WO2024148149A2

WO2024148149A2 - Compositions and methods for controlling glucose levels

Info

Publication number: WO2024148149A2
Application number: PCT/US2024/010285
Authority: WO
Inventors: Kelly J. ABERNATHY; Michael Friedrich ACKERMANN; Stephen E. Butts
Original assignee: Sirtsei Pharmaceuticals, Inc.
Priority date: 2023-01-06
Filing date: 2024-01-04
Publication date: 2024-07-11

Abstract

The present invention relates to methods of improving glucose homeostasis and/or reducing glucose plasma levels by administering a SIRT6 activator. The present invention also provides methods for treating hyperglycemia, prediabetes, and diabetes including Type I diabetes, Type II diabetes or gestational diabetes by administering a SIRT6 activator.

Description

Attorney Docket No.1512.7.WO COMPOSITIONS AND METHODS FOR CONTROLLING GLUCOSE LEVELS STATEMENT OF PRIORITY [0001] This application cliams the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No.63/478,826, filed January 6, 2023, the entire contents of which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods of controlling glucose plasma levels and treating hyperglycemia, prediabetes, and diabetes by administering a SIRT6 activator. BACKGROUND OF THE INVENTION [0003] Diabetes is a major public health challenge with at least 180 million reported cases of diabetes worldwide - a figure set to more than double by 2030 according to the World Health Organization (WHO), consumption of 10% of Western healthcare budgets, and around 3.2 million deaths per year resulting from related complications. This alarming increase in incidence, coupled with the failure of established anti-diabetic drugs to tightly manage or control diabetes, demonstrates the market need for new innovation. [0004] There is a need in the art for effective treatments for maintaining glucose homeostasis and treating prediabetes and diabetes. Attorney Docket No.1512.7.WO SUMMARY OF THE INVENTION [0005] The present invention is based on the determination that activators of sirtuin 6 (SIRT6) provide a significant lowering of blood glucose levels. [0006] Thus, one aspect of the invention relates to a method of improving glucose homeostasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby improving glucose homeostasis. [0007] Another aspect of the invention relates to a method of lowering plasma glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby lowering plasma glucose levels. [0008] A further aspect of the invention relates to a method of treating hyperglycemia, prediabetes, or diabetes (e.g., Type I, Type II or gestational) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the hyperglycemia, prediabetes, or diabetes. [0009] These and other aspects of the invention are set forth in more detail in the description of the invention below. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG.1. Fasting glucose mean values by visit. Subjects received either placebo or a SIRT6 activator (Compound 1). DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION [0011] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with Attorney Docket No.1512.7.WO respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof. [0012] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. [0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. [0014] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety. [0015] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Attorney Docket No.1512.7.WO [0016] As used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0017] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. [0018] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount. [0019] As used herein, the transitional phrase “consisting essentially of” is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising.” [0020] As used herein, the terms “treating”, “treatment”, “treat” and the like mean affecting a subject (e.g., a patient), tissue or cell to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing, or reducing the severity of, a disease or associated symptom, and/or may be therapeutic in terms of a partial or complete cure of a disease. For example, a reference to “treating” diabetes therefore encompasses: (a) arresting the progress of the disease, e.g., preventing worsening of a symptom (e.g., hyperglycemia) or complication over time; (b) relieving or ameliorating the effects of diabetes, i.e., causing an improvement of at least one symptom or complication of diabetes; (c) preventing or delaying additional symptoms or complications of diabetes from developing; (d) preventing or delaying diabetes or a symptom or complication associated with diabetes from occurring in a Attorney Docket No.1512.7.WO subject with prediabetes or insulin resistance; and/or (e) preventing or delaying an increased risk of developing a disease, e.g., preventing the increase of a risk factor for diabetes, such as by reducing blood glucose levels following glucose administration. [0021] The term “administering” refers to providing a pharmaceutical composition to a subject suffering from or at risk of the disease(s) and/or condition(s) to be treated. [0022] By “effective amount” it is meant an amount sufficient that, when administered to the subject, an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of hyperglycemia, prediabetes, diabetes or an associated disease, condition and/or disorder. Therefore, the “effective amount” may be a “therapeutically effective amount”. By “therapeutically effective amount” it is meant an amount sufficient that when administered to the subject an amount of active ingredient is provided to treat the disease or a symptom of the disease. [0023] The term “pharmaceutical composition” relates to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form. By “pharmaceutically acceptable” it is meant that the material is compatible with other ingredients included in the pharmaceutical composition and is suitable for administration to a subject based on avoidance of deleterious effects upon or following administration and any regulatory considerations. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 21^st ed. 2005). Exemplary pharmaceutically acceptable carriers for compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution. Attorney Docket No.1512.7.WO [0024] Mammalian Sirtuin 6 (SIRT6) is an NAD⁺-dependent protein deacylase. SIRT6 efficiently deacetylates nucleosomal histones in vitro and nucleosomes as well as proteins involved in DNA repair in cells. In some aspects, SIRT6-activating compounds or “SIRT6 activators” increase the cellular function of SIRT6. SIRT6 activators may bind in the acyl binding channel, stimulate SIRT6 deacetylation activity, and/or increase SIRT6 expression. [0025] One aspect of the invention relates to a method of improving glucose homeostasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby improving glucose homeostasis. The term "glucose homeostasis" refers to the balance of insulin and glucagon to maintain blood glucose levels within normal levels (i.e., about 70 mg/dL (3.9 mmol/L) to about 100 mg/dL (5.6 mm/L)). In some aspects, the subject being treated has elevated glucose levels, e.g., plasma glucose levels above about 100 mg/dL. In some aspects, a SIRT6 activator that "improves glucose homeostasis" preferably reduces blood glucose levels down to, but not below, normal levels. [0026] Another aspect of the invention relates to a method of lowering plasma glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby lowering plasma glucose levels. In some aspects, the subject being treated has a plasma glucose level above the normal level (e.g., above about 100 mg/dL). In some aspects, the SIRT6 activator reduces the subject’s

glucose level by at least about 1% or more (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or more) relative to a baseline plasma glucose level determined by, e.g., a standard fasting glucose test, prior to treatment with the SIRT6 activator. In some aspects, the SIRT6 activator reduces the subject’s plasma glucose level by at least about 5%, preferably by at least about 10%, or more preferably by at least about 15% relative to a baseline plasma glucose level. In some Attorney Docket No.1512.7.WO aspects, the SIRT6 activator does not reduce the plasma glucose level to a level substantially below normal levels, e.g., below about 70 mg/dL. [0027] A further aspect of the invention relates to methods of treating hyperglycemia, prediabetes, or diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the hyperglycemia, prediabetes, or diabetes. [0028] As used herein, “hyperglycemia” refers to a higher than normal blood glucose concentration, usually 125 mg/dL or greater while fasting and greater than 180 mg/dL two hours postprandial. [0029] As used herein, the term “diabetes” relates to a disease characterized by insulin resistance and disordered glucose metabolism, and is often accompanied by complications including dyslipidemia, inflammation, retinopathy, neuropathy, nephropathy, macrovascular disease and cognitive impairment. Diabetes includes Type I, Type II and gestational diabetes and symptoms and/or complications thereof. Type I diabetes is characterized by a lack of insulin production and Type II diabetes is characterized by insulin resistance. Gestational diabetes is a type of diabetes that can develop during pregnancy in women who do not already have diabetes. In some aspects, the diabetes being treated in accordance with the methods herein is Type I diabetes, Type II diabetes or gestational diabetes. [0030] “Prediabetes” refers to the condition where blood sugar levels are higher than normal, but not high enough yet to be diagnosed as Type II diabetes. There are different blood tests that can diagnose prediabetes. The most common ones are the fasting plasma glucose (FPG) test, which measures blood sugar at a single point in time and the A1C test, which measures average blood sugar over the past 3 months. A result of 100 to 125 mg/dL glucose in the FPG test is indicative Attorney Docket No.1512.7.WO of prediabetes, whereas 126 and above is indicative of diabetes. In the A1C test, a percentage of between 5.7% to 6.4% is indicative of prediabetes, whereas above 6.5% is indicative of diabetes. [0031] The methods of the invention may be carried out with any SIRT6 activator known in the art or later developed. Examples of SIRT6 activators include, without limitation, quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7; You et al. (2017) Angew. Chem. Int. Ed. 56:1007), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-Dihydropyrrolo[1,2- a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3- (Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide (OEA), CL5D (CAS No.2488745-53-3), 10b (2-(1-benzofuran- 2-yl)-N-(diphenylmethyl) quinoline-4-carboxamide), 5-Cl-PZA (5-chloro-pyrazinamide), BHJH- TM3 (N2-L-leucyl-L-prolyl-L-lysyl-N6-tetradecanethioyl-L-lysyl-L-threonine), 15f, 17a (catechin gallate), 19b (OSS_128167; CAS No.887686-02-4), 20b, 21b, 22a (A127-(CONHPr)- B178), and 23. The compounds are described in more detail in Fiorentino et al. (2021) J. Med. Chem. 64:9732 and Akter et al. (2021) Int. J. Mol. Sci. 22:4180, each incorporated by reference herein in its entirety. [0032] A further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: Attorney Docket No.1512.7.WO wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, Attorney Docket No.1512.7.WO a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R³ and R^3’ do not exist; R³ and R^3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or R³ and R^3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. [0033] In some embodiments, the compound of Formula 1 is any compound selected from the following group: (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2- yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol- 2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; or (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’-cyclohex-2- ene]-1’,3-dione. [0034] In some embodiments, the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: Attorney Docket No.1512.7.WO wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, Attorney Docket No.1512.7.WO a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R³ and R^3’ is not present; R³ and R^3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or R³ and R^3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1- C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. [0035] In some embodiments of the compound of Formula 1 or Formula 1′, R¹ is a C1-C6 alkyl group; R² is a C1-C6 alkyl group; A is a 5-membered aromatic heterocyclic ring; and R³ and R^3’ are each independently a hydrogen or a C1-C6 alkyl group. [0036] In some embodiments of the compound of Formula 1 or Formula 1′, R¹ is a methyl group, an ethyl group, or a hydroxyethyl group. [0037] In some embodiments of the compound of Formula 1 or Formula 1′, R² is a methyl group. [0038] In some embodiments of the compound of Formula 1 or Formula 1′, A is a 5-membered aromatic heterocyclic ring; R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R^3’ is a hydrogen atom. [0039] In some embodiments, the compound of Formula 1 is a compound of a Formula 1′′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: wherein

Attorney Docket No.1512.7.WO R¹ is a methyl group or an ethyl group; R² is a methyl group; A is any ring selected from the following group:

R³ is a methyl group or an ethyl group. [0040] In some embodiments, the compound of Formula 1′ is any compound selected from the following group: (2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.7.WO (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; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2- yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol- 2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’-methyl- spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (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; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’-cyclohex-2- ene]-1’,3-dione; or (2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3- dione. [0041] 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 pharmacologically acceptable salt thereof. [0042] 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 pharmacologically acceptable salt thereof. [0043] 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 pharmacologically acceptable salt thereof. [0044] 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 pharmacologically acceptable salt thereof. [0045] 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 pharmacologically acceptable salt thereof. Attorney Docket No.1512.7.WO [0046] In certain embodiments, the 5-membered aromatic heterocyclic ring for A is the same as described above, but more preferably, it represents the following 5-membered ring. (It should be noted that in this case, R^3’ is not present.)

[0047] In the present specification, the “5-membered aromatic heterocyclic ring” is a monocyclic 5-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included. N N N N N N

6-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included. N N N N N N N N N N N Attorney Docket No.1512.7.WO [0049] In the present specification, the “8-10 membered condensed aromatic heterocyclic ring” is an 8-10 membered condensed aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included. N _N ^N N N N N _N N

is a ring in which a monocyclic 5-7 membered saturated heterocyclic ring is partially oxidized or a ring in which an aromatic heterocyclic ring is partially reduced containing one to four atoms selected from Attorney Docket No.1512.7.WO the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included. O S NH N O HN S N N .

is a monocyclic 4-7 membered saturated heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included. H N O S NH O ^S

a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom. [0053] “Cyano” refers to the group -CN. Attorney Docket No.1512.7.WO [0054] “Hydroxy” or “hydroxyl” refers to the group -OH. [0055] “Carboxyl” or “carboxy” refers to -COOH or salts thereof. [0056] “Oxo” refers to the atom (=O). [0057] The term “phenoxy” refers to a group of the formula -O-R, where R is phenyl. [0058] As used herein, the prefix “Cx-Cy” indicates that the following group has from x to y carbon atoms. For example, “C1-C6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0059] The “C1-C6 alkyl group” in the present specification is a linear or branched alkyl group having one to six carbon atoms. Examples thereof include a methyl group, an ethyl group, a 1- propyl group, an isopropyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl- 1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, and a 2,3-dimethyl-1-butyl group, and it is preferably a methyl group or an ethyl group. In some aspects, an alkyl group comprises from 1 to 2 carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms. [0060] The “C2-C6 alkenyl group” in the present specification is a linear or branched alkenyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon double bonds. For example, it is a vinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenyl group, a 3-methyl-2-butenyl group, a 2-hexenyl group, or a 3-methyl-2-pentenyl group, and preferably, it is a vinyl group or an allyl group. In some aspects, an alkenyl group comprises from Attorney Docket No.1512.7.WO 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. [0061] The “C2-C6 alkynyl group” in the present specification is a linear or branched alkynyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon triple bonds. For example, it is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, or 1-hexynyl group, and it is preferably an ethynyl group or a 1-propynyl group. In some aspects, an alkynyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms. [0062] The “C1-C6 alkoxy group” in the present specification is a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-butoxy group, a 2-methyl-1- propoxy group, a 2-methyl-2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3- pentyloxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, and a 3-methyl-1- pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1-propoxy group, or a 2- propoxy group. [0063] The “C3-C6 cycloalkyl group” in the present specification is a cyclic alkyl group having three to six carbon atoms, and it is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. [0064] The “hydroxy C1-C6 alkyl group” in the present specification is a group in which a hydroxyl group is bonded to a C1-C6 alkyl group. For example, it is a hydroxymethyl group or a hydroxyethyl group. Attorney Docket No.1512.7.WO [0065] The “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group. [0066] The “C1-C6 haloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2- iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3-fluoropropyl group, a 3-chloropropyl group, and a 4-fluorobutyl group. It is preferably a trifluoromethyl group. [0067] The “C3-C6 halocycloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group. [0068] The “C1-C6 haloalkoxy group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxy group, a 2-bromoethoxy group, a 2- chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a trichloroethoxy group, a pentafluoroethoxy group, a 3-fluoropropoxy group, a 3- chloropropoxy group, and a 4-fluorobutoxy group. It is preferably a trifluoromethoxy group. Attorney Docket No.1512.7.WO [0069] The “C3-C6 cycloalkoxy group” in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and it is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group. [0070] The “C3-C6 halocycloalkoxy group” in the present specification is a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group. [0071] The “5-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom. [0072] The “6-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom. [0073] The “4-7 membered saturated heterocyclic oxy group” in the present specification is a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom. [0074] The "phenylcarbonyl group" refers to a phenyl ring attached to the remainder of the molecule by a C(=O) radical. [0075] The "C1-C6 alkylcarbonyl group” refers to the group -C(=O)R, where R is a C1-C6 alkyl group. [0076] The “C1-C6 alkylcarbonylamino group” refers to the group -NHC(=O)R, where R is a C1-C6 alkyl group. [0077] The “phenylcarbonylamino group” refers to the group -NHC(=O)-phenyl. [0078] The “C3-C6 cycloalkylcarbonyl group” refers to a cycloalkyl group having 3 to 6 carbon atoms in which one hydrogen atom is replaced by a carbonyl group. [0079] The "carbamoyl group" refers to the group -C (=O)NH₂. Attorney Docket No.1512.7.WO [0080] The “C1-C6 alkoxycarbonyl group” in the present specification is a group in which a C1- C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. [0081] The “C3-C6 cycloalkoxycarbonyl group” in the present specification is a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and it is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group. [0082] The “C1-C6 alkyl carbonyl group” in the present specification is a group in which a C1- C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methyl carbonyl group, an ethyl carbonyl group, or a propyl carbonyl group. [0083] An “amino group” refers to the group -NH₂ or -NH-R, where each R is independently alkyl, aryl, or cycloalkyl. [0084] The “mono (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and it is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group. [0085] The “di (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminocarbonyl group, and it is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group. [0086] The “mono (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminosulfonyl group, and it is Attorney Docket No.1512.7.WO preferably a methylaminosulfonyl group, an ethylaminosulfonyl group, or a propylaminosulfonyl group [0087] The “di (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group. [0088] The “mono (C1-C6 alkyl) amino group” in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, and it is preferably a methylamino group, an ethylamino group, or a propylamino group. [0089] The “di (C1-C6 alkyl) amino group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to an amino group, and it is preferably a dimethylamino group, a diethylamino group, or a dipropyl amino group. [0090] The “C1-C6 alkoxycarbonylamino group” in the present specification is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, and for example, it is a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group. [0091] The “mono (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a mono (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group. [0092] The “di (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably Attorney Docket No.1512.7.WO a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group. [0093] The “5-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group. [0094] The “6-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group. [0095] The “C1-C6 alkylsulfonylamino group” in the present specification is a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and it is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group. [0096] “Substituted” (as in, e.g., “substituted alkyl”) refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, guanidino, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfonamide, sulfonic acid, thiocyanate, thiol, thione, or a combination thereof. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. [0097] The “pharmaceutically acceptable salt” indicates a salt that can be used as a pharmaceutical. When the compound has an acidic group or a basic group it can be converted to a basic salt or an acidic salt by reacting with a base or an acid to form a salt thereof. Attorney Docket No.1512.7.WO [0098] The pharmaceutically acceptable “basic salt” of the compound preferably includes an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; organic base salts such as an N-methyl morpholine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, and a picoline salt; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is preferably an alkali metal salt. [0099] The pharmaceutically acceptable “acidic salt” of the compound preferably includes an inorganic acid salt such as a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide, and a hydroiodide, a nitrate, a perchlorate, a sulfate, and a phosphate; an organic salt such as a lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, an aryl sulfonate such as a benzenesulfonates, and a p-toluene sulfonate, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, a tartrate, an oxalate, a maleate, and the like; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is most preferably a hydrohalide (in particular, a hydrochloride). [0100] Pharmaceutically acceptable salts also include ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Sci.66(1):1-19, and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p.732, Table 38-5, each of which are hereby incorporated by reference herein. [0101] The compound of the present invention or the pharmaceutically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate by leaving in the air or Attorney Docket No.1512.7.WO recrystallization. The present invention also encompasses compounds of such various hydrates, solvates, and crystalline polymorphs. [0102] The compounds of the present invention, their pharmaceutically acceptable salts or solvates thereof, depending on the type and combination of substituents, may have various isomers such as geometric isomers including a cis isomer and a trans isomer, tautomers, or optical isomers such as a D isomer and an L isomer. The invention includes such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Mixtures of these isomers may be resolved by known resolution means. [0103] The compounds of the present invention also include labels, that is, a compound in which one or more atoms of the compounds are substituted with an isotope (for example, ²H, ³H, ¹³C, ¹⁴C, ³⁵S, and the like). [0104] In addition, the present invention also encompasses a prodrug. The prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, it is a group described in Rautio et al. (2018) Nature Rev. Drug Discov.17(8):559– 587; Markovic et al. (2020) Pharmaceutics 12(11):1031 or the like. As the prodrug, more specifically, when an amino group is present in the compound, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, it is a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butylated, or the like) and the like are included, and when a hydroxyl group is present in the compound, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, it is a compound in which the hydroxyl group Attorney Docket No.1512.7.WO is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethyl carbonylated, or the like) and the like are included. In addition, when a carboxy group is present in the compound, a compound in which the carboxy group is esterified or amidated (for example, it is a compound in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, or the like), and the like are included. Particularly favored prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment relative to the parent species. [0105] The compounds of the present invention may be produced by synthetic methods known in the art and as described in WO 2017/170623 and WO 2019/065928, incorporated by reference herein in their entirety. [0106] Administration of the compounds of the present invention may be carried out by any form of oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, or the like, or by any form of parenteral administration by an injection for intra-articular, intravenous, intramuscular, or the like, a suppository, an eye drop, an eye ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant, or the like. [0107] As a solid composition for oral administration, a tablet, a powder, a granule, and the like are used. Such a solid composition is composed of one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline Attorney Docket No.1512.7.WO cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate, and/or the like. The solid composition may contain, according to a conventional method, one or more of an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizer. The tablet or pill may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary. [0108] As a liquid composition for oral administration, a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like is used. To such a liquid composition, it is possible to add a generally used inert diluent such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, one or more of a solubilizer, an adjuvant such as a wetting agent, a sweetening agent, a flavoring agent, a fragrance, and a preservative. [0109] As an injection for parenteral administration, a sterile aqueous or non-aqueous solution, a suspension or an emulsion, and the like are used. The aqueous solvent includes, for example, distilled water for injection, physiological saline, and the like. The non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, and vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80, and the like. Such an injection composition may further contain a one or more of a tonicity agent, a preservative, a wetting agent, an emulsion, a dispersing agent, a stabilizer, or a solubilizer. These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, application of a bactericide, or irradiation. In addition, these injection compositions may be used by producing a sterile solid composition and dissolved or suspended in sterile water or a sterile solvent for injection prior to use. [0110] As an external preparation, an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, an eye drop, an eye ointment, and the like are used. These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, Attorney Docket No.1512.7.WO emulsions, and the like. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like are used. [0111] A transmucosal agent such as an inhalant and a transnasal agent are used in solid, liquid, or semisolid form, and it may be produced according to a conventionally known method. For example, a known excipient, and furthermore, one or more of a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be added as appropriate. With these transmucosal agents, devices appropriate for inhalation or insufflation may be used as the method of administration. For example, the compound may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. A dry powder inhaler or the like may be for single or multiple administration, and a dry powder or powder containing capsule may be also used. Alternatively, an appropriate ejector may be used. For example, it may be in the form of a pressurized aerosol spray or the like using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide. [0112] In the case of normal oral administration, the appropriate daily dose of a SIRT6 activator is about 0.001 mg/kg to 100 mg/kg, preferably 0.1 mg/kg to 30 mg/kg, and more preferably 0.1 mg/kg to 10 mg/kg of body weight. In some aspects, the daily dose of a SIRT6 activator is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg/kg to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, Attorney Docket No.1512.7.WO 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg/kg, or any range or value therein. This is administered in one dose or separated into two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more doses). When administered intravenously, the appropriate daily dose of a SIRT6 activator 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 therein) of body weight, which is administered once or separated into several times a day. In addition, as a transmucosal agent, about 0.001 mg/kg to 100 mg/kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg/kg or any range or value therein) of body weight is administered once or separated into several times a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like. The SIRT6 activator may be administered daily, e.g., in the morning and/or evening, and/or before, during or after one or more daily meals, e.g., breakfast, lunch, and/or dinner. [0113] Improvements in glucose homeostasis, reduction in plasma glucose levels, and/or treatment of hyperglycemia, prediabetes, and/or diabetes may be assessed by one or more conventional tests (e.g., a glycated hemoglobin (A1C) test, a fasting plasma glucose test, an oral glucose tolerance test) and/or a decrease in one or more symptoms associated with therewith (e.g., thirst, appetite, fatigue, weight loss, and/or blurred vision). The period of time following treatment may be at least about 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes or longer. In some aspects, treatment with the SIRT6 activator reduces plasma glucose levels for an extended period of time, e.g., at least 2 weeks, at least 4 weeks, or more. In some embodiments, the plasma glucose levels are reduced without significantly affecting the insulin and/or C-peptide concentration(s). Attorney Docket No.1512.7.WO [0114] In the methods of the present invention, the SIRT6 activator may be administered in combination with various therapeutic agents or preventive agents of use in subjects with elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes. The therapeutic agent may be, for example, one that treats elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes or one that treats a disease, condition and/or disorder associated with elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes. These diseases, conditions and/or disorders include prediabetes, glycosuria, hyperglycemia, hyperinsulinemia, insulin resistance, and combinations thereof. For example, a SIRT6 activator may be used in combination with insulin (e.g., a short-acting insulin that reaches the bloodstream 30 minutes after injection and peaks 2-3 hours afterward, a rapid acting insulin that works within 15 minutes and peaks 1 to 2 hours after use, an intermediate-acting insulin that works about 2-4 hours after use with an average peak time of 12 hours, a long-acting insulin that lower your blood glucose levels for up to 24 hours or longer, or combinations thereof), an amylinomimetic (e.g., pramlintide), an alpha-glucosidase inhibitor (e.g., acarbose or miglitol), a biguanide (e.g., metformin), a dopamine-2 agonist, a dipeptidyl peptidase-4 inhibitor (e.g., alogliptin, linagliptin, saxagliptin or sitagliptin),a glucagon-like peptide-1 receptor agonist (e.g., dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, or tirzepatide), a meglitinide (e.g, nateglinide or repaglinide), a sodium-glucose transporter inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin), a sulfonylurea (e.g., glimepiride, gliclazide, glipizide or glyburide), a thiazolidinedione (e.g., rosiglitazone or pioglitazone). The combination may be administered simultaneously, separately, concurrently, and continuously or at desired time intervals. The co-administered agents may be blended or formulated separately. Attorney Docket No.1512.7.WO [0115] The methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals. The term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. Optionally, the subject is “in need of” the methods of the present invention, e.g., because the subject has or is believed to be at risk for aberrant glucose homeostasis, elevated plasma glucose levels, hyperglycemia, prediabetes, and/or diabetes or that would benefit from treatment with a compound as described herein. As a further option, the subject can be a laboratory animal and/or an animal model of disease. Preferably, the subject is a human. [0116] Having described the present invention, the same will be explained in greater detail in the following examples, which are included herein for illustration purposes only, and which are not intended to be limiting to the invention. EXAMPLES EXAMPLE 1: SIRT6 Activators Normalize Elevated Glucose Levels [0117] SIRT6 is principal regulator of glucose homeostasis (Zhong et al. (2010) Cell 140(2):280- 93). Thus, it was determined whether the SIRT6 activators disclosed herein could reduce fasting glucose levels in subjects with baseline elevated fasting glucose. [0118] Following the successful completion of a Screening Phase, subjects were randomized to one of two treatment groups in an approximately 1:1 ratio and received Compound 1 (SP-624) or placebo over a treatment period of four weeks (Treatment Group #1: SP-62420 mg/day; Treatment Group #2: Placebo). Attorney Docket No.1512.7.WO [0119] 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 [0120] Prior to initiating a Screening/Baseline

period of up to 28 days, during which time all screening assessments were performed. Subjects returned for a Baseline Visit to complete efficacy and safety assessments. During the treatment period, subjects returned to the investigative site to complete efficacy and safety assessments at the end of Weeks 1, 2, 3, and 4. After the final dose of study drug, subjects completed a follow-up period of two weeks and returned at the end of Weeks 5 and 6. [0121] Each dose of Compound 1 was supplied as two capsules, each containing 10 mg of active pharmaceutical ingredient (API). Matching placebo capsules identical in shape and color to the active capsules were used. [0122] In patients with baseline elevated fasting glucose (pre‐diabetes levels), both male and female subjects treated with a SIRT6 activator showed, on average, a substantial reduction in fasting glucose by week 4 (FIG.1, Table 1).

Attorney Docket No.1512.7.WO Table 1 Baseline Week 4 # of Patients with # of Patients with Treatment Glucose Glucose fasting glucose ≥ 100 fasting glucose ≥ 100 Mean (SD) Mean (SD) mg/dL mg/dL Compound 1 20 (14 F, 6 M) 111.7 (12.8) 12 (8 F, 4 M) 96.8 (10.5) Placebo 19 (11 F, 8 M) 105.4 (5.3) 14 (7 F, 7 M) 106.9 (22.2) [0123] The foregoing examples are illustrative of the present invention and are not to be construed as limiting thereof. Although the invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.

Claims

Attorney Docket No.1512.7.WO We Claim: 1. A method of improving glucose homeostasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sirtuin 6 (SIRT6) activator, thereby improving glucose homeostasis. 2. A method of lowering plasma glucose concentration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby lowering plasma glucose concentration. 3. A method of treating hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the hyperglycemia. 4. A method of treating prediabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the prediabetes. 5. A method of treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the diabetes. 6. The method of claim 5, wherein the diabetes is Type I diabetes, Type II diabetes or gestational diabetes. Attorney Docket No.1512.7.WO 7. The method of any one of claims 1-6, wherein the SIRT6 activator is quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-Dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4- (Pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[1,2- a]quinoxaline), UBCS068 (1-(5-((3-(Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2- 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). 8. The method of any one of claims 1-6, wherein the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof: wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or Attorney Docket No.1512.7.WO a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R³ and R^3’ do not exist; R³ and R^3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, Attorney Docket No.1512.7.WO a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or Attorney Docket No.1512.7.WO R³ and R^3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. 9. The method of claim 8, wherein the 5-membered aromatic heterocyclic ring or the 5- membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: Attorney Docket No.1512.7.WO N N N N N N N N N .

10. The method of claim 8 or 9, wherein the 6-membered aromatic heterocyclic ring or the 6- membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N N N N N N N .

11. The method of any one of claims 8-10, wherein the 8-10 membered condensed aromatic heterocyclic ring or the 8-10 membered condensed aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N _N ^N N N N N N

Attorney Docket No.1512.7.WO N N N N N ^N

12. The method of any one of claims 8-11, wherein the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N . Attorney Docket No.1512.7.WO 13. The method of any one of claims 8-12, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group: H N O S NH O ^S .

14. The method any one of claims 8-13, wherein the compound of Formula 1 is any compound selected from the following group: (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (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; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; or (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione. 15. The method of any one of claims 8-14, wherein the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt thereof: Attorney Docket No.1512.7.WO wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, Attorney Docket No.1512.7.WO a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R³ and R^3’ is not present; R³ and R^3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or R³ and R^3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, Attorney Docket No.1512.7.WO a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. 16. The method of claim 15, wherein R¹ is a methyl group, an ethyl group, or a hydroxyethyl group. 17. The method of claim 15 or 16, wherein R² is a methyl group. 18. The method of any one of claims 15-17, wherein the 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N . Attorney Docket No.1512.7.WO 19. The method of any one of claims 15-18, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N N N N N N N N N N .

20. The method of any one of claims 15-19, wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7 membered unsaturated heterocyclic group in A, R³, or R^3’ is any one selected from the group: N N .

21. The method of any one of claims 15-20, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group: Attorney Docket No.1512.7.WO H N O S NH O ^S .

22. The method of any one of claims 15-21, wherein A is a 5-membered aromatic heterocyclic ring; R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R^3’ is a hydrogen atom. 23. The method of any one of claims 15-22, wherein A is any ring selected from the following group, and in the case of two binding groups, R^3’ is not present:

wherein * indicates a binding group. 24. The method of any one of claims 15-17, wherein the compound of Formula 1 is a compound of a Formula 1′′ or a pharmaceutically acceptable salt thereof: Attorney Docket No.1512.7.WO wherein

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

R³ is a methyl group or an ethyl group. 25. The method of any one of claims 15-23, wherein the compound of Formula 1′ is any compound selected from the following group: (2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (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; Attorney Docket No.1512.7.WO (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’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; Attorney Docket No.1512.7.WO (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; or (2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]- 1’,3-dione. 26. The method of claim 25, 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 pharmacologically acceptable salt thereof. 27. The method of claim 25, 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 pharmacologically acceptable salt thereof. Attorney Docket No.1512.7.WO 28. The method of claim 25, 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 pharmacologically acceptable salt thereof. 29. The method of claim 25, 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 pharmacologically acceptable salt thereof. 30. The method of claim 25, 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 pharmacologically acceptable salt thereof.