Compositions and methods for the treatment of anhedonia

Abstract

The present invention relates to a method for treating anhedonia in a human subject by administering a SIRT6 activator. The present invention also provides a method for treating anhedonia in a human female subject by administering a SIRT6 activator, the female subject being identified, for example, by the presence of two X chromosomes or circulating female hormones.

Description

Priority claim

[0001] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 63 / 484,277, filed February 10, 2023, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention relates to a method of treating anhedonia in a human subject by administering an activator of SIRT6. [Background technology]

[0003] Anhedonia, a loss of pleasure or interest, is a common symptom in neuropsychiatric disorders such as major depressive disorder (MDD), anxiety disorders, and schizophrenia. In the United States alone, MDD affects approximately 16 million people, or 7% of the adult population. Anhedonia is a core symptom of MDD and impacts the functioning of individuals with MDD. Furthermore, anhedonia in MDD can be resistant to some antidepressants. Unfortunately, anhedonia may be a predictor of poor long-term prognosis and poor treatment response in some neuropsychiatric disorders, including suicide. (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. Summary of the Invention

[0005] The present invention is based on the conclusion that activators of sirtuin 6 (SIRT6) have a significant therapeutic effect on anhedonia.

[0006] Accordingly, one aspect of the present 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 present 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 described in greater detail below in the description of the invention. [Brief explanation of the drawings]

[0009] [Figure 1] Graph of change from baseline in women's anhedonia subscale scores, as measured using the Montgomery-Asberg Depression Rating Scale (MADRS). Change in MADRS scores over time was measured for women receiving the exemplary SIRT6 activator SP-624 or placebo. p-values, least squares mean (LSM) difference estimates, and 95% confidence intervals (CIs) based on a repeated measures mixed model (MMRM). Error bars represent the standard error (SE) of the LSM estimates. The model for the analysis of change at week 5 differs from the analysis of change through week 4 (treatment period) because it includes data from week 5 (end-of-treatment follow-up period). **—The modified intention-to-treat (mITT) population is defined as all subjects who were randomized, received at least one dose of study medication (SP-624 or placebo), and underwent at least one baseline and one post-treatment efficacy assessment. [Figure 2A] Percentage of patients with exemplary neuropsychiatric disorders who present with anhedonia. [Figure 2B] Differences in individual MADRS items between treatment with exemplary compound SP-624 and placebo at week 4. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention is described in more detail below. This description is not intended to detail all the various ways in which the invention may be implemented or all the features that may be added to the invention. For example, features shown with respect to one embodiment may be incorporated into other embodiments, and features shown with respect to a particular embodiment may be omitted from that embodiment. Moreover, numerous modifications and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of this disclosure without departing from the invention. Therefore, the following specification is intended to exemplify particular embodiments of the invention and is not intended to exhaustively specify all permutations, combinations, and variations of the invention.

[0011] Unless the context requires otherwise, it is specifically contemplated that the various features of the invention described herein can be used in any combination. Furthermore, the present invention also contemplates that, in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted. For example, if a composite is described herein as comprising components A, B, and C, it is specifically contemplated that any of A, B, or C, or any combination thereof, singly or in any combination, can be omitted or discarded.

[0012] 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.

[0013] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety.

[0014] As used in the description of this 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 dictates otherwise.

[0015] As used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, and also refers to the absence of a combination when interpreted in the alternative ("or").

[0016] Furthermore, the present invention contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0017] Additionally, as used herein, the term "about," when referring to a measurable value such as an amount, dosage, time, temperature, etc. of a compound or agent of the invention, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the specified amount.

[0018] As used herein, the transitional phrase "consisting essentially of" is to be construed as inclusive of the materials or steps described and that do not materially affect the basic and novel characteristics of the claimed invention. Thus, as used herein, the term "consisting essentially of" should not be construed as synonymous with "comprising."

[0019] The terms "treat," "treating," or "treatment of" (or grammatical equivalents) mean to reduce the severity or at least partially improve or alleviate the symptoms of a subject, and / or to alleviate, relieve, or reduce at least one clinical symptom, and / or to slow the progression of the symptoms.

[0020] As used herein, the term "prevent" or "prevention" (and their grammatical equivalents) means to delay or inhibit the onset of a disease. The term is not intended to require complete eradication of the disease, but encompasses any type of prophylactic treatment to reduce the incidence of symptoms or delay the onset of symptoms.

[0021] The term "administering" means providing a composition to a subject suffering from or at risk of the disease and / or condition being treated.

[0022] As used herein, " therapeutically effective amount " is the amount that is sufficient to bring about some improvement or benefit to the subject.In other words, " therapeutically effective amount " is the amount that brings about some relief, alleviation, reduction or stabilization of at least one clinical symptom of the subject.Those skilled in the art will understand that the therapeutic effect does not need to be complete or curative, as long as it brings about some benefit to the subject.

[0023] As used herein, a "prophylactically effective amount" is an amount sufficient to prevent and / or delay the onset of a disease, disorder, and / or clinical symptoms in a subject, and / or to reduce the severity and / or delay the onset of a disease, disorder, and / or clinical symptoms in a subject, compared to not using the method of the present invention. One of skill in the art will understand that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0024] The term "pharmaceutical composition" refers to a composition containing at least one active ingredient in a pharmaceutically acceptable form. As used herein, "pharmaceutically acceptable" means that the substance is not biologically or otherwise undesirable, i.e., the substance can be administered to an individual together with the composition of the present invention without causing substantial adverse biological effects or adversely interacting with any of the other components of the composition in which it is contained. The substance will naturally be selected to minimize degradation of the active ingredient and minimize adverse side effects in the subject, as is well known to those skilled in the art (see, e.g., Remington's Pharmaceutical Science; 21st ed. 2005). Examples of pharmaceutically acceptable carriers for use in the compositions of the present invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free saline.

[0025] Mammalian sirtuin 6 (SIRT6) is an NAD+-dependent protein deacetylase. SIRT6 deacetylates nucleosomal histones in vitro and proteins involved in nucleosomes and DNA repair in cells. In some embodiments, SIRT6-activating compounds, i.e., "SIRT6 activators," enhance the cellular function of SIRT6. SIRT6 activators may bind to the acyl-binding channel, stimulate the deacetylation activity of SIRT6, and / or increase SIRT6 expression.

[0026] A first aspect of the present invention relates to a method for treating anhedonia in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating anhedonia. The term "anhedonia" refers to a loss or reduction in the ability to experience pleasure and / or a decreased interest in pleasurable activities. An anhedonic subject may, for example, experience no pleasure at all or experience blunted positive emotions. 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 theory, one possible explanation for the efficacy in women at the doses studied is that SIRT6 functions differently in women compared to men. Differences in the level and extent of SIRT6 activation, differences in inflammatory factors relative to secondary targets such as mitochondria, the endoplasmic reticulum, and the Golgi apparatus, differences between the innate and adaptive immune systems, and differences in targets dependent on regulation by transcription factors such as NF-κB or kinases such as GSK3 may all be potentially relevant. For example, serum concentrations of the SIRT6 enzyme are higher in women than in men (Zhao et al., BMC Geriatrics 21:452 (2021)). Regardless of the mechanism of action, the present invention can advantageously provide gender-specific treatments, dosages, and schedules for the treatment of anhedonia.

[0027] Another aspect of the present invention relates to a method for 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.

[0028] A further aspect of the present invention is a method for 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 being based at least in part on the sex of the subject; The present invention relates to a method comprising:

[0029] A further aspect of the present invention is a method for treating anhedonia in a human subject in need thereof, comprising: a) determining the gender of the subject; and b) if the subject is determined to be female, administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating anhedonia, or if the subject is determined to be male, not administering a therapeutically effective amount of a SIRT6 activator to the subject. The present invention relates to a method comprising:

[0030] Identifying a subject as female or determining the gender of a subject can be carried out by any method known in the art.In some embodiments, this method comprises determining whether a subject has two X chromosomes, that is, whether the subject is genetically female.The term genetically female includes female subjects with one missing or partially missing X chromosome (Turner syndrome), but does not include male subjects with XXY syndrome (Klinefelter syndrome).In other embodiments, this method comprises determining the circulating female hormone (e.g., estrogen and progestin) levels in the subject.If the circulating female hormone levels of the subject are within the average level range of women of the general population at that age, the subject is considered to be female.

[0031] The methods of the present invention can be used to treat or prevent anhedonia as a symptom of a disease or disorder. The methods of the present invention can be used to treat or prevent anhedonia as a symptom of a neuropsychiatric disorder. In one embodiment, the neuropsychiatric disorder is multiple sclerosis, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder. In one embodiment, anhedonia is a symptom of a mood or attention disorder, including attention deficit hyperactivity disorder or depression. Other conditions include substance abuse, chronic pain, chronic fatigue syndrome, anxiety, eating disorders, autoimmune diseases such as rheumatoid arthritis, and metabolic disorders such as diabetes, obesity, and binge eating disorder. The methods of the present invention can be used to treat or prevent anhedonia as a symptom of any type of depression. Types of depression include, but are not limited to, major depressive disorder, persistent depression, minor depression, treatment-resistant depression, substance / drug-induced depression, depression secondary to a medical illness, perinatal and postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, and bipolar disorder.

[0032] Anhedonia can be assessed using any scale or assessment method known in the art, including the anhedonia subscale of the MADRS. Other examples include the Snaith-Hamilton Anhedonia Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), the MASQ-Anhedonic Depression Subscale, the Apathy Rating Scale (AES), and the Jouvent EHD-F1 Anhedonia Scale. See, for example, the scales described in Rizvi et al., Neurosci. Biobehav. Rev. 65:21-35 (2016), which are incorporated herein by reference in their entirety, and Tables 1 and 2, which identify first-generation and second-generation scales for measuring anhedonia, respectively, are specifically incorporated herein. The anhedonia subscale of the MADRS assesses reported sadness (report of depressed mood, whether or not it is expressed outwardly; including feeling low, discouraged, or hopeless and hopeless), overt sadness (discouragement, melancholy, and hopelessness (more than just a temporary low mood) reflected in speech, facial expression, and posture; assessed by severity and inability to brighten one's mood), poor concentration (difficulty organizing thoughts, lack of concentration, and incapacity; assessed by intensity, frequency, and degree of helplessness), fatigue (difficulty initiating or slowness in starting or performing daily activities), and emotional loss (the subjective experience of decreased interest in environments and activities that usually bring pleasure; reduced ability to respond emotionally to situations and people appropriately), each scored from 0 (absence or normal) to 6 (severe or persistent presence of symptoms) out of a total of 30 points. Higher scores indicate more severe symptoms.

[0033] In some embodiments of the methods described herein, after about one week of treatment with a SIRT6 activator, the subject's anhedonia, as measured by the change from baseline in the total score on the Anhedonia subscale of the MADRS, 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%); more specifically, the subject's anhedonia, as measured by the change from baseline in the total score on the Anhedonia subscale of the MADRS, is reduced within about three weeks to about five weeks. For example, the subject's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In some embodiments, the patient's anhedonia, as measured by the change from baseline in the total score on the Anhedonia scale after treatment with a SIRT6 activator, is reduced by at least about 30%. In still other embodiments, the patient's anhedonia, as measured by the change from baseline in the total score on an anhedonia scale after treatment with a SIRT6 activator, is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%. Moreover, in further embodiments, the patient's anhedonia, as measured by the change from baseline in the total score on an anhedonia scale after treatment with a SIRT6 activator, 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%.

[0034] The reduction of anhedonia after the start of treatment with SIRT6 activator can be measured by comparing with the anhedonia of the subject measured before treatment with SIRT6 activator, i.e., the anhedonia measurement at baseline.By doing so, the treating clinician can calculate the change of anhedonia from baseline to the real-time anhedonia measurement at any time after treatment with SIRT6 activator.Therefore, the standard method for measuring anhedonia can be used, such as anhedonia scale, for example, the anhedonia subscale of MADRS.

[0035] Desirably, the baseline anhedonia measurement is obtained up to about one week before initiating treatment with a SIRT6 activator. In some embodiments, the 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 one day before initiating treatment with a SIRT6 activator. In further embodiments, the 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 change in a subject's anhedonia depends on several factors, including, but not limited to, the severity of the anhedonia, the patient's sensitivity to the SIRT6 activator, other medications administered, etc. In some embodiments, the subject's anhedonia is alleviated about one week after SIRT6 activator treatment. In other embodiments, the subject's anhedonia is alleviated about two weeks after SIRT6 activator treatment. In further embodiments, the subject's anhedonia is alleviated about three to five weeks after SIRT6 activator treatment, and in certain embodiments, at five weeks. In certain embodiments, the subject's anhedonia is alleviated by at least about 40% after about five weeks of treatment with a SIRT6 activator, as measured by the change from baseline in the total score on the anhedonia scale. In further embodiments, the subject's anhedonia is alleviated within about three weeks, and in some embodiments, within about three to five weeks, as measured by the change from baseline in the total score on the anhedonia scale and / or by physician / clinical judgment.

[0037] The methods of the present invention can be carried out using any SIRT6 activator known in the art or developed in the future. Examples of SIRT6 activators include quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamine, 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-chloropyrazinamide), BHJH-TM3 (N2-L-leucyl-L-prolyl-L-lysine-N6-tetradecanethiol-L-lysine-L-threonine), 15f, 17a (catechin gallate), 19b (OSS_128167; CAS number 887686-02-4), 20b, 21b, 22a (A127-(CONHPr)-B178), and 23. These compounds are described in further detail in Fiorentino et al., J. Med. Chem. 64:9732 (2021) and Akter et al., Int. J. Mol. Sci. 22:4180 (2021), each of which is incorporated by reference 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:

[0039] [ka]

[0040] where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; six-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, A is a benzene ring, -CH=, or a cyano group, and when A is a cyano group, R 3 and R 3' does not exist; R 3 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 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring fused with A, and the ring is optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The 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, the compound of formula 1 is selected from the group: (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[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 is any compound selected from

[0042] In some embodiments, the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

[0043] [ka]

[0044] where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; six-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, Benzene ring or single bond, in the case of a single bond, R 3 and R 3’ There is no one of R 3 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 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring fused with A, and the ring is optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0045] In some embodiments of the compound of Formula 1 or Formula 1′, R 1 is a C1-C6 alkyl group; R 2 is a C1-C6 alkyl group; A is a 5-membered aromatic heterocycle; R 3 and R 3’ are each independently hydrogen or a C1-C6 alkyl group.

[0046] In some embodiments of the compound of Formula 1 or Formula 1′, R 1 is a methyl group, an ethyl group, or a hydroxyethyl group.

[0047] In some embodiments of the compound of Formula 1 or Formula 1′, R 2 is a methyl group.

[0048] In some embodiments of the compound of Formula 1 or Formula 1′, A is a 5-membered aromatic heterocycle; R 3 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.

[0049] In some embodiments, the compound of Formula 1 is a compound of Formula 1″, or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

[0050] [ka]

[0051] where: R 1 is a methyl or ethyl group; R 2 is a methyl group; A is any ring selected from the group consisting of:

[0052] [ka]

[0053] where * indicates a linking group; and R 3 is a methyl group or an ethyl group.

[0054] In some embodiments, the compound of formula 1′ is selected from the group: (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methylspiro[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'-methylspiro[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-methylethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione is any compound selected from

[0055] In one embodiment, the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0056] 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.

[0057] In one embodiment, the compound is (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0059] 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.

[0060] In certain embodiments, the 5-membered aromatic heterocycle of A is the same as above, but more preferably represents the following 5-membered ring: 3’ Note that does not exist.

[0061] [ka]

[0062] Here, * indicates a bonding group.

[0063] As used herein, the term "5-membered aromatic heterocycle" refers to a monocyclic 5-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0064] [ka]

[0065] As used herein, the term "six-membered aromatic heterocycle" refers to a monocyclic six-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0066] [ka]

[0067] As used herein, the term "8- to 10-membered fused aromatic heterocycle" refers to an 8- to 10-membered fused aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0068] [ka]

[0069] As used herein, the term "5- to 7-membered unsaturated heterocycle" refers to a partially oxidized monocyclic 5- to 7-membered saturated heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, or a partially reduced aromatic heterocycle. Examples of such rings include those shown below.

[0070] [ka]

[0071] As used herein, the term "4- to 7-membered saturated heterocyclic ring" refers to a 4- to 7-membered saturated heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0072] [ka]

[0073] As used herein, a "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

[0074] "Cyano" refers to the radical -CN.

[0075] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0076] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.

[0077] "Oxo" refers to the atom (=O).

[0078] The term "phenoxy" refers to a group of formula -OR, where R is phenyl.

[0079] As used herein, the prefix "Cx-Cy" indicates that the following group has x to y carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0080] In this specification, the term "C1-C6 alkyl group" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, and 2,3-dimethyl-1-butyl groups, and preferably methyl or ethyl. In some embodiments, the alkyl group contains 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.

[0081] As used herein, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, optionally containing one or more carbon-carbon double bonds. For example, it may be 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, preferably a vinyl group or an allyl group. In some embodiments, the alkenyl group contains 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.

[0082] As used herein, the term "C2-C6 alkynyl group" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, optionally containing one or more carbon-carbon triple bonds. For example, it may be 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 a 1-hexynyl group, preferably an ethynyl group or a 1-propynyl group. In some embodiments, the alkynyl group contains 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.

[0083] As used herein, a "C1-C6 alkoxy group" refers to a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentyloxy, and 3-methyl-1-pentyloxy. Preferred are methoxy, ethoxy, 1-propoxy, and 2-propoxy groups.

[0084] In this specification, the term "C3-C6 cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0085] As used herein, a "hydroxy C1-C6 alkyl group" refers to a group in which a hydroxyl group is bonded to a C1-C6 alkyl group, such as a hydroxymethyl group or a hydroxyethyl group.

[0086] As used herein, the term "C1-C6 alkoxy C1-C6 alkyl group" refers to a group in which C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl groups.

[0087] In this specification, "C1-C6 haloalkyl group" refers to a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include fluoromethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-bromoethyl group, 2-chloroethyl group, 2-iodoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, trichloroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 3-chloropropyl group and 4-fluorobutyl group.Preferably, it is trifluoromethyl group.

[0088] As used herein, a "C3-C6 halocycloalkyl group" refers to 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.

[0089] In this specification, the "C1-C6 haloalkoxy group" refers to a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include fluoromethoxy group, difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-bromoethoxy group, 2-chloroethoxy group, 2-iodoethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, trichloroethoxy group, pentafluoroethoxy group, 3-fluoropropoxy group, 3-chloropropoxy group, and 4-fluorobutoxy group. Preferably, it is a trifluoromethoxy group.

[0090] As used herein, the term "C3-C6 cycloalkoxy group" refers to a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

[0091] As used herein, a "C3-C6 halocycloalkoxy group" refers to 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.

[0092] As used herein, the term "five-membered aromatic heterocyclic oxy group" refers to a group in which a five-membered aromatic heterocycle is bonded to an oxygen atom.

[0093] As used herein, the term "six-membered aromatic heterocyclic oxy group" refers to a group in which a six-membered aromatic heterocycle is bonded to an oxygen atom.

[0094] As used herein, the term "4- to 7-membered saturated heterocyclic oxy group" refers to a group in which a 4- to 7-membered saturated heterocycle is bonded to an oxygen atom.

[0095] A "phenylcarbonyl group" refers to a phenyl ring attached to the rest of the molecule by a C(=O) radical.

[0096] A "C1-C6 alkylcarbonyl group" refers to a -C(=O)R group, where R is a C1-C6 alkyl group.

[0097] A "C1-C6 alkylcarbonylamino group" refers to a -NHC(=O)R group, in which R is a C1-C6 alkyl group.

[0098] "Phenylcarbonylamino" refers to the group -NHC(=O)-phenyl.

[0099] The term "C3-C6 cycloalkylcarbonyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms in which one hydrogen atom is substituted with a carbonyl group.

[0100] A "carbamoyl group" refers to the group -C(=O)NH2.

[0101] As used herein, the term "C1-C6 alkoxycarbonyl group" refers to 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.

[0102] As used herein, the term "C3-C6 cycloalkoxycarbonyl group" refers to a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.

[0103] As used herein, the term "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, and a propylcarbonyl group.

[0104] An "amino group" refers to the group -NH2 or -NH-R, where each R is independently alkyl, aryl, or cycloalkyl.

[0105] As used herein, the term "mono(C1-C6 alkyl)aminocarbonyl group" refers to a group in which one C1-C6 alkyl group is bound to the amino group of an aminocarbonyl group, and is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.

[0106] As used herein, the term "di(C1-C6 alkyl)aminocarbonyl group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminocarbonyl group, and is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.

[0107] As used herein, the term "mono(C1-C6 alkyl)aminosulfonyl group" refers to a group in which one C1-C6 alkyl group is bound to the amino group of an aminosulfonyl group, and is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group, or a propylaminosulfonyl group.

[0108] As used herein, the term "di(C1-C6 alkyl)aminosulfonyl group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminosulfonyl group, and is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

[0109] As used herein, the term "mono(C1-C6 alkyl)amino group" refers to a group in which one C1-C6 alkyl group is bound to an amino group, and is preferably a methylamino group, an ethylamino group, or a propylamino group.

[0110] As used herein, the term "di(C1-C6 alkyl)amino group" refers to a group in which two C1-C6 alkyl groups are bound to an amino group, and is preferably a dimethylamino group, a diethylamino group, or a dipropylamino group.

[0111] As used herein, the term "C1-C6 alkoxycarbonylamino group" refers to a group in which a C1-C6 alkoxycarbonyl group is bound to an amino group, such as a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.

[0112] As used herein, the term "mono(C1-C6 alkyl)aminocarbonylamino group" refers to a group bonded to a mono(C1-C6 alkyl)aminocarbonyl amino group, and is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.

[0113] As used herein, the term "di(C1-C6 alkyl)aminocarbonylamino group" refers to a group in which a di(C1-C6 alkyl)aminocarbonyl group is bound to an amino group, and is preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0114] As used herein, the term "5-membered aromatic heterocyclic carbonylamino group" refers to a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0115] As used herein, the term "six-membered aromatic heterocyclic carbonylamino group" refers to a group in which a six-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0116] As used herein, the term "C1-C6 alkylsulfonylamino group" refers to a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.

[0117] "Substituted" (e.g., as in "substituted alkyl") refers to a group in which one or more hydrogens are 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 combinations thereof. It is understood that the above definition is not intended to include impermissible substitution patterns (e.g., a methyl group substituted with five fluoro groups, or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art.

[0118] "Pharmaceutically acceptable salt" refers to a salt that can be used as a medicine. If a compound has an acidic or basic group, it can be converted into a basic salt or acid salt by reacting with a base or acid to form a salt.

[0119] Pharmaceutically acceptable "basic salts" of compounds preferably include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts, preferably alkali metal salts.

[0120] Pharmaceutically acceptable "acid salts" of compounds preferably include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate, with hydrohalides (particularly hydrochloride) being most preferred.

[0121] Pharmaceutically acceptable salts also include ammonium salts and substituted or quaternized ammonium salts.The representative non-limiting list 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 is incorporated herein by reference.

[0122] The compound of the present invention or a pharmaceutically acceptable salt thereof may become a hydrate by absorbing moisture, adsorbing water, or by being left in the air or by recrystallization. The present invention also encompasses such various hydrates, solvates, and crystalline polymorphs of the compound.

[0123] The compounds of the present invention, their pharmaceutically acceptable salts, or solvates thereof may have various isomers, such as geometric isomers including cis and trans isomers, tautomers, or optical isomers such as D and L isomers, depending on the types and combinations of substituents. Unless otherwise specified, the present invention encompasses such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be resolved by known resolution methods.

[0124] The compounds of the present invention may be labeled, i.e., one or more atoms of the compound may be isotoped (e.g., 2 H, 3 H, 13 C. 14 C. 35 Also included are compounds substituted with aryl groups such as S.

[0125] The present invention also encompasses prodrugs. Prodrugs are compounds having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of a compound by hydrolysis or under physiological conditions. Examples of groups that constitute such prodrugs include those described in Rautio et al., Nature Rev. Drug Discov. 17(8):559-587 (2018); Markovic et al., Pharmaceutics 12(11):1031 (2020), etc. More specific examples of prodrugs include, when an amino group is present in the compound, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated, or tert-butylated), and, when a hydroxyl group is present in the compound, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or boronated (e.g., compounds in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarated, alanylated, or dimethylaminomethylcarbonylated). Furthermore, when a carboxy group is present in the compound, the prodrug may be a compound in which the carboxy group is esterified or amidated (e.g., a compound in which the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, amidated, or methylamidated). Particularly preferred prodrugs are those that improve the bioavailability of the compounds of the embodiments when administered to a subject (e.g., by allowing an orally administered compound to be more easily absorbed into the bloodstream) or that enhance the delivery of the parent compound to a biological compartment compared to the parent species.

[0126] The compounds of the present invention can be prepared by synthetic methods known in the art and by methods such as those described in WO 2017 / 170623 and WO 2019 / 065928, the entire contents of which are incorporated herein by reference.

[0127] The compounds of the present invention can be administered in any oral form such as tablets, pills, capsules, granules, powders, solutions, etc., or in any parenteral form such as intraarticular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0128] Solid compositions for oral administration include tablets, powders, granules, etc. These solid compositions contain one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminum metasilicate, etc. The solid compositions may contain one or more inert additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a film of a gastrointestinal-soluble substance, if necessary.

[0129] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. Commonly used inert diluents such as purified water and ethanol can be added to such liquid compositions. In addition to the inert diluent, the liquid composition may contain one or more solubilizing agents, adjuvants such as wetting agents, sweeteners, flavoring agents, perfumes, and preservatives.

[0130] Injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such injectable compositions may further contain one or more isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, application of a disinfectant, or irradiation. Alternatively, these injectable preparations can be prepared as sterile solid compositions, which can be dissolved or suspended in sterile water or a sterile injectable solvent immediately before use.

[0131] Examples of topical preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, and eye ointments. These topical preparations include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, and emulsions. For example, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate are used as ointment or lotion bases.

[0132] Transmucosal preparations, such as inhalants and nasal preparations, can be used in solid, liquid, or semisolid form and can be prepared according to conventional methods. For example, known excipients, and one or more pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., can be added as appropriate. These transmucosal preparations can be administered using devices suitable for inhalation or insufflation. For example, the compound can be administered alone, as a powder mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier using known devices such as metered-dose inhalers and nebulizers. Dry powder inhalers and the like can be used for single or multiple doses, and dry powders or capsules containing powders can also be used. Alternatively, a suitable ejector can be used. For example, the preparation can be in the form of a pressurized aerosol spray using a suitable gas, such as a chlorofluoroalkane, a hydrofluoroalkane, or carbon dioxide.

[0133] For typical oral administration, a suitable daily dose of a SIRT6 activator is about 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.1 mg / kg to 30 mg / kg, and more preferably 0.1 mg / kg to 10 mg / kg. In some embodiments, the daily dosage of the SIRT6 activator is from 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, The SIRT6 activator may be administered at a dose of 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, in a single dose or in two or more divided doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more divided doses). When administered intravenously, a suitable daily dose of the SIRT6 activator is about 0.0001 to 10 mg of body weight (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), administered once or in divided doses. In addition, as a transmucosal agent, approximately 0.001 mg / kg to 100 mg / kg of body weight (e.g., approximately 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) is administered once or several times a day. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.The SIRT6 activator can be administered daily, for example, in the morning and / or evening, and / or before, during, or after one or more meals daily, for example, breakfast, lunch, and / or dinner.

[0134] In the methods of the present invention, the compound can be administered in combination with various therapeutic or prophylactic agents for the disease for which it is believed to be effective. The combination can be administered simultaneously, separately, in parallel, and sequentially or at a desired time interval. The drugs administered in combination can be formulated or formulated separately. The therapeutic agent can, for example, treat the underlying disease causing the anhedonia. In one embodiment, the therapeutic agent treats multiple sclerosis, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder.

[0135] The method of the present invention can be used for both veterinary and medical purposes. Suitable subjects include birds, reptiles, amphibians, fish, and mammals. As used herein, the term "mammal" includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, etc.). Human subjects include newborns, infants, juveniles, and adults. Optionally, the subject is "in need" of the method of the present invention, for example, because the subject is at risk or thought to be at risk for anhedonia, or would benefit from treatment with the compounds described herein. As a further option, the subject may be an experimental animal and / or an animal model of a disease. Preferably, the subject is human.

[0136] Having described the invention, the invention will be further illustrated in the following examples, which are provided for illustrative purposes only and are not intended to limit the invention. [Example]

[0137] [Treatment for anhedonia] A Phase 2, multicenter, double-blind, randomized, placebo-controlled study was conducted to evaluate the safety and efficacy of SP-624 in treating adult subjects with anhedonia, assessed using the five-item anhedonia subscale score of the Montgomery-Asberg Depression Rating Scale (MADRS). The anhedonia subscale consists of five items: reported sadness, apparent sadness, difficulty concentrating, fatigue, and loss of emotion.

[0138] Subjects were randomly assigned 1:1 to one of two treatment groups and received either Compound 1 (SP-624) or placebo for a 4-week treatment period. The baseline number of female patients treated in the study was 98 in the SP-624 group and 107 in the placebo group. The mean (SD) baseline anhedonia score in the SP-624 group was 19.8 (2.53) and in the placebo group was 20.1 (2.25).

[0139] 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).

[0140] [ka]

[0141] Data were obtained for subjects at analysis visits (weeks 1, 2, 3, and 4) and included the MADRS Anhedonia subscale total score and change from baseline. Change from baseline to week 5 (1 week after the final dose) and change from baseline on the MADRS Anhedonia subscale were also measured.

[0142] At week 4, the number of female patients treated in the study was SP-624 group, n=84; placebo group, n=86.

[0143] The results surprisingly showed that Compound 1 demonstrated therapeutic efficacy in women, reducing their anhedonia subscale scores (Table 1, Figure 2B), with a statistically significant difference observed between women receiving SP-624 and those receiving placebo at week 3. The difference between the two treatment groups continued to widen one week after the final dose (Figure 1). No effect on the anhedonia subscale scores was observed in men (Table 2).

[0144] [Table 1-1]

[0145] [Table 1-2]

[0146] [Table 2-1]

[0147] [Table 2-2]

[0148] The above examples are illustrative of the present invention, but are not limiting thereof. Although the present invention has been described in detail with reference to preferred embodiments, variations and modifications can be made within the scope and spirit of the invention as set forth and defined in the following claims.

Claims

1. A method for 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. 10. The method of claim 1, wherein the anhedonia is a symptom of a neuropsychiatric disorder.

3. 3. The method of claim 1 or 2, wherein the neuropsychiatric disorder is multiple sclerosis, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder.

4. 4. The method of claim 3, wherein the depression is major depressive disorder, persistent depression, minor depression, treatment-resistant depression, substance / drug-induced depression, depression secondary to a 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 to 4, wherein the human subject is a female.

6. A method for treating anhedonia in a human female subject in need of treatment, 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.

7. 1. A method for treating anhedonia in a human subject in need thereof, comprising: a) determining the gender of a subject; and b) if the subject is determined to be female, administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating anhedonia, or if the subject is determined to be male, not administering a therapeutically effective amount of a SIRT6 activator to the subject. A method comprising:

8. 8. The method of claim 6 or 7, wherein identifying the subject as female or determining the subject's sex comprises determining whether the subject has two X chromosomes.

9. 8. 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. SIRT6 activators include quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamine, 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), and 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, CL5D (CAS No. 2488745-53-3), or 10b (2-(1-benzofuran-2-yl)-N-(diphenylmethyl)quinoline-4-carboxamide).

11. The SIRT6 activator is a compound of formula 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; six-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, A is a benzene ring, -CH=, or a cyano group, and when A is a cyano group, R 3 and R 3' does not exist; R 3 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 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as the ring fused with A, and the ring is optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. The method of any one of claims 1 to 9.

12. A, R 3 or R 3’ The 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group in 【Chemistry 2】 The method of claim 11, wherein the compound is any one selected from the group consisting of:

13. A, R 3 or R 3’ The 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group in 【Transformation 3】 The method of claim 11 or 12, wherein the compound is any one selected from the group consisting of:

14. A, R 3 or R 3’ The 8- to 10-membered aromatic heterocycle or 8- to 10-membered aromatic heterocyclic group in 【Chemistry 4】 The method according to any one of claims 11 to 13, wherein the compound is any one selected from the group consisting of:

15. A, R 3 or R 3’ The 5- to 7-membered unsaturated heterocycle or 5- to 7-membered unsaturated heterocyclic group in 【Transformation 5】 The method according to any one of claims 11 to 14, wherein the compound is any one selected from the group consisting of:

16. A, R 1 , R 2 or R 3 The 4- to 7-membered saturated heterocyclic ring or 4- to 7-membered saturated heterocyclic group in 【Transformation 6】 The method according to any one of claims 11 to 15, wherein the compound is any one selected from the group consisting of:

17. The compounds of formula 1 are of the following group: (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[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 The method of any one of claims 11 to 16, wherein the compound is any compound selected from the group consisting of:

18. The compound of formula 1 is a compound of formula 1′ or a pharmaceutically acceptable salt thereof: 【Transformation 7】 where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; six-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, Benzene ring or single bond, in the case of a single bond, R 3 and R 3’ Either of these does not exist, R 3 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 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as the ring fused with A, and the ring is optionally substituted with 1 to 2 identical or different substituents selected from 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different 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 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. The method of any one of claims 11 to 17.

19. R 1 19. The method of claim 18, wherein is a methyl group, an ethyl group, or a hydroxyethyl group.

20. R 2 The method of claim 18 or 19, wherein is a methyl group.

21. A, R 3 or R 3’ The 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group in 【Transformation 8】 The method according to any one of claims 18 to 20, wherein the compound is any one selected from the group consisting of:

22. A, R 3 or R 3’ The 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group in 【Chemistry 9】 The method according to any one of claims 18 to 21, wherein the compound is any one selected from the group consisting of:

23. A, R 3 or R 3’ The 5- to 7-membered unsaturated heterocycle or 5- to 7-membered unsaturated heterocyclic group in 【Chemistry 10】 The method according to any one of claims 18 to 22, wherein the compound is any one selected from the group consisting of:

24. A, R 1 , R 2 or R 3 The 4- to 7-membered saturated heterocyclic ring or 4- to 7-membered saturated heterocyclic group in 【Chemistry 11】 The method according to any one of claims 18 to 23, wherein the compound is any one selected from the group consisting of:

25. A is a 5-membered aromatic heterocycle; R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R 3' The method of any one of claims 18 to 24, wherein is a hydrogen atom.

26. A is any ring selected from the following group, and when there are two bonding groups, R 3’ does not exist, 【Chemistry 12】 26. The method of any one of claims 18 to 25, wherein * represents a linking group.

27. The compound of formula 1 is a compound of formula 1″, or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 where: R 1 is a methyl group or an ethyl group; R 2 is a methyl group; A is any ring selected from the group consisting of: 【Chemistry 14】 where * indicates a linking group; and R 3 The method of any one of claims 18 to 20, wherein is a methyl group or an ethyl group.

28. The compounds of formula 1' are selected from the group: (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methylspiro[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'-methylspiro[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-methylethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[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'-methylspiro[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'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione The method of any one of claims 18 to 26, wherein the compound is any compound selected from the group consisting of:

29. 29. The method of claim 28, wherein the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

30. 29. 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. 29. 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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

32. 29. The method of claim 28, wherein the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

33. 29. 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.

Images