Compositions and methods for controlling glucose levels

Abstract

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

Description

Priority claim

[0001] This application claims 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 are incorporated herein by reference. [Technical Field]

[0002] The present invention relates to a method for controlling plasma glucose levels and treating hyperglycemia, prediabetes, and diabetes by administering a SIRT6 activator. [Background technology]

[0003] Diabetes has become a major public health challenge, with at least 180 million people reported to have the disease worldwide, a number that is expected to more than double by 2030 according to the World Health Organization (WHO), accounting for 10% of healthcare costs in Western countries and resulting in approximately 3.2 million deaths per year from related complications. This alarming increase in incidence and the current inability of existing diabetes medications to tightly control and contain the disease highlights the market demand for new innovations.

[0004] There is a need in the art for effective therapies for maintaining glucose homeostasis and treating pre-diabetes and diabetes. Summary of the Invention

[0005] The present invention is based on the conclusion that activators of sirtuin 6 (SIRT6) significantly reduce blood glucose levels.

[0006] Accordingly, one aspect of the present invention relates to a method of improving glucose homeostasis in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby improving glucose homeostasis.

[0007] Another aspect of the present invention relates to a method of lowering plasma glucose levels in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby lowering the plasma glucose level.

[0008] A further aspect of the present invention relates to a method of treating hyperglycemia, pre-diabetes, or diabetes (e.g., type I, type II, or gestational) in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating the hyperglycemia, pre-diabetes, or diabetes.

[0009] These and other aspects of the invention are explained in more detail below in the description of the invention. [Brief explanation of the drawings]

[0010] [Figure 1] Mean fasting glucose levels at each visit. Subjects received either placebo or a SIRT6 activator (Compound 1). DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention is described in more detail below. This description is not intended to provide a detailed listing of all the various ways in which the invention may be implemented or all the features that may be added to the invention. For example, features shown with respect to one embodiment may be incorporated into other embodiments, and features shown with respect to a particular embodiment may be omitted from that embodiment. Moreover, numerous modifications and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of this disclosure without departing from the invention. Thus, the following specification is intended to illustrate some specific embodiments of the invention, but is not intended to exhaustively identify all permutations, combinations, and variations thereof.

[0012] Unless the context requires otherwise, it is specifically contemplated that the various features of the invention described herein can be used in any combination. Furthermore, the present invention also contemplates that, in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted. For example, if a composite is described herein as comprising components A, B, and C, it is specifically contemplated that any or any combination of A, B, or C, singly or in any combination, can be omitted and discarded.

[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 this invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0016] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, but also includes the absence of a combination when interpreted in the alternative ("or").

[0017] Furthermore, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0018] Additionally, as used herein, the term "about," when referring to a measurable value such as an amount, dosage, time, temperature, etc. of a compound or agent of the invention, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the specified amount.

[0019] As used herein, the transitional phrase "consisting essentially of" is to be construed as inclusive of the described materials or steps, as well as those that do not materially affect the basic and novel characteristics of the claimed invention. Accordingly, as used herein, the term "consisting essentially of" should not be construed as synonymous with "comprising."

[0020] As used herein, the terms "treating," "treatment," "treating," and the like refer to acting on a subject (e.g., a patient), tissue, or cell to achieve a desired pharmacological and / or physiological effect. This effect can be preventative, in that it completely or partially prevents or reduces the severity of a disease or associated symptoms, and / or therapeutic, in that it partially or completely cures a disease. Thus, for example, reference to "treating" diabetes encompasses: (a) arresting the progression of the disease, e.g., preventing the worsening of symptoms (e.g., hyperglycemia) or complications over time; (b) alleviating or ameliorating the effects of diabetes, i.e., causing an improvement in at least one symptom or complication of diabetes; (c) preventing or delaying the onset of further symptoms or complications of diabetes; (d) preventing or delaying the onset of diabetes or symptoms or complications associated with diabetes in a prediabetic or insulin-resistant subject; and / or (e) preventing or delaying an increased risk of developing the disease, e.g., preventing an increase in risk factors for diabetes by lowering blood glucose levels after glucose administration.

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

[0022] An "effective amount" means that, when administered to a subject, a sufficient amount of agent is provided to achieve an effect. In the case of a treatment, this effect may refer to treatment of hyperglycemia, prediabetes, diabetes, or related diseases, conditions, and / or disorders. Thus, an "effective amount" may be a "therapeutically effective amount." A "therapeutically effective amount" means that, when administered to a subject, a sufficient amount of active ingredient is provided to treat a disease or a symptom of a disease.

[0023] The term "pharmaceutical composition" refers to a composition containing at least one active ingredient in a pharmaceutically acceptable form. "Pharmaceutically acceptable" means that the material is compatible with other ingredients contained in the pharmaceutical composition, suitable for administration to a subject based on avoidance of adverse effects during or after administration, and any regulatory considerations. The material will, of course, be selected to minimize degradation of any active ingredient and minimize any adverse side effects in the subject, as is well known to those skilled in the art (see, e.g., Remington's Pharmaceutical Science; 21st ed. 2005). Examples of pharmaceutically acceptable carriers for use in the compositions of the present invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free saline.

[0024] Mammalian sirtuin 6 (SIRT6) inhibits NAD + SIRT6 is a dependent protein deacetylase.SIRT6 efficiently deacetylates nucleosomal histones in vitro, and in cells, nucleosomes and proteins involved in DNA repair.In some embodiments, SIRT6 activating compound or "SIRT6 activator" enhances the cellular function of SIRT6.SIRT6 activator can bind to acyl-binding channel, stimulate the deacetylation activity of SIRT6, and / or enhance the expression of SIRT6.

[0025] One aspect of the invention relates to a method for 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., between about 70 mg / dL (3.9 mmol / L) and about 100 mg / dL (5.6 mmol / L)). In some embodiments, the subject being treated has elevated glucose levels, e.g., plasma glucose levels above about 100 mg / dL. In some embodiments, a SIRT6 activator that "improves glucose homeostasis" preferably reduces blood glucose levels to normal levels, but not below normal levels.

[0026] Another aspect of the present invention relates to a method for lowering plasma glucose levels in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby lowering the plasma glucose level. In some embodiments, the treated subject has a plasma glucose level above normal (e.g., above about 100 mg / dL). In some embodiments, the SIRT6 activator reduces the subject's plasma 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) compared to the baseline plasma glucose level measured, for example, by a standard fasting glucose test, before treatment with the SIRT6 activator. In some embodiments, the SIRT6 activator reduces the subject's plasma glucose level by at least about 5%, preferably at least about 10%, more preferably at least about 15% compared to the baseline plasma glucose level. In some embodiments, the SIRT6 activator does not reduce the plasma glucose level to a level substantially below normal, for example, below about 70 mg / dL.

[0027] A further aspect of the present invention relates to a method of treating hyperglycemia, prediabetes, or diabetes in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating the hyperglycemia, prediabetes, or diabetes.

[0028] As used herein, "hyperglycemia" refers to a higher than normal blood glucose concentration, typically greater than 125 mg / dL in a fasting state and greater than 180 mg / dL two hours after a meal.

[0029] As used herein, the term "diabetes" refers to a disease characterized by insulin resistance and abnormal glucose metabolism, and is often accompanied by complications such as dyslipidemia, inflammation, retinopathy, neuropathy, nephropathy, macrovascular disease, and cognitive impairment. Diabetes includes type I diabetes, type II diabetes, and gestational diabetes, as well as their symptoms and / or complications. Type I diabetes is characterized by insufficient insulin production, and type II diabetes is characterized by insulin resistance. Gestational diabetes is a type of diabetes that may develop during pregnancy in women who do not have diabetes. In some embodiments, the diabetes treated according to the methods herein is type I diabetes, type II diabetes, or gestational diabetes.

[0030] "Prediabetes" refers to blood glucose levels higher than the normal range but not high enough to be diagnosed as type 2 diabetes. There are different blood tests that can diagnose prediabetes. The most common are the fasting plasma glucose (FPG) test, which measures blood glucose levels at a single point in time, and the A1C test, which measures average blood glucose over the past three months. An FPG test result of 100 to 125 mg / dL glucose suggests prediabetes, while a result of 126 or higher suggests diabetes. An A1C test percentage of 5.7% to 6.4% suggests prediabetes, while a result above 6.5% suggests diabetes.

[0031] The methods of the present invention can be carried out using any SIRT6 activator known in the art or developed in the future. Examples of SIRT6 activators include quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamine, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7; You et al. (2017) Angew. Chem. Int. Ed. 56:1007), UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide (OEA), CL5D (CAS No. 2488745-53-3), 10b (2-(1-benzofuran-2-yl)-N-(diphenylmethyl)quinoline-4-carboxamide), 5-Cl-PZA (5-chloropyrazinamide), BHJH-TM3 (N2-L-leucyl-L-prolyl-L-lysyl-N6-tetradecanethiol-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 of which is incorporated herein by reference in its entirety.

[0032] Further examples of SIRT6 activators are compounds of Formula 1 or pharmaceutically acceptable salts, racemates, stereoisomers, or prodrugs thereof:

[0033] [ka]

[0034] where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; 6-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, A is a benzene ring, -CH=, or a cyano group, and when A is a cyano group, R 3 and R 3’ does not exist; R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring fused with A, and the ring may be optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0035] In some embodiments, the compound of Formula 1 is any compound selected from the group consisting of: (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

[0036] In some embodiments, the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

[0037] [ka]

[0038] where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; 6-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, Benzene ring or single bond, in the case of a single bond, R 3 and R 3’ neither of the two is present; R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring fused with A, and the ring may be substituted with 1 to 2 identical or different substituents selected from substituent group X; Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0039] In some embodiments of the compound of Formula 1 or Formula 1′, R1 is a C1-C6 alkyl group; R 2 is a C1-C6 alkyl group; A is a 5-membered aromatic heterocycle; and R 3 and R 3’ are each independently hydrogen or a C1-C6 alkyl group.

[0040] In some embodiments of the compound of Formula 1 or Formula 1′, R 1 is a methyl group, an ethyl group, or a hydroxyethyl group.

[0041] In some embodiments of the compound of Formula 1 or Formula 1′, R 2 is a methyl group.

[0042] In some embodiments of the compound of Formula 1 or Formula 1′, A is a 5-membered aromatic heterocycle; R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R 3’ is a hydrogen atom.

[0043] In some embodiments, the compound of Formula 1 is a compound of Formula 1″, or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:

[0044] [ka]

[0045] where: R 1 is a methyl or ethyl group; R 2 is a methyl group; A is any ring selected from the group consisting of:

[0046] [ka]

[0047] where * indicates a linking group; and R 3 is a methyl group or an ethyl group.

[0048] In some embodiments, the compound of Formula 1′ is any compound selected from the group consisting of: (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-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-methylethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or (2S,5'R)-7-Chloro-3',4,6-trimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

[0049] In one embodiment, the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the compound is (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the compound is (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the compound is (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

[0054] In certain embodiments, the 5-membered aromatic heterocycle of A is the same as above, but more preferably represents the following 5-membered ring: 3’ Note that does not exist.)

[0055] [ka]

[0056] Here, * indicates a bonding group.

[0057] As used herein, the term "five-membered aromatic heterocycle" refers to a monocyclic five-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0058] [ka]

[0059] As used herein, the term "six-membered aromatic heterocycle" refers to a monocyclic six-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0060] [ka]

[0061] As used herein, the term "8- to 10-membered fused aromatic heterocycle" refers to an 8- to 10-membered fused aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Examples of such rings include those shown below.

[0062] [ka]

[0063] As used herein, the term "5- to 7-membered unsaturated heterocycle" refers to a partially oxidized monocyclic 5- to 7-membered saturated heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, or a partially reduced aromatic heterocycle. Examples of such rings include those shown below.

[0064] [ka]

[0065] As used herein, the term "4- to 7-membered saturated heterocycle" refers to a monocyclic 4- to 7-membered saturated heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of such rings include those shown below.

[0066] [ka]

[0067] As used herein, a "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

[0068] "Cyano" refers to the group --CN.

[0069] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0070] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.

[0071] "Oxo" refers to the atom (=O).

[0072] "Phenoxy" refers to a group of the formula --OR where R is phenyl.

[0073] As used herein, the prefix "Cx-Cy" indicates that the following group has x to y carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0074] In this specification, the term "C1-C6 alkyl group" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, and 2,3-dimethyl-1-butyl groups, and preferably methyl or ethyl. In some embodiments, the alkyl group contains 1 to 2 carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0075] As used herein, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, optionally containing one or more carbon-carbon double bonds. For example, it may be a vinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenyl group, a 3-methyl-2-butenyl group, a 2-hexenyl group, or a 3-methyl-2-pentenyl group, preferably a vinyl group or an allyl group. In some embodiments, the alkenyl group contains 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0076] As used herein, the term "C2-C6 alkynyl group" refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, optionally containing one or more carbon-carbon triple bonds. For example, it may be an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, or a 1-hexynyl group, preferably an ethynyl group or a 1-propynyl group. In some embodiments, the alkynyl group contains 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0077] As used herein, a "C1-C6 alkoxy group" refers to a C1-C6 alkyl group to which an oxygen atom is bonded. Examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentyloxy, and 3-methyl-1-pentyloxy. Preferred are methoxy, ethoxy, 1-propoxy, and 2-propoxy groups.

[0078] In this specification, the term "C3-C6 cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0079] As used herein, a "hydroxy C1-C6 alkyl group" refers to a C1-C6 alkyl group to which a hydroxyl group is bonded, such as a hydroxymethyl group or a hydroxyethyl group.

[0080] As used herein, the term "C1-C6 alkoxy C1-C6 alkyl group" refers to a C1-C6 alkyl group to which a C1-C6 alkoxy is bonded. Examples include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl groups.

[0081] In this specification, the "C1-C6 haloalkyl group" refers to a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2-iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3-fluoropropyl group, a 3-chloropropyl group, and a 4-fluorobutyl group. A trifluoromethyl group is preferred.

[0082] As used herein, the term "C3-C6 halocycloalkyl group" refers to a C3-C6 cycloalkyl group having a halogen atom bonded thereto, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.

[0083] As used herein, the term "C1-C6 haloalkoxy group" refers to a C1-C6 alkoxy group to which a halogen atom is bonded, and examples thereof include fluoromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trichloroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, and 4-fluorobutoxy groups. Trifluoromethoxy is preferred.

[0084] As used herein, the term "C3-C6 cycloalkoxy group" refers to a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

[0085] As used herein, a "C3-C6 halocycloalkoxy group" refers to a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.

[0086] The term "five-membered aromatic heterocyclic oxy group" as used herein refers to a group in which a five-membered aromatic heterocycle is bonded to an oxygen atom.

[0087] As used herein, the term "six-membered aromatic heterocyclic oxy group" refers to a group in which a six-membered aromatic heterocycle is bonded to an oxygen atom.

[0088] As used herein, the term "4- to 7-membered saturated heterocyclic oxy group" refers to a group in which a 4- to 7-membered saturated heterocyclic ring is bonded to an oxygen atom.

[0089] A "phenylcarbonyl group" refers to a phenyl ring attached to the rest of the molecule by a C(=O) radical.

[0090] A "C1-C6 alkylcarbonyl group" refers to a -C(=O)R group, where R is a C1-C6 alkyl group.

[0091] A "C1-C6 alkylcarbonylamino group" refers to a -NHC(=O)R group, where R is a C1-C6 alkyl group.

[0092] "Phenylcarbonylamino" refers to the group -NHC(=O)-phenyl.

[0093] A "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.

[0094] A "carbamoyl group" refers to a -C(=O)NH2 group.

[0095] As used herein, the term "C1-C6 alkoxycarbonyl group" refers to a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

[0096] As used herein, the term "C3-C6 cycloalkoxycarbonyl group" refers to a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.

[0097] As used herein, the term "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, and a propylcarbonyl group.

[0098] An "amino group" refers to an -NH2 or -NH-R group, where each R is independently alkyl, aryl, or cycloalkyl.

[0099] As used herein, the term "mono(C1-C6 alkyl)aminocarbonyl group" refers to an aminocarbonyl group having one C1-C6 alkyl group bound to the amino group, and is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.

[0100] As used herein, the term "di(C1-C6 alkyl)aminocarbonyl group" refers to an aminocarbonyl group having two C1-C6 alkyl groups bonded to the amino group, and is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.

[0101] As used herein, the term "mono(C1-C6 alkyl)aminosulfonyl group" refers to a group in which one C1-C6 alkyl group is bound to the amino group of an aminosulfonyl group, and is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group, or a propylaminosulfonyl group.

[0102] As used herein, the term "di(C1-C6 alkyl)aminosulfonyl group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminosulfonyl group, and is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

[0103] As used herein, the term "mono(C1-C6 alkyl)amino group" refers to an amino group to which one C1-C6 alkyl group is bound, and is preferably a methylamino group, an ethylamino group, or a propylamino group.

[0104] As used herein, the term "mono(C1-C6 alkyl)amino group" refers to an amino group to which one C1-C6 alkyl group is bound, and is preferably a methylamino group, an ethylamino group, or a propylamino group.

[0105] As used herein, the term "di(C1-C6 alkyl)amino group" refers to an amino group to which two C1-C6 alkyl groups are bound, and is preferably a dimethylamino group, a diethylamino group, or a dipropylamino group.

[0106] As used herein, the term "C1-C6 alkoxycarbonylamino group" refers to a group in which a C1-C6 alkoxycarbonyl group is bound to an amino group, and examples include a methoxycarbonylamino group, an ethoxycarbonylamino group, and a propoxycarbonylamino group.

[0107] As used herein, the term "mono(C1-C6 alkyl)aminocarbonylamino group" refers to a group in which a mono(C1-C6 alkyl)aminocarbonyl group is bound to an amino group, and is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.

[0108] As used herein, the term "di(C1-C6 alkyl)aminocarbonylamino group" refers to a group in which a di(C1-C6 alkyl)aminocarbonyl group is bound to an amino group, and is preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0109] As used herein, the term "5-membered aromatic heterocyclic carbonylamino group" refers to a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0110] As used herein, the term "six-membered aromatic heterocyclic carbonylamino group" refers to a group in which a six-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0111] As used herein, the term "C1-C6 alkylsulfonylamino group" refers to a sulfonylamino group in which a C1-C6 alkyl group is bonded to the sulfonyl group, and is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.

[0112] "Substituted" (e.g., "substituted alkyl") refers to a group in which one or more hydrogens are independently replaced with one or more substituents, including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, guanidino, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfonamide, sulfonic acid, thiocyanate, thiol, thione, or combinations thereof. It is understood that the above definition is not intended to include impermissible substitution patterns (e.g., a methyl group substituted with five fluoro groups or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art.

[0113] "Pharmaceutically acceptable salt" refers to a salt that can be used as a medicine. If a compound has an acidic or basic group, it can be converted into a basic salt or acid salt by reacting with a base or acid to form the salt.

[0114] Pharmaceutically acceptable "basic salts" of compounds preferably include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts, with alkali metal salts being preferred.

[0115] Pharmaceutically acceptable "acid salts" of compounds preferably include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, and the like; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate, with hydrohalides (particularly hydrochloride) being the most preferred.

[0116] Pharmaceutically acceptable salts also include ammonium salts and substituted ammonium salts, or quaternized ammonium salts.A representative non-limiting list of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Sci. 66(1):1-19 and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p. 732, Table 38-5, each of which is incorporated herein by reference.

[0117] The compound of the present invention or a pharmaceutically acceptable salt thereof may absorb moisture, may adhere to adsorbed water, or may become a hydrate upon exposure to air or recrystallization. The present invention also encompasses such various hydrates, solvates, and crystalline polymorphs of the compound.

[0118] The compounds of the present invention, their pharmaceutically acceptable salts, or solvates thereof may have various isomers, such as geometric isomers including cis and trans isomers, tautomers, or optical isomers such as D and L isomers, depending on the types and combinations of substituents. Unless otherwise specified, the present invention encompasses these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known separation means.

[0119] The compounds of the invention may be labeled, i.e., one or more atoms of the compound may be isotoped (e.g., 2 H, 3 H, 13 C. 14 C. 35 S, etc.) are also included.

[0120] The present invention also encompasses prodrugs. A prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of a compound by hydrolysis or under physiological conditions. Examples of groups that constitute such prodrugs include those described in Rautio et al. (2018) Nature Rev. Drug Discov. 17(8):559-587; Markovic et al. (2020) Pharmaceutics 12(11):1031, etc. More specifically, prodrugs include, when an amino group is present in the compound, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated, or tert-butylated), and, when a hydroxyl group is present in the compound, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or boronated (e.g., compounds in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarated, alanylated, or dimethylaminomethylcarbonylated). Also included are compounds in which the carboxy group, when present in the compound, is esterified or amidated (e.g., compounds in which the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, amidated, or methylamidated). Particularly preferred prodrugs are those that increase the bioavailability of the compound of the embodiments when administered to a subject (e.g., by making the orally administered compound more easily absorbed into the blood) or that enhance delivery of the parent compound to a biological compartment compared to the parent species.

[0121] The compounds of the present invention can be prepared by synthetic methods known in the art and such as those described in WO2017 / 170623 and WO2019 / 065928, the entire contents of which are incorporated herein by reference.

[0122] The compounds of the present invention can be administered orally in the form of tablets, pills, capsules, granules, powders, solutions, etc., or parenterally in the form of intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0123] Solid compositions for oral administration include tablets, powders, granules, etc. Such solid compositions consist of one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminum metasilicate, and / or the like. The solid compositions may also contain one or more inert additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a film of a gastrointestinal-soluble substance, if necessary.

[0124] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. A commonly used inert diluent such as purified water or ethanol can be added to such liquid compositions. In addition to the inert diluent, the liquid composition may contain one or more of the following: a solubilizing agent, a wetting agent, or other adjuvant, a sweetener, a flavoring agent, a fragrance, and a preservative.

[0125] Injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such injectable compositions may further contain one or more of an isotonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, application of a disinfectant, or irradiation. Alternatively, these injectable compositions may be prepared as sterile solid compositions, which can be dissolved or suspended in sterile water or a sterile injectable solvent immediately before use.

[0126] Examples of topical preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, and eye ointments. These topical preparations include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, and emulsions. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

[0127] Transmucosal preparations, such as inhalants and nasal preparations, can be used in solid, liquid, or semisolid form and can be prepared according to conventional methods. For example, known excipients, and one or more pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., can be added as appropriate. These transmucosal preparations can be administered using devices suitable for inhalation or insufflation. For example, the compounds can be administered as powders, either alone or in a blended mixture, or as solutions or suspensions in combination with pharmaceutically acceptable carriers using known devices such as metered-dose inhalers and nebulizers. Dry powder inhalers and the like can be used for single or multiple doses, and dry powders or capsules containing powders can also be used. Alternatively, a suitable ejector can be used. For example, the preparations can be in the form of a pressurized aerosol spray using a suitable gas, such as a chlorofluoroalkane, a hydrofluoroalkane, or carbon dioxide.

[0128] In the case of normal oral administration, the appropriate daily dose of the SIRT6 activator is about 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.1 mg / kg to 30 mg / kg, and more preferably 0.1 mg / kg to 10 mg / kg. In some embodiments, the daily dosage of the SIRT6 activator is from about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, The SIRT6 activator may be administered at a dose of 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / kg, or any range or value therein, in a single dose or in two or more divided doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more divided doses). For intravenous administration, a suitable daily dose of the SIRT6 activator is about 0.0001 to 10 mg per body weight (e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 mg / kg, or any range or value therein), administered once or in divided doses per day. Furthermore, as a transmucosal agent, approximately 0.001 mg / kg to 100 mg / kg of body weight (e.g., approximately 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg / kg, or any range or value therein) is administered once or several times a day. The dosage is determined appropriately for each individual case, taking into consideration symptoms, age, sex, etc.The SIRT6 activator can be administered daily, for example, in the morning and / or evening, and / or before, during, or after one or more meals daily, for example, breakfast, lunch, and / or dinner.

[0129] Improvement in glucose homeostasis, reduction in plasma glucose concentrations, and / or treatment of hyperglycemia, prediabetes, and / or diabetes can be assessed by one or more conventional tests (e.g., glycosylated hemoglobin (A1C) test, fasting plasma glucose test, oral glucose tolerance test) and / or reduction in one or more associated symptoms (e.g., thirst, appetite, fatigue, weight loss, and / or decreased vision). The post-treatment period may be at least about 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, or more. In some embodiments, treatment with a SIRT6 activator reduces plasma glucose concentrations for an extended period of time, e.g., at least 2 weeks, at least 4 weeks, or longer. In some embodiments, plasma glucose concentrations are reduced without significantly affecting insulin and / or C-peptide concentrations.

[0130] In the method of the present invention, the SIRT6 activator can be administered in combination with various therapeutic or preventive agents useful in subjects with elevated plasma glucose levels, hyperglycemia, prediabetes, and / or diabetes. The therapeutic agent may, for example, treat elevated plasma glucose levels, hyperglycemia, prediabetes, and / or diabetes, or treat diseases, conditions, and / or disorders related to elevated plasma glucose levels, hyperglycemia, prediabetes, and / or diabetes. These diseases, conditions, and / or disorders include prediabetes, diabetes, hyperglycemia, hyperinsulinemia, insulin resistance, and combinations thereof. For example, SIRT6 activating drugs include insulin (e.g., a rapid-acting insulin that reaches the bloodstream 30 minutes after injection and peaks after 2-3 hours, a rapid-acting insulin that acts within 15 minutes and peaks after 1-2 hours, an intermediate-acting insulin that acts about 2-4 hours after administration and has an average peak time of 12 hours, a long-acting insulin that lowers blood glucose levels for up to 24 hours or more, or a combination thereof), an amylinomimetic drug (e.g., pramlintide), an α-glucosidase inhibitor (e.g., acarbose or miglitol), a biguanide drug (e.g., metformin), a dopamine-2 agonist, a dipeptidyl peptidase-4 inhibitor (e.g., aloglytol), a steroid drug (e.g., steroid agonist), a steroid agonist ... It may also be used in combination with other drugs, such as thiazolidinedione (e.g., thiazolidinedione ...

[0131] The method of the present invention can be used in both veterinary and medical applications. Suitable subjects include birds, reptiles, amphibians, fish, and mammals. As used herein, the term "mammal" includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), and the like. Human subjects include newborns, infants, juveniles, and adults. Optionally, the subject is "in need" of the method of the present invention because, for example, they have or are at risk for abnormal glucose homeostasis, elevated plasma glucose levels, hyperglycemia, prediabetes, and / or diabetes, or because they may benefit from treatment with the compounds described herein. As a further option, the subject may be an experimental animal and / or an animal model of disease. Preferably, the subject is human.

[0132] The present invention has been described above and is further illustrated in the following examples, which are provided for illustrative purposes only and are not intended to limit the invention. [Example]

[0133] Example 1: SIRT6 activators normalize high glucose levels SIRT6 is a key regulator of glucose homeostasis (Zhong et al. (2010) Cell 140(2):280-93). Therefore, we determined whether the SIRT6 activators disclosed herein can reduce fasting glucose levels in subjects with elevated baseline fasting glucose.

[0134] After successful completion of the screening phase, subjects were randomized in an approximately 1:1 ratio to one of two treatment groups and administered Compound 1 (SP-624) or placebo for a 4-week treatment period (treatment group 1: SP-624 20 mg / day; treatment group 2: placebo).

[0135] 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)

[0136] [ka]

[0137] Prior to the start of the 4-week treatment period, subjects completed a screening / baseline period of up to 28 days, during which 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 study site at the end of weeks 1, 2, 3, and 4 to complete efficacy and safety assessments. After the final dose of study drug, subjects completed a 2-week follow-up period and returned at the end of weeks 5 and 6.

[0138] Each dose of Compound 1 was provided as two capsules, each containing 10 mg of the active pharmaceutical ingredient (API). Matching placebo capsules identical in shape and color to the active capsules were used.

[0139] In patients with high baseline fasting glucose (prediabetic levels), both male and female subjects treated with SIRT6 activators showed significant reductions in fasting glucose by week 4, on average ( Figure 1 , Table 1 ).

[0140] [Table 1]

[0141] The above examples are illustrative of the invention and should not 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

1. A method for improving glucose homeostasis in a subject in need thereof, comprising administering a therapeutically effective amount of a sirtuin 6 (SIRT6) activator to the subject, thereby improving glucose homeostasis.

2. A method for lowering plasma glucose levels in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby lowering the plasma glucose level.

3. A method for treating hyperglycemia in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating the hyperglycemia.

4. A method for treating prediabetes in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating the prediabetes.

5. A method for treating diabetes in a subject in need thereof, comprising administering a therapeutically effective amount of a SIRT6 activator to the subject, thereby treating the diabetes.

6. 6. The method of claim 5, wherein the diabetes is type I, type II, or gestational diabetes.

7. SIRT6 activators were found to be quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamine, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), and UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide, CL5D (CAS No. 2488745-53-3), or 10b (2-(1-benzofuran-2-yl)-N-(diphenylmethyl)quinoline-4-carboxamide).

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

9. A, R 3 , or R 3’ The method according to claim 8, wherein the 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group is any one selected from the following group: 【Chemistry 2】

10. A, R 3 , or R 3’ The method according to claim 8 or 9, wherein the 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group is any one selected from the following group: 【Transformation 3】

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

12. A, R 3 , or R 3’ The method according to any one of claims 8 to 11, wherein the 5-7 membered unsaturated heterocycle or 5-7 membered unsaturated heterocyclic group is any one selected from the following group: 【Transformation 5】

13. A, R 1 , R 2 , or R 3 The method according to any one of claims 8 to 12, wherein the 4- to 7-membered saturated heterocyclic ring or 4- to 7-membered saturated heterocyclic group is any one selected from the following group: 【Transformation 6】

14. The method of any one of claims 8 to 13, wherein the compound of formula 1 is any compound selected from the group consisting of: (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione

15. The method of any one of claims 8 to 14, wherein the compound of formula 1 is a compound of formula 1' or a pharmaceutically acceptable salt thereof. 【Transformation 7】 Where: R 1 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; R 2 represents a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; A is a 5-membered aromatic heterocycle; 6-membered aromatic heterocycles, 8-10 membered fused aromatic heterocycles, 5-7 membered unsaturated heterocycle, 4-7 membered saturated heterocycle, Benzene ring or single bond, in the case of a single bond, R 3 and R 3’ is not present; R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C2-C6 alkynyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C3-C6 cycloalkyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an amino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a carbamoyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 5- to 7-membered unsaturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X; an 8- to 10-membered fused aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group X, or R 3 and R 3’ may be bonded to each other to form a 5- to 7-membered unsaturated heterocycle, a 4- to 7-membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring fused with A, and the ring may be substituted with 1 to 2 identical or different substituents selected from substituent group X; Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic group optionally substituted with 1 to 2 identical or different substituents selected from the substituent group Y; a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 5-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 6-membered aromatic heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; a 4- to 7-membered saturated heterocyclic oxy group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; C1-C6 alkoxycarbonyl group, C3-C6 cycloalkoxycarbonyl group, carboxy group, C1-C6 alkylcarbonyl group, C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y; Carbamoyl group, mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino group, mono(C1-C6 alkyl)aminocarbonylamino group, di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with 1 to 2 identical or different substituents selected from substituent group Y, or a C1-C6 alkylsulfonylamino group; and The substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

16. R 1 16. The method of claim 15, wherein is a methyl group, an ethyl group, or a hydroxyethyl group.

17. R 2 The method of claim 15 or 16, wherein is a methyl group.

18. A, R 3 , or R 3’ The method according to any one of claims 15 to 17, wherein the 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group is any one selected from the following group: 【Transformation 8】

19. A, R 3 , or R 3’ The method according to any one of claims 15 to 18, wherein the 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group is any one selected from the following group: 【Chemistry 9】

20. A, R 3 , or R 3’ The method according to any one of claims 15 to 19, wherein the 5-7 membered unsaturated heterocycle or 5-7 membered unsaturated heterocyclic group is any one selected from the following group: 【Chemistry 10】

21. A, R 1 , R 2 , or R 3 The method according to any one of claims 15 to 20, wherein the 4- to 7-membered saturated heterocyclic ring or 4- to 7-membered saturated heterocyclic group is any one selected from the following group: 【Chemistry 11】

22. A is a 5-membered aromatic heterocycle; R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R 3’ The method of any one of claims 15 to 21, wherein is a hydrogen atom.

23. When A is any ring selected from the group consisting of the following and has two bonding groups, R 3’ The method of any of claims 15 to 22, wherein is not present. 【Chemistry 12】 Here, * indicates a bonding group.

24. The method of any of claims 15 to 17, wherein the compound of formula 1 is a compound of formula 1" or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 where: R 1 is a methyl group or an ethyl group; R 2 is a methyl group; A is any ring selected from the group consisting of: 【Chemistry 14】 where * indicates a linking group; and R 3 is a methyl group or an ethyl group.

25. The method of any one of claims 15 to 23, wherein the compound of formula 1' is any compound selected from the group consisting of: (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-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-methylethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-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'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or (2S,5'R)-7-chloro-3',4,6-trimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione

26. 26. The method of claim 25, wherein the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

27. 26. 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 pharmaceutically acceptable salt thereof.

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

29. 26. The method of claim 25, wherein the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methylethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methylspiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

30. 26. 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 pharmaceutically acceptable salt thereof.

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