SIRT6. SIRT6 activators may bind in the acyl binding channel, stimulate SIRT6 deacetylation activity, and/or increase SIRT6 expression. [0027] A first aspect of the invention relates to a method of treating anhedonia in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia. The term “anhedonia” refers to an inability or reduced ability to experience pleasure and/or a diminished interest in engaging in pleasurable activities. A subject with anhedonia may, e.g., feel no joy at all or have positive emotions that are dulled. In some embodiments, the human subject being treated for anhedonia is male. In some embodiments, the human subject being treated for anhedonia is female. Without being bound by Attorney Docket No.1512.8.WO theory, one possible explanation for the effectiveness in females at the dosages studied is that there are differences in SIRT6 function in females versus males. Differences in levels and degree of activation of SIRT6, differences of inflammatory agents on secondary targets such as mitochondria, endoplasmic reticulum, and Golgi apparatus as well as differences in the innate and adaptive immune system and targets dependent on regulation by transcription factors such as NF- kB or kinases like GSK3 are all potentially relevant. For example, serum concentrations of SIRT6 enzyme are higher in females than in males (Zhao et al., BMC Geriatrics 21:452 (2021)). Regardless of the mechanism of action, the present invention may advantageously provide gender- specific treatments, dosages and schedules for treatment of anhedonia. [0028] Another aspect of the invention relates to a method of treating anhedonia in a human female subject in need thereof, comprising identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia. [0029] A further aspect of the invention relates to a method of treating anhedonia in a human subject in need thereof, comprising: a) determining the gender of the subject; and b) administering to the subject a therapeutically effective amount of a SIRT6 activator, the therapeutically effective amount based at least in part on the gender of the subject. [0030] A further aspect of the invention relates to a method of treating anhedonia in a human subject in need thereof, comprising: a) determining the gender of the subject; and b) administering to the subject a therapeutically effective amount of a SIRT6 activator if the subject is determined to be female, thereby treating the anhedonia, or not administering to the Attorney Docket No.1512.8.WO subject a therapeutically effective amount of a SIRT6 activator if the subject is determined to be male. [0031] Identifying a subject as female or determining the gender of the subject may be carried out by any method known in the art. In some embodiments, the method comprises determining whether the subject has two X chromosomes, i.e., whether the subject is a genetic female. The term genetic female incudes female subjects wherein one of the X chromosomes is missing or partially missing (Turner Syndrome) but excludes male subjects with XXY syndrome (Klinefelter Syndrome). In other embodiments, the method comprises determining the level of circulating female hormones (e.g., estrogen and progestin) in the subject. If the subject has a level of circulating female hormones that is within the average level in the general population for a female of that age, the subject is considered female. [0032] The methods of the invention may be used to treat or prevent anhedonia as a symptom of a disease or a disorder. The methods of the invention may be used to treat or prevent anhedonia as a symptom of a neuropsychiatric disease. In an embodiment, the neuropsychiatric disease is multiple sclerosis, traumatic brain injury, Parkinson’s disease, Huntington disease, Alzheimer’s disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder. In an embodiment, the anhedonia is a symptom of a mood or attention disorder, including attention deficit hyperactivity disorder or depression. Additional conditions include substance misuse, chronic pain, chronic fatigue syndrome, anxiety, eating disorders, autoimmune disorders like rheumatoid arthritis and metabolic disorders like diabetes, obesity and binge eating disorder. The methods of the invention may be used to treat or prevent anhedonia as a symptom of any type of depression. Types of depression include, without limitation, major depressive disorder, persistent depressive disorder, minor depression, treatment-resistant depression, substance/medication- Attorney Docket No.1512.8.WO induced depression, depressive disorder secondary to medical illness, perinatal and postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, and bipolar disorder. [0033] Assessment of anhedonia can be performed by scales or assessments known in the art, including assessments such as the anhedonia subscale of MADRS. Other examples include the Snaith-Hamilton Pleasure Scale (SHAPS), Dimensional Anhedonia Rating Scale (DARS), MASQ-Anhedonic Depression subscale, Apathy Evaluation Scale (AES) and Jouvent EHD-F1 Anhedonia Scale. See, e.g., the scales described in Rizvi et al., Neurosci. Biobehav. Rev.65:21-35 (2016), incorporated herein by reference in its entirety, with specific incorporation of Tables 1 and 2, identifying first generation and second-generation scales to measure anhedonia, respectively. The anhedonia subscale of MADRS evaluates Reported Sadness (reports of depressed mood, regardless of whether it is reflected in appearance or not; includes low spirits, despondency, or the feeling of being beyond help and without hope), Apparent Sadness (despondency, gloom, and despair (more than just ordinary transient low spirits), reflected in speech, facial expression, and posture; rate by depth and inability to brighten up), Concentration Difficulty (difficulties in collecting one’s thoughts mounting to incapacitating lack of concentration; rate by intensity, frequency, and degree of incapacity produced), Lassitude (difficulty getting started or slowness initiating and performing everyday activities), and Inability to Feel (subjective experience of reduced interest in the surroundings or activities that normally give pleasure; the ability to react with adequate emotion to circumstances or people is reduced), each of which is scored from 0 (item not present or normal) to 6 (symptoms severe or present continuously), with a total possible score of 30. Higher scores indicate more severe conditions. Attorney Docket No.1512.8.WO [0034] In some embodiments of the methods herein, a subject’s anhedonia, as measured by the change from baseline in the total score on the anhedonia subscale of MADRS after about one week of treatment with a SIRT6 activator, is reduced by at least about 20% (e.g., at least about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42%) and more particularly, the subject’s anhedonia, as measured by the change from baseline in the total score on the anhedonia subscale of MADRS, is reduced within about 3 to about 5 weeks. For example, a subject’s anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In some embodiments, the patient’s anhedonia is reduced by at least about 30%, as measured by the change from baseline in total score in an anhedonia scale following treatment with a SIRT6 activator. In yet other embodiments, the patient’s anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, as measured by the change from baseline in total score in an anhedonia scale following treatment with a SIRT6 activator. In still further embodiments, the patient’s anhedonia is reduced by about 20% to about 90%, about 40% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 20% to about 80%, about 40% to about 80%, about 60% to about 80%, about 70% to about 80%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 40% to about 60%, or about 50% to about 60%, as measured by the change from baseline in total score in an anhedonia scale following treatment with a SIRT6 activator. [0035] Reduction of anhedonia after initiating treatment with a SIRT6 activator may be measured relative to the anhedonia of the subject as measured before treatment with a SIRT6 activator, i.e., a baseline anhedonia measurement. In doing so, the treating clinician is able to calculate the change of anhedonia from the baseline to the real time anhedonia measurement at Attorney Docket No.1512.8.WO any point after treatment with a SIRT6 activator. Thus, standard methods for measuring anhedonia may be used, such as an anhedonia scale, e.g., the anhedonia subscale of MADRS. [0052] Desirably, a baseline anhedonia measurement is obtained no more than about 1 week before initiating treatment with a SIRT6 activator. In some embodiments, a baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day before treatment with a SIRT6 activator. In further embodiments, a baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes before initiating treatment with a SIRT6 activator. [0036] The subject’s change of anhedonia will depend on several factors including, without limitation, anhedonia severity, patient’s sensitivity to the SIRT6 activator, other pharmaceutical agents being administered, among others. In some embodiments, the subject’s anhedonia is reduced after about 1 week of SIRT6 activator treatment. In other embodiments, the subject’s anhedonia is reduced after about 2 weeks of SIRT6 activator treatment. In further embodiments, the subject’s anhedonia is reduced after about 3 weeks to about 5 weeks and, in certain embodiments, through week 5, of SIRT6 activator treatment. In certain embodiments, the subject’s anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following about 5 weeks of the treatment with SIRT6 activator. In further embodiments, the anhedonia of the subject is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 5 weeks, as measured by the change from baseline in total score in an anhedonia scale and/or by physician/clinical judgement. [0037] 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, Attorney Docket No.1512.8.WO isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7; You et al. (2017) Angew. Chem. Int. Ed. 56:1007), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-Dihydropyrrolo[1,2- a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3- (Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide (OEA), CL5D (CAS No.2488745-53-3), 10b (2-(1-benzofuran- 2-yl)-N-(diphenylmethyl) quinoline-4-carboxamide), 5-Cl-PZA (5-chloro-pyrazinamide), BHJH- TM3 (N2-L-leucyl-L-prolyl-L-lysyl-N6-tetradecanethioyl-L-lysyl-L-threonine), 15f, 17a (catechin gallate), 19b (OSS_128167; CAS No.887686-02-4), 20b, 21b, 22a (A127-(CONHPr)- B178), and 23. 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. [0038] A further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

wherein: Attorney Docket No.1512.8.WO R¹ is 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; R² is 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, -CH=, or a cyano group, wherein when A is a cyano group, R³ and R^3’ do not exist; R³ and R^3’ 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, Attorney Docket No.1512.8.WO 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 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, Attorney Docket No.1512.8.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, 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 R³ and R^3’ 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 C1-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, Attorney Docket No.1512.8.WO 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 C1- 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; and Attorney Docket No.1512.8.WO substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. [0039] 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-1,3,4-oxadiazol-2- yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol- 2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-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-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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]-1’,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]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy- 5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-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-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,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. [0040] In some embodiments, the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

wherein: Attorney Docket No.1512.8.WO R¹ is 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; R² is 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 R³ and R^3’ is not present, R³ and R^3’ 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, Attorney Docket No.1512.8.WO 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 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, Attorney Docket No.1512.8.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, 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 R³ and R^3’ 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 C1-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, Attorney Docket No.1512.8.WO 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 C1- 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; and Attorney Docket No.1512.8.WO substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. [0041] In some embodiments of the compound of Formula 1 or Formula 1′, R¹ is a C1-C6 alkyl group; R² is a C1-C6 alkyl group; A is a 5-membered aromatic heterocyclic ring; and R³ and R^3’ are each independently a hydrogen or a C1-C6 alkyl group. [0042] In some embodiments of the compound of Formula 1 or Formula 1′, R¹ is a methyl group, an ethyl group, or a hydroxyethyl group. [0043] In some embodiments of the compound of Formula 1 or Formula 1′, R² is a methyl group. [0044] In some embodiments of the compound of Formula 1 or Formula 1′, A is a 5-membered aromatic heterocyclic ring; R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R^3’ is a hydrogen atom. [0045] In some embodiments, the compound of Formula 1 is a compound of a Formula 1″ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

wherein R¹ is a methyl group or an ethyl group; R² is a methyl group; A is any ring selected from the following group: Attorney Docket No.1512.8.WO

R³ is a methyl group or an ethyl group. [0046] In some embodiments, 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’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-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-1,3,4-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-1,2,4-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)-1,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy- 5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-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-6-[5-[(1R)-1-hydroxyethyl]-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-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-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-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’-methoxy- 5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(3-methyl-1,2,4- oxadiazol-5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,2,4- oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (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-1,3,4-oxadiazol-2- yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol- 2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-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-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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]-1’,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]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-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-(1H-pyrazol-5-yl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-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-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; or (2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]- 1’,3-dione. [0047] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof. [0048] In one embodiment, the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5- methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof. [0049] In one embodiment, the compound is (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 or a pharmaceutically acceptable salt thereof. [0050] In one embodiment, the compound is (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)- 1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3- dione or a pharmaceutically acceptable salt thereof. [0051] In one embodiment, the compound is (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]-1’,3-dione or a pharmaceutically acceptable salt thereof. Attorney Docket No.1512.8.WO [0052] 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, R^3’ is not present.

[0053] 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. N N N N N

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. N N N N N N N N N N N Attorney Docket No.1512.8.WO [0055] 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. N _N N N N _N _N _N N

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.1512.8.WO O S NH N O HN S N N N N

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. H N O S NH O ^S

a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom. [0059] “Cyano” refers to the group -CN. [0060] “Hydroxy” or “hydroxyl” refers to the group -OH. [0061] “Carboxyl” or “carboxy” refers to -COOH or salts thereof. [0062] “Oxo” refers to the atom (=O). Attorney Docket No.1512.8.WO [0063] The term “phenoxy” refers to a group of the formula -O-R, where R is phenyl. [0064] As used herein, the prefix “Cx-Cy” indicates that the following group has from x to y carbon atoms. For example, “C1-C6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0065] The “C1-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-1-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- 1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-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. In some aspects, an alkyl group comprises from 1 to 2 carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms. [0066] 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. In some aspects, an alkenyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms. [0067] 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 Attorney Docket No.1512.8.WO 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. In some aspects, an alkynyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms. [0068] 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-1-pentyloxy group, and a 3-methyl-1-pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1-propoxy group, or a 2-propoxy group. [0069] 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. [0070] 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 hydroxyethyl group. [0071] 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. [0072] 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 Attorney Docket No.1512.8.WO 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. [0073] 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. [0074] 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. [0075] 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. [0076] 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. Attorney Docket No.1512.8.WO [0077] 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. [0078] 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. [0079] 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. [0080] The "phenylcarbonyl group" refers to a phenyl ring attached to the remainder of the molecule by a C(=O) radical. [0081] The "C1-C6 alkylcarbonyl group” refers to the group -C(=O)R, where R is a C1-C6 alkyl group. [0082] The “C1-C6 alkylcarbonylamino group” refers to the group -NHC(=O)R, where R is a C1- C6 alkyl group. [0083] The “phenylcarbonylamino group” refers to the group -NHC(=O)-phenyl. [0084] The “C3-C6 cycloalkylcarbonyl group” refers to a cycloalkyl group having 3 to 6 carbon atoms in which one hydrogen atom is replaced by a carbonyl group. [0085] The "carbamoyl group" refers to the group -C (=O)NH₂. [0086] 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. [0087] 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.1512.8.WO [0088] 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. [0089] An “amino group” refers to the group -NH₂ or -NH-R, where each R is independently alkyl, aryl, or cycloalkyl. [0090] 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. [0091] 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. [0092] 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 [0093] 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. Attorney Docket No.1512.8.WO [0094] 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. [0095] 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. [0096] 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. [0097] 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. [0098] 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. [0099] 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. Attorney Docket No.1512.8.WO [0100] 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. [0101] 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. [0102] “Substituted” (as in, e.g., “substituted alkyl”) refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, guanidino, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfonamide, sulfonic acid, thiocyanate, thiol, thione, or a combination thereof. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups or heteroaryl groups having two adjacent

ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. [0103] The “pharmaceutically acceptable salt” indicates a salt that can be used as a pharmaceutical. When the compound has 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. [0104] The pharmaceutically acceptable “basic salt” of the compound 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; Attorney Docket No.1512.8.WO 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. [0105] The pharmaceutically acceptable “acidic salt” of the compound 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, an ornithine salt, a glutamate, and an aspartate, and it is most preferably a hydrohalide (in particular, a hydrochloride). [0106] Pharmaceutically acceptable salts also include ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Sci.66(1):1-19, and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p.732, Table 38-5, each of which are hereby incorporated by reference herein. [0107] The compound 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. [0108] 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 including a cis isomer and a trans isomer, tautomers, or optical isomers such as a D isomer and an L isomer. The invention includes such isomers, stereoisomers, and mixtures of Attorney Docket No.1512.8.WO these isomers and stereoisomers in any ratio unless otherwise specified. Mixtures of these isomers may be resolved by known resolution means. [0109] 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). [0110] In addition, the present invention also encompasses a prodrug. 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 Rautio et al., Nature Rev. Drug Discov.17(8):559–587 (2018); Markovic et al., Pharmaceutics 12(11):1031 (2020) 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-1,3-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 Attorney Docket No.1512.8.WO like are included. Particularly favored prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment relative to the parent species. [0111] The 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. [0112] 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-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. [0113] As 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. Attorney Docket No.1512.8.WO [0114] As 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. [0115] As 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 non-aqueous 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, 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. [0116] As 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. Attorney Docket No.1512.8.WO [0117] 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. [0118] In the case of normal oral administration, the appropriate daily dose of a SIRT6 activator is about 0.001 mg/kg to 100 mg/kg, preferably 0.1 mg/kg to 30 mg/kg, and more preferably 0.1 mg/kg to 10 mg/kg of body weight. In some aspects, the daily dose of a SIRT6 activator is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg/kg to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg/kg, or any range or value therein. This is administered in one dose or separated into two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more doses). When administered intravenously, the appropriate daily dose of the SIRT6 activator is about 0.0001 Attorney Docket No.1512.8.WO mg/kg to 10 mg/kg (e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 mg/kg or any range or value therein) of body weight, which is administered once or separated into several times a day. In addition, as a transmucosal agent, about 0.001 mg/kg to 100 mg/kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg/kg or any range or value therein) 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. The SIRT6 activator may be administered daily, e.g., in the morning and/or evening, and/or before, during or after one or more daily meals, e.g., breakfast, lunch, and/or dinner. [0119] In the methods of the present invention, the compound may be administered in combination with 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 co-administered agents may be blended or formulated separately. The therapeutic agent may be, for example, one that treats an underlying disorder that is causing anhedonia. In an embodiment, the therapeutic agent is one that treats multiple sclerosis, traumatic brain injury, Parkinson’s disease, Huntington disease, Alzheimer’s disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder. [0120] The methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals. The 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 to be at risk for anhedonia or that would benefit from treatment with a Attorney Docket No.1512.8.WO 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. [0121] Having described the present invention, the same will be explained in greater detail in the following examples, which are included herein for illustration purposes only, and which are not intended to be limiting to the invention. EXAMPLE 1 Treatment of Anhedonia [0122] A Phase 2, multicenter, double-blind, randomized, placebo-controlled study of the safety and efficacy of SP-624 in the treatment of adult subjects assessed for anhedonia by means of the Montgomery-Asberg Depression Rating Scale (MADRS) 5-item anhedonia subscale score was carried out. The anhedonia subscale is comprised of 5 items: Reported Sadness, Apparent Sadness, Concentration Difficulty, Lassitude, and Inability to Feel. [0123] Subjects were randomized to one of two treatment groups in a 1:1 ratio and received either Compound 1 (SP-624) or placebo over a treatment period of four weeks. The baseline number of female patients treated in the study included treatment group SP-624, n = 98; and treatment group Placebo, n = 107. The baseline anhedonia mean (SD) for treatment group SP-624 was 19.8 (2.53) and treatment group Placebo, 20.1 (2.25). [0124] Compound 1 (SP-624; DS-7830a; (2S,6’R)-7-Chloro-2’,4-dimethoxy-6’-methyl-6- (5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[1-benzofuran-2,1’-cyclohex[2]ene]-3,4’-dione). Attorney Docket No.1512.8.WO [0125] Data for subjects

4) was obtained and included MADRS anhedonia subscale total score and change from baseline. Change from baseline to week 5 (1 week after last dose) in MADRS anhedonia subscale and change from baseline was also measured. [0126] At week 4, the number of female patients treated in the study included treatment group SP- 624, n = 84; and treatment group Placebo, n = 86. [0127] The study results surprisingly showed that Compound 1 was therapeutically effective in females, lowering the anhedonia subscale score in females (Table 1, FIG. 2B), showing a statistically significant separation between females treated with SP-624 and females treated with placebo at week 3. The separation between the two treatment groups continued widening at 1 week after the last dose. (FIG.1). No effect in the anhedonia subscale score is shown in males (Table 2).

Attorney Docket No.1512.8.WO Table 1. Analysis of the Female Change from Baseline MADRS 5-Item Anhedonia Subscale Total Score Over Time Using Mixed Model for Repeated Measures (MMRM), Modified intent to treat (mITT) Population Change from Baseline LSM P 24 Pl P 24 Pl Diff ¹ ¹

Attorney Docket No.1512.8.WO Change from Baseline LSM SP-624 Placebo SP-624 Placebo Difference¹ ¹

Table 2. Analysis of the Male Change from Baseline MADRS 5-Item Anhedonia Subscale Total Score Over Time Using MMRM, mITT Population Change from Baseline LSM 1

Attorney Docket No.1512.8.WO [0128] 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.1512.8.WO We Claim: 1. A method of treating anhedonia in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sirtuin 6 (SIRT6) activator, thereby treating the anhedonia. 2. The method of claim 1, wherein the anhedonia is a symptom of a neuropsychiatric disease. 3. The method of claim 1 or 2, wherein the neuropsychiatric disease is multiple sclerosis, traumatic brain injury, Parkinson’s disease, Huntington disease, Alzheimer’s disease, post- traumatic stress disorder, depression, schizophrenia, or bipolar disorder. 4. The method of claim 3, wherein the depression is major depressive disorder, persistent depressive disorder, minor depression, treatment-resistant depression, substance/medication- induced depression, depressive disorder secondary to medical illness, perinatal and postpartum depression, postmenopausal depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, or bipolar disorder. 5. The method of any one of claims 1-4, wherein the human subject is female. 6. A method of treating anhedonia in a human female subject in need thereof, comprising identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator, thereby treating anhedonia. Attorney Docket No.1512.8.WO 7. A method of treating anhedonia in a human subject in need thereof, comprising: a) determining the gender of the subject; and b) administering to the subject a therapeutically effective amount of a SIRT6 activator if the subject is determined to be female, thereby treating the anhedonia, or not administering to the subject a therapeutically effective amount of a SIRT6 activator if the subject is determined to be male. 8. The method of claim 6 or 7, wherein identifying the subject as female or determining the gender of the subject comprises determining whether the subject has two X chromosomes. 9. The method of claim 6 or 7, wherein identifying the subject as female or determining the gender of the subject comprises determining the level of circulating female hormones in the subject. 10. The method of any one of claims 1-9, 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-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-Dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4- (Pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[1,2- a]quinoxaline), UBCS068 (1-(5-((3-(Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2- Attorney Docket No.1512.8.WO a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide, CL5D (CAS No. 2488745-53-3), or 10b (2-(1-benzofuran-2-yl)-N-(diphenylmethyl) quinoline-4-carboxamide). 11. The method of any one of claims 1-9, wherein the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof:

wherein: R¹ is 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; R² is 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; Attorney Docket No.1512.8.WO 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, R³ and R^3’ do not exist; R³ and R^3’ 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 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, Attorney Docket No.1512.8.WO 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, or R³ and R^3’ 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 C1-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, Attorney Docket No.1512.8.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 C1- 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.1512.8.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; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. 12. The method of claim 11, wherein the 5-membered aromatic heterocyclic ring or the 5- membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N .

13. The method of claim 11 or 12, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N N N N N N N . Attorney Docket No.1512.8.WO 14. The method of any one of claims 11-13, wherein the 8-10 membered condensed aromatic heterocyclic ring or the 8-10 membered condensed aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N _N N N N _N _N _N N .

15. The method of any one of claims 11-14, wherein the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group in A, R³, or R^3’ is any one selected from the group: Attorney Docket No.1512.8.WO O S NH N O HN S N N N N .

16. The method of any one of claims 11-15, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group: H N O S NH O S .

17. The method any one of claims 11-16, wherein 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; Attorney Docket No.1512.8.WO (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]-1’,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]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-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-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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]-1’,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]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-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-(1H-pyrazol-5-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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. 18. The method of any one of claims 11-17, wherein the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt thereof: wherein:

R¹ is 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; Attorney Docket No.1512.8.WO R² is 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 R³ and R^3’ is not present; R³ and R^3’ 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, Attorney Docket No.1512.8.WO 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, or R³ and R^3’ 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 Attorney Docket No.1512.8.WO 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 C1-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, Attorney Docket No.1512.8.WO a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1- 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; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. 19. The method of claim 18, wherein R¹ is a methyl group, an ethyl group, or a hydroxyethyl group. 20. The method of claim 18 or 19, wherein R² is a methyl group. Attorney Docket No.1512.8.WO 21. The method of any one of claims 18-20, wherein the 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N N N N .

22. The method of any one of claims 18-21, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N N N N N N N .

23. The method of any one of claims 18-22, wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7 membered unsaturated heterocyclic group in A, R³, or R^3’ is any one selected from the group: O S NH

Attorney Docket No.1512.8.WO O N O O N HN HN ^N _{HN N} O HN N .

24. The method of any one of claims 18-23, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group: H N O S NH O S .

25. The method of any one of claims 18-24, wherein A is a 5-membered aromatic heterocyclic ring; R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R^3’ is a hydrogen atom. 26. The method of any one of claims 18-25, wherein A is any ring selected from the following group, and in the case of two binding groups, R^3’ is not present: Attorney Docket No.1512.8.WO O * N * N ^* N * * _* * N N * ^O * *

27. The method of any one of claims 18-20, wherein the compound of Formula 1 is a compound of a Formula 1′′ or a pharmaceutically acceptable salt thereof: wherein

R¹ is a methyl group or an ethyl group; R² is a methyl group; A is any ring selected from the following group: O * N * N * _N *

a group; R³ is a methyl group or an ethyl group. Attorney Docket No.1512.8.WO 28. The method of any one of claims 18-26, 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’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-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-1,3,4-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-1,2,4-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)-1,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(1-hydroxy-1-methyl-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-6-[5-[(1S)-1-hydroxyethyl]-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-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-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-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’- methoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(3-methyl-1,2,4- oxadiazol-5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,2,4- oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (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-1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4- oxadiazol-2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-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-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.8.WO (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]-1’,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]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-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-(1H-pyrazol-5-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-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-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,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-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; or Attorney Docket No.1512.8.WO (2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]- 1’,3-dione. 29. The method of claim 28, wherein the compound is (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3- yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof. 30. The method of claim 28, wherein the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’- methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof. 31. The method of claim 28, wherein the compound is (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 or a pharmaceutically acceptable salt thereof. 32. The method of claim 28, wherein the compound is (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1- methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex- 2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof. 33. The method of claim 28, wherein the compound is (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]- 1’,3-dione or a pharmaceutically acceptable salt thereof.