KR20250141162A - Compositions and methods for treating anhedonia - Google Patents

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 female human subject by administering a SIRT6 activator, wherein the female subject can be identified, for example, by the presence of two X chromosomes or circulating female hormones.

Description

Compositions and methods for treating anhedonia

Check priority

This application claims the benefit of U.S. Provisional Application No. 63/484,277, filed February 10, 2023, under 35 U.S.C. §119(e), the entire contents of which are incorporated herein by reference in their entirety.

Technology field

The present invention relates to a method for treating anhedonia in a human subject by administering a SIRT6 activator.

Anhedonia, a decreased ability to experience pleasure or loss of interest, is a common symptom of neuropsychiatric disorders, including major depressive disorder (MDD), anxiety disorders, and schizophrenia. In the United States alone, approximately 16 million people, or 7% of the adult population, suffer from MDD. Anhedonia is a core symptom of MDD and impacts functioning in patients with MDD. Furthermore, anhedonia in MDD may be resistant to some antidepressant medications. Unfortunately, anhedonia may be a predictor of poor long-term outcomes or poor treatment response in some neuropsychiatric disorders, including suicide (Craske et al., ADAA Scientific Res. Symposium 33(10):927-938 (2016)).

There is a pressing need in this field for effective treatments for anhedonia.

Summary of the Invention

The present invention is based on the finding that sirtuin 6 (SIRT6) activators provide significant therapeutic effects for anhedonia.

Accordingly, one 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 to treat the anhedonia.

Another aspect of the present invention relates to a method of treating anhedonia in a human female subject in need thereof, comprising the steps of identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia.

These and other aspects of the present invention are described in more detail in the detailed description of the invention below.

Figure 1. Graph of change from baseline in women's anhedonia subscale scores on the Montgomery-Asberg Depression Rating Scale (MADRS). MADRS scores were determined over time for the treatment groups of women receiving the SIRT6 activator SP-624 or placebo. Differences in least squares means (LSM) estimates and 95% CIs based on a mixed model for repeated measures (MMRM). Error bars represent the standard error (SE) of the LSM estimates. The change analysis model at Week 5 differs from the change analysis through Week 4 (treatment period) because data from Week 5 (posttreatment follow-up) were included. ** - The modified intention-to-treat (mITT) population is defined as all subjects who were randomized to receive at least 1 dose of study drug (SP-624 or placebo) and had baseline and at least 1 post-dose efficacy assessment.
Figures 2A-2B. Figure 2A. Percentage of patients with an example of a neuropsychiatric disorder experiencing anhedonia. Figure 2B. Differences at week 4 between the example compound SP-624 and placebo treatment on individual MADRS items.

Detailed description of embodiments of the present invention

The present invention is described in more detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented or all the features that may be added to the invention. For example, features illustrated in connection with one embodiment may be incorporated into another embodiment, and features illustrated in connection with a particular embodiment may be deleted from that embodiment. Furthermore, numerous modifications and additions to the various embodiments presented herein will become apparent to those skilled in the art without departing from the scope of the invention. Accordingly, the following description is intended to illustrate some specific embodiments of the invention and is not intended to be a comprehensive description of all permutations, combinations, and variations of the invention.

Unless the context dictates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Furthermore, the present invention contemplates that, in some embodiments of the invention, features or combinations of features described herein may be excluded or omitted. For example, if the specification states that a complex comprises components A, B, and C, it is specifically intended that any one or combination of A, B, or C, alone or in any combination, may be omitted or omitted.

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 pertains. The terminology used in the description of the present invention is for the purpose of describing specific embodiments only and is not intended to be limiting of the present invention.

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

As used in the description of the present 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.

As used herein, “and/or” refers to and encompasses all possible combinations of one or more of the items listed in connection therewith, including the absence of any combination when interpreted as the alternative (“or”).

Additionally, the present invention contemplates that in some embodiments of the present invention, features or combinations of features described herein may be excluded or omitted.

Additionally, when referring to a measurable value such as an amount, dose, time, temperature, etc. of a compound or agent of the present invention, the term “about” as used herein is intended to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

The transitional phrase "consisting essentially of" as used herein should be interpreted to include recited materials or steps that do not materially affect the basic and novel characteristics(s) of the claimed invention. Therefore, the term "consisting essentially of" as used herein should not be construed as equivalent to "comprising."

The terms “treat,” “treating,” or “treatment” (or grammatically equivalent terms) mean reducing the severity of a subject’s condition or at least partially improving or ameliorating it, or alleviating, alleviating, or reducing at least one clinical symptom or delaying the progression of the condition.

As used herein, the terms "prevent," "prevents," or "prevention" (and grammatically equivalent terms) refer to delaying or inhibiting the onset of a disease. These terms encompass all types of preventative treatment aimed at reducing the incidence or delaying the onset of a disease, without requiring complete cure.

The term “administering” means providing a composition to a subject suffering from or at risk of the disease(s) and/or condition(s) to be treated.

As used herein, a "therapeutically effective" or "therapeutically effective" amount refers to an amount sufficient to provide some improvement or benefit to a subject. Alternatively, a "therapeutically effective" or "therapeutically effective" amount refers to an amount capable of providing some alleviation, relief, reduction, or stabilization of at least one clinical symptom in a subject. Those skilled in the art will recognize that a therapeutic effect need not be complete or curative, as long as some benefit is provided to the subject.

As used herein, a “prophylactically effective” or “prophylactically effective” amount is an amount sufficient to prevent and/or delay the onset of a disease, disorder, and/or clinical symptom in a subject, and/or to reduce and/or delay the severity of the onset of the disease, disorder, and/or clinical symptom in a subject compared to what would occur in the absence of the method of the present invention. One of ordinary skill in the art will recognize that the level of prevention need not be complete, as long as some benefit is provided to the subject.

The term "pharmaceutical composition" relates to a composition comprising at least one active ingredient in a pharmaceutically acceptable form. As used herein, "pharmaceutically acceptable" refers to a biologically or otherwise undesirable material, i.e., a material that can be administered to an individual with the composition of the present invention without causing substantial adverse biological effects or interacting in a deleterious manner with other components of the composition in which it is contained. Such materials will be selected to minimize degradation of the active ingredient and to 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. 2005). Exemplary pharmaceutically acceptable carriers for the composition of the present invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free saline.

Mammalian sirtuin 6 (SIRT6) is an NAD+-dependent protein deacylase. SIRT6 deacetylates nucleosomal histones and nucleosomes, as well as proteins involved in cellular DNA repair in vitro . In some instances, SIRT6-activating compounds, or “activators,” enhance the cellular function of SIRT6. SIRT6 activators can bind to acyl-binding channels, stimulating SIRT6 deacetylation activity or increasing SIRT6 expression.

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 to treat the anhedonia. The term “anhedonia” refers to a state of inability or reduced ability to experience pleasure and/or reduced interest in pleasurable activities. For example, a subject with anhedonia may experience no pleasure at all or may have 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 effects in women at the studied doses is differences in SIRT6 function between women and men. Potentially relevant factors include differences in SIRT6 levels and activation, differential responses of inflammatory agents to secondary targets such as mitochondria, the endoplasmic reticulum, and the Golgi apparatus, differences in the innate and adaptive immune systems, and differences in targets dependent on regulation by transcription factors such as NF-kB or kinases such as GSK3. 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 may advantageously provide gender-specific treatments, dosages, and schedules for the treatment of anhedonia.

Another aspect of the present invention relates to a method of treating anhedonia in a human female subject in need thereof, comprising the steps of identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator, thereby treating the anhedonia.

Another aspect of the present invention relates to a method for treating anhedonia in a human subject in need thereof, comprising:

a) A step for determining the gender of the subject; and

b) A step of administering a therapeutically effective amount of a SIRT6 activator to the subject, wherein the therapeutically effective amount is based at least in part on the subject's gender.

Another aspect of the present invention relates to a method for treating anhedonia in a human subject in need thereof, comprising:

a) A step for 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 treat anesthesia, or if the subject is determined to be male, not administering a therapeutically effective amount of a SIRT6 activator to the subject.

Identifying a subject as female or determining the sex of a subject can be performed by any method known to those of ordinary skill in the art. In some embodiments, the method comprises determining whether the subject has two X chromosomes, i.e., whether the subject is a genetic female. The term genetic female includes female subjects with a missing or partially missing one of the X chromosomes (Turner syndrome), but excludes male subjects with XXY syndrome (Klinefelter syndrome). In other embodiments, the method comprises determining circulating levels of female hormones (e.g., estrogen and progestin) in the subject. If the circulating levels of female hormones in the subject are within the average levels for the general population of women of that age, the subject is considered to be a female.

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. Additional conditions include substance abuse, chronic pain, chronic fatigue syndrome, anxiety, eating disorders, autoimmune disorders 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 depressive disorder, minor depression, treatment-resistant depression, substance/medication-induced depression, depressive disorder secondary to a medical condition, prenatal and postpartum depression, postmenopausal depression, seasonal affective disorder, premenstrual dysphoric disorder, psychotic depression, or bipolar disorder.

Anhedonia can be assessed using existing scales or assessment tools, such as the Anhedonia subscale of the MADRS. Other examples include the Snaith-Hamilton Anhedonia Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), the MASQ-Anhedonia Depression Subscale, the Apathy Rating Scale (AES), and the Juvent 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 in their entirety, and Tables 1 and 2 specifically identify first- and second-generation scales for measuring anhedonia, respectively. The anhedonia subscale of the MADRS assesses reported depression (reporting a depressed mood regardless of how it is reflected; includes low mood, hopelessness, or feeling unhelpful and hopeless); depression reflected in appearance, speech, facial expression, and posture (hopelessness, gloom, and despair (more than just a brief low mood); rated by depth and inability to lighten); difficulty concentrating (increased difficulty in gathering thoughts, leading to a lack of concentration; rated by intensity, frequency, and level of lack); listlessness (difficulty or slowness in initiating or carrying out daily activities); and lack of affect (subjective experience of decreased interest in one's surroundings or in activities that are usually pleasurable; decreased ability to respond with appropriate emotional responses to situations or people). Each item is scored from 0 (absent or normal) to 6 (severe or persistent symptoms), for a maximum total score of 30. Higher scores indicate more severe symptoms.

In some embodiments of the invention, the subject's anhedonia, as measured by a change from baseline in the Anhedonia subscale total score of the MADRS, is reduced by at least about 20% (e.g., by 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%) after about 1 week of SIRT6 activator treatment, and particularly, the subject's anhedonia, as measured by a change from baseline in the Anhedonia subscale total score of the MADRS, is reduced within about 3 to about 5 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 Anhedonia Scale total score, is reduced by at least about 30% following treatment with the SIRT6 activator. In other embodiments, the patient's anhedonia, as measured by the change from baseline in the Anhedonia Scale total score, is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% following treatment with the SIRT6 activator. In another embodiment, the patient's anhedonia is reduced from baseline in total score on an Anhedonia Scale 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% after treatment with a SIRT6 activator.

The reduction in anhedonia after initiating SIRT6 activator treatment can be measured by comparing the subject's anhedonia measurement prior to SIRT6 activator treatment, i.e., baseline anhedonia measurement. This allows the treating healthcare provider to calculate the change in anhedonia from baseline to real-time anhedonia measurement at any point after SIRT6 activator administration. Therefore, standard methods for measuring anhedonia, such as the anhedonia subscale of the MADRS, can be used.

Preferably, the baseline anhedonia measurement is obtained about 1 week prior to starting SIRT6 activator treatment. 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 1 day prior to starting SIRT6 activator treatment. 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 prior to starting SIRT6 activator treatment.

The change in the subject's anhedonia may vary depending on several factors, including but not limited to the severity of the anhedonia, the patient's sensitivity to the SIRT6 activator, and other medications administered. In some embodiments, the subject's anhedonia is reduced after about 1 week of treatment with the SIRT6 activator. In other embodiments, the subject's anhedonia is reduced after about 2 weeks of treatment with the SIRT6 activator. In further embodiments, the subject's anhedonia is reduced after about 3 to about 5 weeks of treatment with the SIRT6 activator, and in certain embodiments, after 5 weeks. In certain embodiments, the subject's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the Anhedonia Scale after about 5 weeks of treatment with the SIRT6 activator. In further embodiments, the subject's anhedonia is reduced as measured by change from baseline in the total score on the Anhedonia Scale and/or as determined by the physician/clinician, within about 3 weeks, and in some embodiments, within about 3 to about 5 weeks.

The method of the present invention can be performed with any SIRT6 activator currently known or developed in the future. Examples of SIRT6 activators include quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide (OEA), CL5D (CAS No. 2488745-53-3), These compounds include, but are not limited to, 10b (2-(1-benzofuran-2-yl)-N-(diphenylmethyl)quinoline-4-carboxamide), 5-Cl-PZA (5-chloro-pyrazinamide), BHJH-TM3 (N2-L-leucine-L-proline-L-lysine-N6-tetradecanethioyl-L-lysine-L-threonine), 15f, 17a (catechin gallate), 19b (OSS_128167; CAS No. 887686-02-4), 20b, 21b, 22a (A127-(CONHPr)-B178), and 23. These compounds are disclosed in Fiorentino et al., J. Med. Chem . 64:9732 (2021) and Akter et al., Int. J. Mol. Sci . 22:4180 (2021), which is incorporated herein by reference in its entirety.

Another example of a SIRT6 activator is a compound of formula 1 or a pharmaceutically acceptable salt, racemate, stereoisomer or prodrug thereof:

Here:

R ¹ is 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 one to two identical or different substituents selected from the substituent group X, or

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

R ² is 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 one to two identical or different substituents selected from the substituent group X, or

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

A is a 5-membered aromatic heterocyclic ring,

6-membered aromatic heterocyclic ring,

8-10 membered condensed aromatic heterocyclic ring,

5-7 membered unsaturated heterocyclic ring,

4-7 membered saturated heterocyclic ring,

A benzene ring, -CH= or a cyano group, wherein when A is a cyano group, R ³ and R ³ ' do 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 the substituent group X,

A C1-C6 alkoxy group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C2-C6 alkenyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C2-C6 alkynyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C3-C6 cycloalkyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,

An amino group optionally substituted with one to two identical or different substituents selected from the substituent group X,

A C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A carbamoyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,

A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 5-7 membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

An 8-10 membered condensed aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or

R ³ and R ³ ' may be combined with each other to form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring which is a ring condensed with A, said ring being optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group,

A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkoxy group, C3-C6 halocycloalkoxy group,

A phenoxy group optionally substituted with one or two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 4-7 membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the 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 one to two identical or different substituents selected from the 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 one to two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y, or

is 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.

In some embodiments, the compound of formula 1 is any compound selected from the group consisting of:

(2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-Chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]decan-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]decane-2-en-3-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or

(2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

In some embodiments, the compound of formula 1 is a compound of formula 1' or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

Here:

R ¹ is 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 one to two identical or different substituents selected from the substituent group X, or

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

R ² is 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 one to two identical or different substituents selected from the substituent group X, or

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

A is a 5-membered aromatic heterocyclic ring,

6-membered aromatic heterocyclic ring,

8-10 membered condensed aromatic heterocyclic ring,

5-7 membered unsaturated heterocyclic ring,

4-7 membered saturated heterocyclic ring,

As a benzene ring or a single bond, when it is a single bond, R ³ and R ³ ' do 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 the substituent group X,

A C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A C2-C6 alkenyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C2-C6 alkynyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C3-C6 cycloalkyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,

An amino group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A carbamoyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,

A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,

A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 5-7 membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,

An 8-10 membered condensed aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or

R ³ and R ³ ' may be combined with each other to form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring which is a ring condensed with A, said ring being optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;

Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group,

A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkoxy group, C3-C6 halocycloalkoxy group,

A phenoxy group optionally substituted with one or two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 4-7 membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the 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 one to two identical or different substituents selected from the 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 one to two identical or different substituents selected from the substituent group Y,

A 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,

A 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y, or

is 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.

In some embodiments, in 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 heterocyclic ring; and R ³ and R ³ ' are each independently hydrogen or a C1-C6 alkyl group.

In some embodiments, in the compound of formula 1 or formula 1', R ¹ is a methyl group, an ethyl group, or a hydroxyethyl group.

In some embodiments, in the compound of formula 1 or formula 1', R ² is a methyl group.

In some embodiments, in the compound of formula 1 or formula 1', A is a 5-membered aromatic heterocyclic ring; 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.

The compound of formula 1 is a compound of formula 1'' or a pharmaceutically acceptable salt, racemate, stereoisomer or prodrug thereof:

Here

R ¹ is a methyl group or an ethyl group;

R ² is a methyl group;

A is any one ring selected from the following group:

Here, * represents a binding group; and

R ³ is a methyl group or an ethyl group.

In some embodiments, the compound of formula 1' is any compound selected from the group consisting of:

(2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl) spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5′chloro-6-(1-ethylpyrazol-3-yl)-3′dimethoxy-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-3′dimethoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-3′dimethoxy-5′methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-Chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-Chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5′chloro-4-ethoxy-3′methoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-4-(difluoromethoxy)-3′methoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-3′dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3′dimethoxy-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-3′dimethoxy-5′methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-3′dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;

(2S,5′chloro-6-(1,8-dioxa-2-azaspiro [4 5] dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro [benzofuran-2,4′-cyclohex-2-ene]-1′ dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexth-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexth-2-ene]-1',3-dione;

(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl) spiro [benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or

(2S,5'R)-7-chloro-3',4,6-trimethoxy-5'-methyl spiro [benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

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

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.

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

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

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.

In certain embodiments, the 5-membered aromatic heterocyclic ring A is the same as described above, but more preferably represents the following 5-membered ring. In this case, R ³ ' is absent:

Here, * represents a combined group.

As used herein, a “5-membered aromatic heterocyclic ring” is a 5-membered aromatic heterocyclic ring of a single ring containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples thereof include the rings shown below.

As used herein, a “6-membered aromatic heterocyclic ring” is a 6-membered aromatic heterocyclic ring of a single ring containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples thereof include the rings shown below.

As used herein, an “8-10 membered fused aromatic heterocyclic ring” is an 8-10 membered fused aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples thereof include the rings shown below.

As used herein, a “5-7 membered unsaturated heterocyclic ring” is a 5-7 membered saturated heterocyclic ring that is partially oxidized or an aromatic heterocyclic ring that contains 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples thereof include the rings shown below.

As used herein, a “4-7 membered saturated heterocyclic ring” is a 4-7 membered saturated heterocyclic ring of a single ring containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples thereof include the rings shown below.

In this specification, “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

“Cyano” refers to the -CN group.

“Hydroxy” or “hydroxyl” refers to the -OH group.

“Carboxyl” or “carboxy” refers to -COOH or a salt thereof.

“Oxo” refers to the (=O) atom.

The term “phenoxy” refers to the chemical formula -O-R, where R is phenyl.

The prefix "Cx-Cy" as used herein indicates that the group has from x to y carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

In the present specification, “C1-C6 alkyl group” is a straight or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, and a 2,3-dimethyl-1-butyl group, and preferably a methyl group or an ethyl group. In some embodiments, the alkyl group comprises 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.

As used herein, a “C2-C6 alkenyl group” is a straight or branched alkyl group having 2 to 6 carbon atoms, and may have 1 or more carbon-carbon double bonds. For example, it is a vinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenyl group, a 3-methyl-2-butenyl group, a 2-hexenyl group, or a 3-methyl-2-pentenyl group, and is preferably a vinyl group or an allyl group. In some aspects, the alkenyl group comprises 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.

As used herein, “C2-C6 alkynyl group” means a straight or branched alkynyl group having 2 to 6 carbon atoms, which may have 1 or more carbon-carbon triple bonds. For example, it is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, or a 1-hexynyl group, and preferably an ethynyl group or a 1-propynyl group. In some aspects, the alkynyl group includes 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.

As used herein, a “C1-C6 alkoxy group” is a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-butoxy group, a 2-methyl-1-propoxy group, a 2-methyl-2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, and a 3-methyl-1-pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1-propoxy group, or a 2-propoxy group.

In this specification, “C3-C6 cycloalkyl group” is 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.

As used herein, “hydroxy C1-C6 alkyl group” refers to a group in which a hydroxyl group is bonded to a C1-C6 alkyl group. For example, a hydroxymethyl group or a hydroxyethyl group.

As used herein, “C1-C6 alkoxy C1-C6 alkyl group” refers to a group bonded to a C1-C6 alkoxy C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.

As used herein, the term “C1-C6 haloalkyl group” refers to a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2-iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3-fluoropropyl group, a 3-chloropropyl group, and a 4-fluorobutyl group. Preferably, it is a trifluoromethyl group.

In this specification, “C3-C6 halocycloalkyl group” is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, examples of which include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.

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

In this specification, “C3-C6 cycloalkoxy group” is 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.

In this specification, “C3-C6 halocycloalkoxy group” is a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, examples of which include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.

As used herein, “5-membered aromatic heterocyclic oxy group” is a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom.

As used herein, “6-membered aromatic heterocyclic oxy group” is a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom.

In this specification, “4-7 membered saturated heterocyclic oxy group” is a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom.

“Phenylcarbonyl group” refers to a phenyl ring attached to the remainder of the molecule with a C(=O) radical.

“C1-C6 alkylcarbonyl group” refers to a -C(=O)R group where R is a C1-C6 alkyl group.

“C1-C6 alkylcarbonylamino group” refers to a -NHC(=O)R group where R is a C1-C6 alkyl group.

“Phenylcarbonylamino group” refers to a -NHC(=O)-phenyl group.

A “C3-C6 cycloalkylcarbonyl group” refers to a cycloalkyl group having 3 to 6 carbon atoms, with one hydrogen atom replaced by a carbonyl group.

“Carbamoyl group” refers to the -C(=O)NH ₂ group.

In this specification, “C1-C6 alkoxycarbonyl group” is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, examples of which include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

In this specification, “C3-C6 cycloalkoxycarbonyl group” is 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.

In this specification, “C1-C6 alkylcarbonyl group” is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, examples of which include a methylcarbonyl group, an ethylcarbonyl group, or a propylcarbonyl group.

“Amino group” refers to a -NH ₂ or -NH-R group, where each R is independently alkyl, aryl, or cycloalkyl.

In this specification, “mono (C1-C6 alkyl) aminocarbonyl group” is a group in which a C1-C6 alkyl group is bonded to the amino group of the aminocarbonyl group, and is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group or a propylaminocarbonyl group.

In this specification, “di (C1-C6 alkyl) aminocarbonyl group” is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminocarbonyl group, and is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group or a dipropylaminocarbonyl group.

In this specification, “mono (C1-C6 alkyl) aminosulfonyl group” is a group in which one C1-C6 alkyl group is bonded to the amino group of the aminosulfonyl group, and is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group or a propylaminosulfonyl group.

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

In this specification, “mono (C1-C6 alkyl) amino group” is a group in which one C1-C6 alkyl group is bonded to an amino group, preferably a methylamino group, an ethylamino group or a propylamino group.

In this specification, “di (C1-C6 alkyl) amino group” is a group in which two C1-C6 alkyl groups are bonded to an amino group, and is preferably a dimethylamino group, a diethylamino group or a dipropylamino group.

In this specification, “C1-C6 alkoxycarbonylamino group” is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, for example, a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.

In this specification, “mono (C1-C6 alkyl) aminocarbonylamino group” is a group in which a mono (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.

In this specification, “di (C1-C6 alkyl) aminocarbonylamino group” is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and is preferably a dimethylamino carbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

In this specification, “5-membered aromatic heterocyclic carbonylamino group” is a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

As used herein, “6-membered aromatic heterocyclic carbonylamino group” is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

In this specification, “C1-C6 alkylsulfonylamino group” is a group in which a C1-C6 alkyl group is bonded to a sulfonyl group of a sulfonylamino group, and is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.

"Substituted" (e.g., substituted alkyl) refers to a group in which one or more hydrogens are independently replaced by 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 should be understood that the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluoro groups or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are not intended to include the Well known to technicians in the field.

"Pharmaceutically acceptable salt" refers to a salt that can be used pharmaceutically. If a compound contains an acidic or basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or acid to form the corresponding salt.

Pharmaceutically acceptable “basic salts” of the compound preferably include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; organic salts such as N-methyl morpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt and picoline salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid and aspartate salt, preferably alkali metal salts.

Pharmaceutically acceptable “acid salts” of the compound are preferably inorganic acid salts such as hydrohalides, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, phosphate; organic acid salts such as lower alkanesulfonates, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate; aryl sulfonates such as benzenesulfonate, p-toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, and the like; And amino acid salts include glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, and most preferably hydrohalides (especially hydrochlorides).

Pharmaceutically acceptable salts include ammonium and substituted or quaternary ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Sci. 66(1):1-19, and Remington : The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p. 732, Table 38-5, each of which is incorporated herein by reference.

The compound of the present invention or a pharmaceutically acceptable salt thereof may absorb moisture, adhere to the absorbed water, remain in the air, or recrystallize to form a hydrate. The present invention also includes such compounds in various hydrates, solvates, and crystalline polymorphs.

The compounds of the present invention, and their pharmaceutically acceptable salts or solvates, 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 type and combination of substituents. The present invention includes such isomers, stereoisomers, and mixtures of such isomers and stereoisomers in any ratio, unless otherwise specified. Such mixtures of isomers can be decomposed by known decomposition means.

The compounds of the present invention also include compounds in which one or more atoms of the compound are substituted with an isotope (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ³⁵ S, etc.).

The present invention also encompasses prodrugs. Prodrugs are compounds having a group that can be substituted with an amino group, hydroxyl group, carboxyl group, or similar group of the corresponding compound under hydrolysis or physiological conditions. The groups forming such prodrugs are described in Rautio et al., Nature Rev. Drug Discov . 17(8):559-587 (2018); Markovic et al., Pharmaceutics 12(11):1031 (2020), etc. As a precursor, especially when an amino group is present in the compound, compounds in which the amino group is acylated, alkylated or phosphorylated (e.g., the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butylated, or the like), and when a hydroxyl group is present in the compound, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarated, alanylated, or dimethylaminomethylated) Compounds in which the carboxyl group is esterified or amidated (e.g., the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated or the like) are included. Particularly preferred prodrugs are those that increase the bioavailability of a compound according to an embodiment of the invention when the compound is administered to a subject (e.g., by making an orally administered compound more readily absorbable into the blood) or that enhance the delivery of the parent compound to a biological compartment compared to the parent compound.

The compounds of the present invention can be prepared by synthetic methods known in the art and described in WO 2017/170623 and WO 2019/065928, which are incorporated herein by reference in their entirety.

Administration of the compound of the present invention may be carried out in oral dosage forms such as tablets, pills, capsules, granules, powders, solutions, etc., or in parenteral dosage forms such as intra-articular, intravenous, intramuscular or similar injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal penetrating solutions, transmucosal penetrating patches, inhalants, or similar forms.

Solid dosage forms for oral administration include tablets, powders, and granules. These solid dosage forms consist of one or more active ingredients and one or more harmless excipients, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, or magnesium metasilicate aluminate. Solid preparations may also include one or more inert additives, such as lubricants like magnesium stearate, disintegrants like sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Optionally, tablets or pills may be coated with a sugar coating or film of a substance that dissolves in the stomach or intestines.

Pharmaceutically acceptable liquid formulations for oral administration include emulsions, solutions, suspensions, syrups, and elixirs. These liquid compositions may contain commonly used inert diluents, such as purified water or ethanol. In addition to these inert diluents, liquid compositions may also contain excipients such as solubilizers, one or more wetting agents, sweeteners, flavoring agents, fragrances, and preservatives.

Injectable preparations for intravenous administration may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection, physiological saline, etc. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80, etc. These injectable compositions may also include one or more osmotic pressure regulators, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These injectable compositions may be sterilized, for example, by filtering through a bacterial filter, applying a disinfectant, or irradiating. Furthermore, these injectable compositions may be prepared as sterile solid compositions prior to use and then dissolved or suspended in sterile water or a sterile injectable solvent.

Topical agents include ointments, patches, creams, gels, cataplasms, sprays, lotions, eye drops, and eye ointments. These topical agents commonly contain ingredients such as ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, and emulsions. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

Mucosal penetrating preparations, such as inhalants or nasal preparations, are used in solid, liquid, or semi-solid forms and can be manufactured by generally known methods. For example, one or more pH adjusting agents, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. may be added as appropriate along with known excipients. These mucosal penetrating preparations can be administered by inhalation or by a device suitable for inhalation administration. For example, the compound can be administered alone or in powder form in a prepared mixture, or as a solution or suspension combined with a pharmaceutically acceptable carrier, using known devices such as metered-dose inhalation devices and nebulizers. Dry powder inhalers or similar devices, as well as dry powder or powder-containing capsules, can also be used for single or multiple doses. Alternatively, a suitable spraying device can be used. For example, this can be a pressurized aerosol spray or similar form using a suitable gas such as a chlorofluoroalkane, a hydrofluoroalkane, or carbon dioxide.

For general oral administration, an appropriate daily dosage 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 dose 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, 0.0 or 1 mg/kg to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg/kg or any range or value thereof. This may be administered as a single dose or divided into two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or more times). An appropriate daily dose of the SIRT6 activator when administered intravenously is about 0.0001 mg/kg to 10 mg/kg (e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5 or 10 mg/kg or any range or value thereof), administered once daily or in multiple divided doses. Additionally, the mucosal penetrating formulation is administered once a day or in divided doses at a dose of about 0.001 mg/kg to 100 mg/kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg/kg or any range or value thereof). The dosage is determined appropriately on an individual basis, taking into account symptoms, age, sex, etc. The SIRT6 activator may be administered daily, for example, in the morning and/or evening, and/or before, during, or after one or more meals during the day, for example, at breakfast, lunch, and/or dinner.

In the methods of the present invention, the compound may be administered together with various therapeutic or preventative agents for diseases for which the compound is believed to exhibit the corresponding efficacy. The combination may be administered simultaneously, separately, simultaneously, continuously, or at desired time intervals. The co-administered agents may be mixed or formulated separately. The therapeutic agent may be, for example, an agent that treats the underlying condition causing anhedonia. In one embodiment, the therapeutic agent may be a drug that treats multiple sclerosis, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease, post-traumatic stress disorder, depression, schizophrenia, or bipolar disorder.

The methods of the present invention can be applied to both veterinary and medical fields. Applicable species include birds, reptiles, amphibians, fish, and mammals. The term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, etc.), and the like. Human subjects include newborns, infants, adolescents, and adults. Optionally, a subject is “in need of a method of the present invention,” e.g., a subject is suspected of suffering from or at risk for anhedonia, or who would benefit from treatment with a compound described herein. Additionally, the subject may be a laboratory animal and/or a disease model animal. Preferably, the subject is a human.

As described in the present invention, the following examples are included herein for illustrative purposes and are not intended to limit the scope of the present invention.

Example 1

Treatment of anhedonia

A phase 2, multicenter, double-blind, randomized, placebo-controlled study was conducted to evaluate the safety and efficacy of SP-624 in the treatment of adults using the 5-item anhedonia subscale of the Montgomery-Asberg Depression Rating Scale (MADRS). The anhedonia subscale includes five items: reported depressed mood, apparent depressed mood, impaired concentration, listlessness, and emotional deficit.

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

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)

1

Subject data were collected at the analysis visits (weeks 1, 2, 3, and 4), including the total MADRS anhedonia subscale score and the change from baseline. The change from baseline at week 5 (1 week after the final dose) and the change from baseline in the MADRS anhedonia subscale were also measured.

The number of female patients treated in the study at week 4 was treatment group SP-624, n = 84; and treatment group placebo, n = 86.

Surprisingly, the study results showed that compound 1 significantly reduced the anhedonia subscale score in women, demonstrating its therapeutic efficacy in women ( Table 1 , Figure 2B ), and the difference between women receiving SP-624 and those receiving placebo was statistically significant at week 3. The difference between the two treatment groups continued to widen one week after the last dose ( Figure 1 ). In men, no effect was observed on the anhedonia subscale score ( Table 2 ).

Table 1. Analysis of change from baseline in the MADRS 5-item anhedonia subscale total score over time in women using repeated measures analysis of variability (MMRM) with mixed models, modified intention-to-treat (mITT) group.

Table 2. Analysis of change from baseline in MADRS 5-item anhedonia subscale total score over time in men using MMRM, mITT group

The above examples are illustrative examples of the present invention and are not intended to limit it. While the present invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the invention as set forth and defined in the following claims.

Claims (33)

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 to treat the anhedonia. A method according to claim 1, wherein anhedonia is a symptom of a neuropsychiatric disorder. A method according to claim 1 or 2, wherein the neuropsychiatric disease 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 the third paragraph, the depression is major depressive disorder, persistent depressive disorder, minor depression, treatment-resistant depression, substance/drug-induced depression, depressive disorder secondary to a medical condition, prenatal and postpartum depression, postmenopausal depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, or bipolar disorder. A method according to any one of claims 1 to 4, wherein the human subject is a female. A method for treating anhedonia in a human female subject in need thereof, comprising the steps of identifying the subject as female and administering to the identified female subject a therapeutically effective amount of a SIRT6 activator to treat the anhedonia. A method for treating anhedonia in a human subject in need thereof, comprising:
a) a step of 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 to treat anesthesia, or if the subject is determined to be male, not administering a therapeutically effective amount of a SIRT6 activator to the subject. A method according to claim 6 or 7, wherein the step of identifying the subject as a female or the step of determining the sex of the subject comprises the step of determining whether the subject has two X chromosomes. A method according to claim 6 or 7, wherein the step of identifying the subject as a female or the step of determining the sex of the subject comprises the step of determining the level of female hormones circulating in the subject. In any one of claims 1 to 9, the SIRT6 activator is quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-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). A method according to any one of claims 1 to 9, wherein the SIRT6 activator is a compound of formula 1 or a pharmaceutically acceptable salt thereof:

Here:
R ¹ is 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 one to two identical or different substituents selected from the substituent group X, or
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
R ² is 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 one to two identical or different substituents selected from the substituent group X, or
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
A is a 5-membered aromatic heterocyclic ring,
6-membered aromatic heterocyclic ring,
8-10 membered condensed aromatic heterocyclic ring,
5-7 membered unsaturated heterocyclic ring,
4-7 membered saturated heterocyclic ring,
A benzene ring, -CH= or a cyano group, wherein when A is a cyano group, R ³ and R ³ ' do 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 the substituent group X,
A C1-C6 alkoxy group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A C2-C6 alkenyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A C2-C6 alkynyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A C3-C6 cycloalkyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,
An amino group optionally substituted with one to two identical or different substituents selected from the substituent group X,
A C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A carbamoyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,
A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 5-7 membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
An 8-10 membered condensed aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or
R ³ and R ³ ' may be combined with each other to form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring which is a ring condensed with A, said ring being optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group,
A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkoxy group, C3-C6 halocycloalkoxy group,
A phenoxy group optionally substituted with one or two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 4-7 membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the 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 one to two identical or different substituents selected from the 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 one to two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y, or
is 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. In the 11th paragraph, the 5-membered aromatic heterocyclic ring or 5-membered aromatic heterocyclic group of A, R ³ or R ³ ' is any one selected from the following group:
. In claim 11 or 12, the 6-membered aromatic heterocyclic ring or 6-membered aromatic heterocyclic group of A, R ³ or R ³ ' is any one selected from the following group:
. In any one of claims 11 to 13, the 8-10 membered fused aromatic heterocyclic ring or 8-10 membered fused aromatic heterocyclic group of A, R ³ or R ³ ' is one selected from the following group:
. In any one of claims 11 to 14, the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group of A, R ³ or R ³ ' is one selected from the following group:
. In any one of claims 11 to 15, the 4-7 membered saturated heterocyclic ring or 4-7 membered saturated heterocyclic group of A, R ¹ , R ² or R ³ is any one selected from the following group:
. A method according to any one of claims 11 to 16, wherein the compound of formula 1 is any one compound selected from the following group:
(2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-Chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]decan-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]decane-2-en-3-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or
(2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione. A method according to any one of claims 11 to 17, wherein the compound of formula 1 is a compound of formula 1' or a pharmaceutically acceptable salt thereof:

Here:
R ¹ is 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 one to two identical or different substituents selected from the substituent group X, or
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
R ² is 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 one to two identical or different substituents selected from the substituent group X, or
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
A is a 5-membered aromatic heterocyclic ring,
6-membered aromatic heterocyclic ring,
8-10 membered condensed aromatic heterocyclic ring,
5-7 membered unsaturated heterocyclic ring,
4-7 membered saturated heterocyclic ring,
As a benzene ring or a single bond, when it is a single bond, R ³ and R ³ ' do 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 the substituent group X,
A C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A C2-C6 alkenyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A C2-C6 alkynyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A C3-C6 cycloalkyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,
An amino group optionally substituted with one to two identical or different substituents selected from the substituent group X,
A C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A carbamoyl group optionally substituted with one or two identical or different substituents selected from the substituent group X,
A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group X,
A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 5-7 membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X,
An 8-10 membered condensed aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X, or
R ³ and R ³ ' may be combined with each other to form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring which is a ring condensed with A, said ring being optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X;
Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group,
A phenyl group optionally substituted with one to two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 4-7 membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkoxy group, C3-C6 halocycloalkoxy group,
A phenoxy group optionally substituted with one or two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 4-7 membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from the 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 one to two identical or different substituents selected from the 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 one to two identical or different substituents selected from the substituent group Y,
A 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y,
A 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y, or
is 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. A method according to claim 18, wherein R ¹ is a methyl group, an ethyl group or a hydroxyethyl group. A method according to claim 18 or 19, wherein R ² is a methyl group. In any one of claims 18 to 20, the 5-membered aromatic heterocyclic ring or 5-membered aromatic heterocyclic group of A, R ³ or R ³ ' is one selected from the following group:
. In any one of claims 18 to 21, the 6-membered aromatic heterocyclic ring or 6-membered aromatic heterocyclic group of A, R ³ or R ³ ' is any one selected from the following group:
. In any one of claims 18 to 22, the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group of A, R ³ or R ³ ' is one selected from the following group:

. In any one of claims 18 to 23, the 4-7 membered saturated heterocyclic ring or 4-7 membered saturated heterocyclic group of A, R ¹ , R ² or R ³ is any one selected from the following group:
. A method according to any one of claims 18 to 24, wherein A is a 5-membered aromatic heterocyclic ring; 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. In any one of claims 18 to 25, wherein A is any one ring selected from the following group, and when it is two bonding groups, R ³ ' is absent:

Here, * represents a combined group. A method according to any one of claims 18 to 20, wherein the compound of formula 1 is a compound of formula 1'' or a pharmaceutically acceptable salt thereof:

Here
R ¹ is a methyl group or an ethyl group;
R ² is a methyl group;
A is any one ring selected from the following group:

Here, * represents a binding group; and
R ³ is a methyl group or an ethyl group. A method according to any one of claims 18 to 26, wherein the compound of formula 1' is any compound selected from the following group:
(2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl) spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5′chloro-6-(1-ethylpyrazol-3-yl)-3′dimethoxy-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-3′dimethoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-3′dimethoxy-5′methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-Chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-Chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5′chloro-4-ethoxy-3′methoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-4-(difluoromethoxy)-3′methoxy-5′methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-3′dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3′dimethoxy-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-3′dimethoxy-5′methyl-6-(1H-pyrazol-5-yl) spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-3′dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5′methyl-spiro[benzofuran-2,4′cyclohex-2-ene]-1′dione;
(2S,5′chloro-6-(1,8-dioxa-2-azaspiro [4 5] dec-2-en-3-yl)-3′,4-dimethoxy-5′-methyl-spiro [benzofuran-2,4′-cyclohex-2-ene]-1′ dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexth-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexth-2-ene]-1',3-dione;
(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl) spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or
(2S,5'R)-7-chloro-3',4,6-trimethoxy-5'-methyl spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione. A method according to claim 28, wherein the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methyl spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof. A method according to 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. A method according to claim 28, wherein the compound is (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof. A method according to claim 28, wherein the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof. A method according to 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.