Compositions and methods for treating joint and bone diseases

Abstract

This invention relates to a method of treating a joint and / or bone disease, slowing progression of a reduction in bone mass, increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death, slowing progression of a reduction in joint mobility and / or function, slowing progression of a reduction in cartilage, and / or reducing chondrocyte senescence and / or death by administering a therapeutically effective amount of a SIRT6 activator, optionally with nicotinamide adenine dinucleotide (NAD+) and / or an NAD+ precursor.

Description

COMPOSITIONS AND METHODS FOR TREATING JOINT AND BONE DISEASESSTATEMENT OF PRIORITY

[0001] This application claims the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No. 63 / 635,838, filed April 18, 2024, the entire contents of which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to methods of treating a joint and / or bone disease by administering a sirtuin 6 (SIRT6) activator.BACKGROUND OF THE INVENTION

[0003] Joint and bone diseases are a group of debilitating conditions that affect millions of people worldwide. Aging and inflammation (e.g., chronic inflammation) are primary risk factors in many of these diseases. Specifically, aging leads to the failure or dysregulation of maintenance mechanisms. On a cellular level, aging can cause genomic instability, decreased DNA repair efficiency, telomere shortening, reduced protein homeostasis (proteostasis), chronic inflammation and mitochondrial dysfunction. Inflammation causes macrophages and lymphocytes to invade the tissue and produce inflammatory cytokines, growth factors, and enzymes. Chronic inflammation in particular is the predominant immunological factor in aging and bone-related diseases. For bones, inflammation (e.g., chronic inflammation) can increase osteoclast function leading to bone resorption; and for joints, the macrophages and lymphocytes attracted by inflammation (e.g., chronic inflammation) result in thickening of the joint lining as well as damage and destruction of the joint cartilage. Thus, both aging and inflammation (e.g., chronic inflammation) contribute to cellular senescence, apoptosis, and dysfunction, which in turn contributes to tissue dysfunction and subsequent failure in the bones and / or joints.

[0004] Griseofulvin derivatives have been developed that have anti-inflammatory activity and have been disclosed for use in treating inflammatory diseases, including central inflammatory disease such as neurodegenerative diseases. See WO 2017 / 170623 and WO 2019 / 065928.

[0005] There is a need in the art for effective treatments for joint and bone diseases.SUMMARY OF THE INVENTION

[0006] The present invention is based on the relationship between the SIRT6 factors associated with age- and / or inflammation-related disease, and the discovery that the compounds disclosed in WO 2017 / 170623 and WO 2019 / 065928 are potent activators of SIRT6.

[0007] SIRT6 is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme that is NAD+ dependent and functions in multiple molecular pathways related to both aging and inflammation (e.g., chronic inflammation), including DNA repair, telomere maintenance, and glycolysis. SIRT6 activation facilitates chromatin localization of SIRT6 upon DNA damage.

[0008] Thus, one aspect of the invention relates to a method of treating a joint and / or bone disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby treating the joint and / or bone disease.

[0009] Another aspect of the invention relates to a method of slowing progression of a reduction in bone mass in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in bone mass. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may increase bone mass in a subject.

[0010] Another aspect of the invention relates to a method of increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death.

[0011] Another aspect of the invention relates to a method of slowing progression of a reduction in joint mobility and / or function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in joint mobility and / or function. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may improve joint mobility and / or function.

[0012] Another aspect of the invention relates to a method of slowing progression of a reduction in cartilage (e.g., reducing cartilage degradation) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in cartilage (e.g., reducing cartilage degradation).

[0013] Another aspect of the invention relates to a method of reducing chondrocyte senescence and / or death in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby reducing chondrocyte senescence and / or death.

[0014] In some embodiments, the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof:wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring,an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R3and R3do not exist;R3and R3are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy carbonyl group, a C3-C6 cycloalkoxy carbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group,a phenyl carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C 1 -C6 alkyl group, a C 1 -C6 alkoxy group, a halogen atom, or a hydroxy group.

[0015] These and other aspects of the invention are set forth in more detail in the description of the invention below.DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.

[0017] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0018] 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. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.

[0019] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety.

[0020] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0021] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or ”).

[0022] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0023] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount.

[0024] As used herein, the transitional phrase “consisting essentially of’ is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel character! stic(s) of the claimed invention. Thus, the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”

[0025] The term “enhance” or “increase” refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold.

[0026] The term “inhibit” or “reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity of at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).

[0027] A “therapeutically effective” or “treatment effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a “therapeutically effective” or “treatment effective” amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e g., in the case of joint and / or bone disease, reduced loss of bone density and / or mass, increased bone density and / or mass, increased joint mobility and / or function, reduced joint pain, reduced swelling, increased osteoblast formation, decreased osteoclast formation, reduced osteocyte death, reduced cartilage loss, reduced chondrocyte senescence, or any combination thereof). Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0028] By the term “treat,” “treating,” or “treatment of’ (or grammatically equivalent terms) is meant to reduce or to at least partially improve or ameliorate the severity of the subj ect’ s condition and / or to alleviate, mitigate or decrease in at least one clinical symptom and / or to delay the progression of the condition.

[0029] As used herein, the term “prevent,” “prevents,” or “prevention” (and grammatical equivalents thereof) means to delay or inhibit the onset of a disease, and / or reduce the progression of a disease. The terms are not meant to require complete abolition of disease, and encompass any type of prophylactic treatment to reduce the incidence of the condition, reduce the progression of the condition, or delay the onset of the condition.

[0030] A “prevention effective” amount as used herein is an amount that is sufficient to prevent and / or delay the onset of a disease, disorder and / or clinical symptoms in a subject and / or to reduce and / or delay the severity of the onset of a disease, disorder and / or clinical symptoms in a subject relative to what would occur in the absence of the methods of the invention. Those skilled in theart will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0031] As used herein, the terms “protein” and “polypeptide” are used interchangeably and encompass both peptides and proteins, unless indicated otherwise.

[0032] “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science,' 21sted. 2005). Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, phosphate buffered saline (PBS), sterile pyrogen-free water, and other sterile pyrogen- free physiological saline solutions.

[0033] The term “administering” or “administration” of a composition of the present invention to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function (e.g., for treating a joint and / or bone disease).

[0034] A “subject” of the invention may include any animal in need thereof. In some embodiments, a subject may be, for example, a mammal, a reptile, a bird, an amphibian, or a fish. A mammalian subject may include, but is not limited to, a laboratory animal (e.g., a rat, mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., cattle, pig, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, gerbil, hamster, etc.). In some embodiments, a mammalian subject may be a primate, or a non-human primate (e.g., a chimpanzee, baboon, macaque (e.g., rhesus macaque, crab-eating macaque, stump-tailed macaque, pig-tailed macaque), monkey (e.g., squirrel monkey, owl monkey, etc.), marmoset, gorilla, etc.). In some embodiments, a mammalian subject may be a human.

[0035] A “subject in need” of the methods of the invention can be any subject known or suspected of having increased risk of developing joint and / or bone disease, reduced bone mass, reduced osteoblast formation, increased osteoclast formation, increased osteocyte death, poor joint mobility and / or function, reduced cartilage and / or cartilage thickness, and / or increasedchondrocyte senescence and / or death herein to which administering a compound as described herein may provide beneficial health effects.

[0036] A “sample”, “biological sample”, and / or “ex vivo sample” of this invention can be any biological material, such as a biological fluid, an extract from a cell, an extracellular matrix isolated from a tissue, a cell (in solution or bound to a solid support), a tissue, a tissue homogenate, and the like as are well known in the art.

[0037] By “effective amount” it is meant an amount sufficient that, when administered to the subject, an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of a joint and / or bone disease. Therefore, the “effective amount” may be a “therapeutically effective amount”. By “therapeutically effective amount” it is meant an amount sufficient that when administered to the subject an amount of active ingredient is provided to treat the disease or a symptom of the disease.

[0038] The term “pharmaceutical composition” relates to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form. By “pharmaceutically acceptable” it is meant that the material is compatible with other ingredients included in the pharmaceutical composition and is suitable for administration to a subject based on avoidance of deleterious effects upon or following administration and any regulatory considerations. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science,' 21sted. 2005). Exemplary pharmaceutically acceptable carriers for compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution.

[0039] Mammalian Sirtuin 6 (SIRT6) is an NAD+-dependent protein that primarily acts as a deacetylase and mono-ADP -ribosyltransferase. SIRT6 efficiently deacetylates nucleosomal histones in vitro and nucleosomes as well as proteins involved in DNA repair in cells. In some aspects, SIRT6-activating compounds or “SIRT6 activators” increase the cellular function of SIRT6. SIRT6 activators may bind in the acyl binding channel, stimulate SIRT6 deacetylation activity, and / or increase SIRT6 expression.Compounds

[0040] The methods of the invention may be carried out with any SIRT6 activator known in the art or later developed. Examples of SIRT6 activators include, without limitation, quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7; You et al. (2017) Angew. Chem. Int. Ed. 56: 1007), UBCS039 (CAS No. 358721-70-7), UBCS040 (l-(4,5-Dihydropyrrolo[l,2- tz]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[l,2-rz]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[l,2-a]quinoxaline), UBCS068 (l-(5-((3- (Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[l,2-cz]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoyl ethanol ami de (OEA), CL5D (CAS No. 2488745-53-3), 10b (2-(l-benzofuran- 2-yl)-A-(diphenylmethyl) quinoline-4-carboxamide), 5-C1-PZA (5-chloro-pyrazinamide), BHJH- TM3 (N2-L-leucyl-L-prolyl-L-lysyl-N6-tetradecanethioyl-L-lysyl-L-threonine), 15f„ 17a(catechin gallate), 19b (OSS_128167; CAS No. 887686-02-4), 20b, 21b, 22a (A127-(CONHPr)- B178), 23, SP-624 (Forvisirvat), or any combination thereof. Exemplary compounds are described in more detail in Fiorentino et al. (2021) J. Med. Chem. 64:9732 and Akter et al. (2021) Int. J. Mol. Sci. 22:4180, each incorporated by reference herein in its entirety.

[0041] The term “SIRT6 activator” also includes SIRT6 itself, either in the form of the protein or a functional fragment or variant thereof, or in the form of a nucleic acid encoding SIRT6 or a functional fragment or variant thereof. The nucleic acid may be in a vector, e.g., a viral vector such as an adeno-associated virus vector (e.g., as disclosed in WO 2025 / 032584 or US 2023 / 0018934, incorporated herein by reference). SIRT6 variants may include those disclosed in US 2024 / 0277868, incorporate herein by reference).

[0042] In some embodiments, the methods of the invention may comprise administering more than one SIRT6 activator, e.g., 2, 3, 4, or more SIRT6 activators.

[0043] A further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R3and R3do not exist;R3and R3are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X,a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y,a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; andsubstituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0044] In some embodiments, the compound of Formula 1 is any compound selected from the following group:(2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-l,3,4-oxadiazol-2-yl) spiro [benzofuran -2, 4 ’ -cy clohex-2-ene] - 1 ’ , 3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(l-methyl-4-piperidyl)-l,3,4-oxadiazol-2- yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-T, 3-dione;(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-3’, 4-dimethoxy-6-[5-[(lS)-l -methoxy ethyl]- 1,3, 4-oxadi azol -2 -yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4 ’ -cy cl ohex -2-ene] - 1’ , 3 -di one;(2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol- 2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-T, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-[3-(l -methoxy ethyl)-l, 2, 4-oxadiazol-5-yl]-5 ’-methylspiro [benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2 S, ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl -6-( 1 H-pyrazol -5 -yl) spiro [benzofuran-2,4 ’ - cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[l-(2-methoxyethyl) pyrazol -3 -yl]-5 ’-methyl-spiro [benzofuran-2,4 ’ -cyclohex -2-ene] - 1’ , 3 -di one;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’ -methyl- spiro [benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1 ’ ,3 -dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’ -methyl -spiro [benzofuran- 2,4’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’ -cyclohex-2-ene] - 1 ’ ,3 -di one; or(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2, 4’ -cyclohex - 2-ene]-l’,3-dione.

[0045] In some embodiments, the compound of Formula 1 is a compound of Formula 1' or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring,a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R3and R3is not present;R3and R3are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkyl sulfonylamino group; and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0046] In some embodiments of the compound of Formula 1 or Formula 1', R1is a C1-C6 alkyl group; R2is a C1-C6 alkyl group; A is a 5-membered aromatic heterocyclic ring; and R3and R3are each independently a hydrogen or a C1-C6 alkyl group.

[0047] In some embodiments of the compound of Formula 1 or Formula 1', R1is a methyl group, an ethyl group, or a hydroxy ethyl group.

[0048] In some embodiments of the compound of Formula 1 or Formula 1', R2is a methyl group.

[0049] In some embodiments of the compound of Formula 1 or Formula 1', A is a 5-membered aromatic heterocyclic ring; R3is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R3is a hydrogen atom.

[0050] In some embodiments, the compound of Formula 1 is a compound of a Formula 1" or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof:whereinR1is a methyl group or an ethyl group;R2is a methyl group;A is any ring selected from the following group:wherein * indicates a binding group; andR3is a methyl group or an ethyl group.

[0051] In some embodiments, the compound of Formula 1' is any compound selected from the following group:(2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’ - cyclohex-2-ene]- 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]- 1 ’ ,3 -di one;(2S, 5 ’R)-7-chloro-3 ’ ,4-dimethoxy-5 ’ -methyl-6-( 1 -methylpyrazol-3 -yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-6-(l-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro[benzofuran-2,4 ’ -cyclohex -2-ene] - 1 ’ , 3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-methyl-l,2,4-oxadiazol-5-yl) spiro[benzofuran-2,4 ’-cyclohex -2-ene] -1’, 3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-l,2,4-oxadiazol-3-yl) spiro[benzofuran-2,4 ’-cyclohex -2-ene] -1’, 3 -di one;(2S,5’R)-7-chloro-6-[5-(l-hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-6-[5-[(lS)-l -hydroxy ethyl]- 1,3, 4-oxadiazol-2-yl]-3 ’,4-dimethoxy-5 ’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-6-[5-[(lR)-l -hydroxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-3 ’ , 4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-ethoxy-6-[5-(l -hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3’- methoxy-5’ -methyl -spiro [benzofuran-2,4’-cyclohex-2-ene]-r,3-dione;(2S, 5 ’R)-7-chloro-4-ethoxy-6-[5-[(lS)-l -hydroxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-3’-methoxy-5’ - methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxyethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl- spiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1’ , 3 -di one;(2S, 5 ’R)-7-chloro-4-(2 -hydroxy ethoxy)-3’-methoxy-5 ’-methyl -6-(5-methyl- 1,3, 4-oxadiazol -2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2 S, 5 ’R)-7-chloro-4-(2-hy droxy ethoxy)-3 ’ -methoxy-5 ’ -methyl -6-(3 -methyl - 1 ,2, 4-oxadiazol - 5-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-4-(2 -hydroxy ethoxy)-3’ -methoxy-5 ’-methyl -6-(5-methyl- 1,2, 4-oxadiazol -3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-6-(5-ethyl-l, 3, 4-oxadiazol -2 -yl)-3’,4-dimethoxy-5’ -methyl-spiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1’ , 3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-[5-(l-methyl-4-piperidyl)- 1,3, 4-oxadiazol -2- yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’, 4-dimethoxy-6-[5-[(lS)-l -methoxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-4-ethoxy-3 ’-methoxy-5 ’-methyl-6-(5-m ethyl- 1, 3, 4-oxadiazol-2-yl) spiro [benzofuran-2,4 ’-cyclohex -2-ene] -1’, 3 -di one;(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]-l’, 3-dione;(2S, 5 ’R)-7-chl oro-3 ’,4-dimethoxy-6-[3-(l -methoxy ethyl)-l, 2, 4-oxadiazol-5-yl]-5 ’-methyl- spiro [benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-(lH-pyrazol-5-yl) spiro [benzofuran-2,4’ - cyclohex-2-ene]- 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[l-(2-methoxyethyl) pyrazol-3-yl]-5’-methyl-spiro [benzofuran-2,4 ’ -cyclohex -2-ene] - 1’ , 3 -di one;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’ -methylspiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2- en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro [benzofuran- 2,4’ -cy cl ohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2,4’ -cy cl ohex-2-ene] - 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’ -cyclohex -2-ene]-l’, 3-dione; or(2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3- dione.

[0052] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(l-ethylpyrazol-3-yl)-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.

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

[0054] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)- 3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

[0055] In one embodiment, the compound is (2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)- l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’ -cyclohex -2-ene]- 1’, 3- dione or a pharmacologically acceptable salt thereof.

[0056] In one embodiment, the compound is (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl- 6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

[0057] In certain embodiments, the 5-membered aromatic heterocyclic ring for A is the same as described above, but more preferably, it represents the following 5-membered ring. (It should be noted that in this case, R3is not present.)wherein * indicates a binding group.

[0058] In the present specification, the “5-membered aromatic heterocyclic ring” is a monocyclic 5-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0059] In the present specification, the “6-membered aromatic heterocyclic ring” is a monocyclic 6-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0060] In the present specification, the “8-10 membered condensed aromatic heterocyclic ring” is an 8-10 membered condensed aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0061] In the present specification, the “5-7 membered unsaturated heterocyclic ring” is a ring in which a monocyclic 5-7 membered saturated heterocyclic ring is partially oxidized or a ring in which an aromatic heterocyclic ring is partially reduced containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0062] In the present specification, the “4-7 membered saturated heterocyclic ring” is a monocyclic 4-7 membered saturated heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. For example, rings such as those shown below are included.

[0063] The “halogen atom” in the present specification is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

[0064] “Cyano” refers to the group -CN.

[0065] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0066] “Carboxyl” or “carboxy” refers to -COOH or salts thereof.

[0067] “ Oxo” refers to the atom (=0).

[0068] The term “phenoxy” refers to a group of the formula -O-R, where R is phenyl.

[0069] As used herein, the prefix “Cx-Cy” indicates that the following group has from x to y carbon atoms. For example, “C1-C6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0070] The “C1-C6 alkyl group” in the present specification is a linear or branched alkyl group having one to six carbon atoms. Examples thereof include a methyl group, an ethyl group, a 1- propyl group, an isopropyl group, a 1 -butyl group, a 2-butyl group, a 2 -m ethyl- 1 -propyl group, a 2-methyl-2-propyl group, a 1 -pentyl group, a 2-pentyl group, a 3 -pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1 -pentyl group, a 3 -m ethyl -1 -pentyl group, a 2-ethyl-l -butyl group, a 2, 2-di methyl -1 -butyl group, and a 2, 3 -dimethyl -1 -butyl group, and it is preferably a methyl group or an ethyl group. In some aspects, an alkyl group comprises from 1 to 2 carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0071] The “C2-C6 alkenyl group” in the present specification is a linear or branched alkenyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon double bonds. For example, it is a vinyl group, a 2-propenyl (allyl) group, a 2-butenyl group, a 2-pentenyl group, a 3 -methyl -2-butenyl group, a 2-hexenyl group, or a 3-methyl-2-pentenyl group, and preferably, it is a vinyl group or an allyl group. In some aspects, an alkenyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0072] The “C2-C6 alkynyl group” in the present specification is a linear or branched alkynyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon triple bonds. For example, it is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1 -pentynyl group, a 2-pentynyl group, or 1 -hexynyl group, and it is preferably an ethynyl group or a 1-propynyl group. In some aspects, an alkynyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.

[0073] The “C1-C6 alkoxy group” in the present specification is a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include a methoxy group, an ethoxy group, a 1 -propoxy group, a 2-propoxy group, a 1 -butoxy group, a 2-butoxy group, a 2-methyl-l -propoxy group, a 2-methyl -2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-2-butoxy group, a 3 -methyl-2 -butoxy group, a 1 -hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl -I -pentyl oxy group, and a 3 -methyl- 1-pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1 -propoxy group, or a 2-propoxy group.

[0074] The “C3-C6 cycloalkyl group” in the present specification is a cyclic alkyl group having three to six carbon atoms, and it is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0075] The “hydroxy C1-C6 alkyl group” in the present specification is a group in which a hydroxyl group is bonded to a C1-C6 alkyl group. For example, it is a hydroxymethyl group or a hydroxy ethyl group.

[0076] The “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxy ethyl group, an ethoxymethyl group, and an ethoxy ethyl group.

[0077] The “C1-C6 haloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2- iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3 -fluoropropyl group, a 3 -chloropropyl group, and a 4-fluorobutyl group. It is preferably a trifluoromethyl group.

[0078] The “C3-C6 halocycloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.

[0079] The “C1-C6 haloalkoxy group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2 -fluoroethoxy group, a 2-bromoethoxy group, a 2- chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a tri chloroethoxy group, a pentafluoroethoxy group, a 3 -fluoropropoxy group, a 3- chloropropoxy group, and a 4-fluorobutoxy group. It is preferably a trifluoromethoxy group.

[0080] The “C3-C6 cycloalkoxy group” in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and it is preferably a cyclopropyl oxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

[0081] The “C3-C6 halocycloalkoxy group” in the present specification is a group in which a C3- C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.

[0082] The “5-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0083] The “6-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0084] The “4-7 membered saturated heterocyclic oxy group” in the present specification is a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom.

[0085] The "phenyl carbonyl group" refers to a phenyl ring attached to the remainder of the molecule by a C(=O) radical.

[0086] The " C1-C6 alkylcarbonyl group” refers to the group -C(=O)R, where R is a C1-C6 alkyl group.

[0087] The “C1-C6 alkylcarbonylamino group” refers to the group -NHC(=0)R, where R is a Cl- C6 alkyl group.

[0088] The “phenylcarbonylamino group” refers to the group -NHC(=O)-phenyl.

[0089] The “C3-C6 cycloalkylcarbonyl group” refers to a cycloalkyl group having 3 to 6 carbon atoms in which one hydrogen atom is replaced by a carbonyl group.

[0090] The "carbamoyl group" refers to the group -C (=0)NH2.

[0091] The “C1-C6 alkoxy carbonyl group” in the present specification is a group in which a Cl- C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxy carbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

[0092] The “C3-C6 cycloalkoxycarbonyl group” in the present specification is a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and it is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.

[0093] The “C1-C6 alkyl carbonyl group” in the present specification is a group in which a Cl- C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methyl carbonyl group, an ethyl carbonyl group, or a propyl carbonyl group.

[0094] An “amino group” refers to the group -NH2 or -NH-R, where each R is independently alkyl, aryl, or cycloalkyl.

[0095] The “mono (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and it ispreferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.

[0096] The “di (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminocarbonyl group, and it is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.

[0097] The “mono (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminosulfonyl group, and it is preferably a methylaminosulfonyl group, an ethyl aminosulfonyl group, or a propylaminosulfonyl group

[0098] The “di (C 1 -C6 alkyl) aminosulfonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

[0099] The “mono (C1-C6 alkyl) amino group” in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, and it is preferably a methylamino group, an ethylamino group, or a propylamino group.

[0100] The “di (C1-C6 alkyl) amino group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to an amino group, and it is preferably a dimethylamino group, a diethylamino group, or a dipropyl amino group.

[0101] The “C1-C6 alkoxy carbonylamino group” in the present specification is a group in which a C1-C6 alkoxy carbonyl group is bonded to an amino group, and for example, it is a methoxy carbonylamino group, an ethoxy carbonylamino group, or a propoxycarbonylamino group.

[0102] The “mono (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a mono (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.

[0103] The “di (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferablya dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0104] The “5-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0105] The “6-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0106] The “C1-C6 alkyl sulfonylamino group” in the present specification is a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and it is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.

[0107] “ Substituted” (as in, e.g., “substituted alkyl”) refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, guanidino, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfonamide, sulfonic acid, thiocyanate, thiol, thione, or a combination thereof. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.

[0108] The “pharmaceutically acceptable salt” indicates a salt that can be used as a pharmaceutical. When the compound has an acidic group or a basic group it can be converted to a basic salt or an acidic salt by reacting with a base or an acid to form a salt thereof.

[0109] The pharmaceutically acceptable “basic salt” of the compound preferably includes an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; organic base salts such as an N-methyl morpholine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, and a picoline salt; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is preferably an alkali metal salt.

[0110] The pharmaceutically acceptable “acidic salt” of the compound preferably includes an inorganic acid salt such as a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide, and a hydroiodide, a nitrate, a perchlorate, a sulfate, and a phosphate; an organic salt such as a lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, an aryl sulfonate such as a benzenesulfonates, and a p-toluene sulfonate, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, a tartrate, an oxalate, a maleate, and the like; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is most preferably a hydrohalide (in particular, a hydrochloride).

[0111] Pharmaceutically acceptable salts also include ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Set. 66(1): 1-19, and Remington. The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p. 732, Table 38-5, each of which are hereby incorporated by reference herein.

[0112] The compound of the present invention or the pharmaceutically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate by leaving in the air or recrystallization. The present invention also encompasses compounds of such various hydrates, solvates, and crystalline polymorphs.

[0113] The compounds of the present invention, their pharmaceutically acceptable salts or solvates thereof, depending on the type and combination of substituents, may have various isomers such as geometric isomers including a cis isomer and a trans isomer, tautomers, or optical isomers such as a D isomer and an L isomer. The invention includes such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Mixtures of these isomers may be resolved by known resolution means.

[0114] The compounds of the present invention also include labels, that is, a compound in which one or more atoms of the compounds are substituted with an isotope (for example,2H,3H,13C,14C,35S, and the like).

[0115] In addition, the present invention also encompasses a prodrug. The prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, it is a group described in Rautio et al. (2018) Nature Rev. DrugDiscov. 17(8):559- 587; Markovic et al. (2020) Pharmaceutics 12(11): 1031 or the like. As the prodrug, morespecifically, when an amino group is present in the compound, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, it is a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4- yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butyl ated, or the like) and the like are included, and when a hydroxyl group is present in the compound, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, it is a compound in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethyl carbonylated, or the like) and the like are included. In addition, when a carboxy group is present in the compound, a compound in which the carboxy group is esterified or amidated (for example, it is a compound in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, or the like), and the like are included. Particularly favored prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment relative to the parent species.

[0116] The compounds of the present invention may be produced by synthetic methods known in the art and as described in WO 2017 / 170623 and WO 2019 / 065928, incorporated by reference herein in their entirety.

[0117] Administration of the compounds of the present invention may be carried out by any form of oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, or the like, or by any form of parenteral administration by an injection for intra-articular, intravenous, intramuscular, or the like, a suppository, an eye drop, an eye ointment, a transdermal solution, an ointment, a transdermal patch or other topical means, a transmucosal solution, a transmucosal patch, an inhalant, a mouthwash, a lozenge, or the like.

[0118] As a solid composition for oral administration, a tablet, a powder, a granule, and the like are used. Such a solid composition is composed of one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate, and / or the like. Thesolid composition may contain, according to a conventional method, one or more of an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizer. The tablet or pill may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary.

[0119] As a liquid composition for oral administration or as a mouthwash, a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like is used. To such a liquid composition, it is possible to add a generally used inert diluent such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, one or more of a solubilizer, an adjuvant such as a wetting agent, a sweetening agent, a flavoring agent, a fragrance, and a preservative.

[0120] As an injection for parenteral administration, a sterile aqueous or non-aqueous solution, a suspension or an emulsion, and the like are used. The aqueous solvent includes, for example, distilled water for injection, physiological saline, and the like. The non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, and vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80, and the like. Such an injection composition may further contain a one or more of a tonicity agent, a preservative, a wetting agent, an emulsion, a dispersing agent, a stabilizer, or a solubilizer. These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, application of a bactericide, or irradiation. In addition, these injection compositions may be used by producing a sterile solid composition and dissolved or suspended in sterile water or a sterile solvent for injection prior to use.

[0121] As an external preparation such as for topical or transdermal administration, an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, an eye drop, an eye ointment, a patch, and the like are used. These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like are used.

[0122] A transmucosal agent such as an inhalant and a transnasal agent are used in solid, liquid, or semisolid form, and it may be produced according to a conventionally known method. For example, a known excipient, and furthermore, one or more of a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be added as appropriate. Withthese transmucosal agents, devices appropriate for inhalation or insufflation may be used as the method of administration. For example, the compound may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. A dry powder inhaler or the like may be for single or multiple administration, and a dry powder or powder containing capsule may be also used. Alternatively, an appropriate ejector may be used. For example, it may be in the form of a pressurized aerosol spray or the like using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

[0123] In some embodiments, the methods of the invention may further include administering NAD+ or an NAD+ precursor. The NAD+ or NAD+ precursor may be administered at the same time as the SIRT6 activator or at different time, e.g., on a different administration schedule. The NAD+ or NAD+ precursor may be administered in the same composition as the SIRT6 activator or in a separate composition.

[0124] The methods of the invention may be carried out with any NAD+ precursor known in the art or later developed. The term “NAD+ precursor” is intended to mean compounds that are known to increase the level of NAD+ in a subject after administration. Example NAD+ precursors useful to the present invention include, but are not limited to, nicotinamide riboside, nicotinic acid riboside, nicotinic acid, nicotinamide, nicotinamide mononucleotide, niacin, and tryptophan. NAD+ precursors may be converted into NAD+ by any pathway, reaction, or synthesis method known to those in the art. Example synthesis pathways of NAD+ from NAD+ precursors include, but are not limited to, the Kynurenine pathway, the Preiss-Handler pathway, the NAD+ salvage pathway, and / or the NRH salvage pathway. The methods of the invention may be carried out with NAD+ by itself or in addition to a NAD+ precursor.Methods of Use

[0125] A first aspect of the invention relates to a method of treating a joint and / or bone disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby treating the joint and / or bone disease. In some embodiments, the joint and / or bone disease is an age-related joint and / or bone disease. In some embodiments, the age-related joint and / or bone disease is osteoporosis, osteoarthritis, and / or osteopenia. In some embodiments, the osteoarthritis is post-traumatic osteoarthritis. In some embodiments, the joint and / or bone disease is an inflammation- related joint and / or bone disease. In some embodiments, the inflammation-related joint and / or bone disease is periodontal disease and / or inflammatory arthritis (e.g., rheumatoid arthritis). In some embodiments, the periodontal disease is gingivitis, diabetic periodontitis, aggressive periodontitis, chronic periodontitis, and / or necrotizing periodontal disease. In some embodiments, the inflammation-related bone disease is caused by an increase in inflammatory cytokines (e.g., IL-6, IL-ip, and / or TNF-a) that activate osteoclasts. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce the level of inflammatory cytokines (e.g., IL-6, IL-ip, and / or TNF- a) by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more), thereby reducing bone loss and treating the inflammation-related bone disease. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce the osteoclast activity by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more), thereby reducing bone loss and treating the inflammation-related bone disease. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, with NAD+ and / or an NAD+ precursor, may reduce the number of preosteoclasts (e.g., by apoptosis) by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more), thereby reducing the osteoclast activity. In some embodiments, the inflammation is acute inflammation. In some embodiments, the acute inflammation is caused by infection (e.g., a viral infection, a bacterial infection, and / or a fungal infection), an injury, and / or a surgery. In some embodiments, the inflammation is chronic inflammation. In some embodiments, the chronic inflammation is caused by infection (e.g., a viral infection, a bacterial infection, and / or a fungal infection), repeated injury, and / or an overuse injury.

[0126] Another aspect of the invention relates to a method of slowing progression of a reduction in bone mass (e.g., reducing bone loss) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in bone mass by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, the reduction in bone mass iscaused by increased bone resorption and / or decreased bone formation. Tn some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce the bone resorption by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may increase the bone formation, mass, and / or density by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce the osteoclast activity by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more), thereby slowing progression of a reduction in bone mass. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may prevent a reduction in bone mass.

[0127] Another aspect of the invention relates to a method of increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may increase osteoblast formation by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may decrease osteoclast formation by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce osteocyte death by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more).

[0128] Another aspect of the invention relates to a method of slowing progression of a reduction in joint mobility and / or function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in joint mobility and / or function. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may slow the progression of a reduction in joint mobility and / or function by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may improve joint mobility and / or function in a subject in need thereof. In some embodiments, improving joint mobility and / or function comprises improving mobility, improving range of motion, improving flexibility, reducing swelling, and / or reducing pain in one or more joints of the subject. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may improve joint mobility and / or function by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may prevent a reduction in joint mobility and / or function.

[0129] Another aspect of the invention relates to a method of slowing progression of a reduction in cartilage (e.g., reducing cartilage degradation) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby slowing progression of a reduction in cartilage. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator may slow the reduction in cartilage by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may prevent cartilage reduction (e.g., may prevent cartilage degradation).

[0130] Another aspect of the invention relates to a method of reducing chondrocyte senescence and / or death in a subject in need thereof, comprising administering to the subject a therapeuticallyeffective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, thereby reducing chondrocyte senescence and / or death. The SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce chondrocyte senescence and / or death through any mechanism that is known to those in the field. For example, in some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may preserve telomere function and / or reduce DNA damage, thereby reducing the chondrocyte senescence and / or death. In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may reduce chondrocyte senescence and / or death by about 5% to about 95% (e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or more). In some embodiments, administering to the subject a therapeutically effective amount of a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may prevent chondrocyte senescence and / or death.

[0131] In the case of normal oral administration, the appropriate daily dose of a SIRT6 activator is about 0.001 mg / kg to 100 mg / kg, preferably 0.1 mg / kg to 30 mg / kg, and more preferably 0.1 mg / kg to 10 mg / kg of body weight. In some aspects, the daily dose of a SIRT6 activator is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg to about 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, or 100 mg / kg, or any range or value therein. This is administered in one dose or separated into two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more doses). When administered intravenously, the appropriate daily dose of a SIRT6 activator is about 0.0001 mg / kg to 10 mg / kg (e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 mg / kg or any range or value therein) of body weight, which is administered once or separated into several times a day. In addition, as a transmucosal agent, about 0.001 mg / kg to 100 mg / kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg / kg or any range or value therein) of body weight is administered once or separated into several times a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like. The SIRT6 activator may be administered daily, e.g., in the morning and / or evening, and / or before, during orafter one or more daily meals, e.g., breakfast, lunch, and / or dinner. Tn some embodiments, the SIRT6 activator may be administered for a length of time (e.g., a length of treatment) as necessary until a measurable improvement is seen in the symptoms of the joint and / or bone disease, the reduction in bone mass, osteoblast formation, osteoclast formation, osteocyte death, joint mobility and / or function, reduction in cartilage, and / or chondrocyte senescence and / or death, or until such symptoms return to normal (e.g., return to a level established as within an acceptable range as indicated by the subject or a medical professional who is familiar with the disease or disorder). In some embodiments, the SIRT6 activator may be administered for about 1 day to about 6 days (e.g., about 1, 2, 3, 4, 5, or about 6 days), or about 1 week to about 4 weeks (e.g., about 1, 2, 3, or about 4 weeks), or about 1 month to about 12 months (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or about 12 months), or more until the measurable improvement is seen in the symptoms of the joint and / or bone disease, the reduction in bone mass, osteoblast formation, osteoclast formation, osteocyte deathjoint mobility and / or function, reduction in cartilage, and / or chondrocyte senescence and / or death.

[0132] The NAD+ and / or an NAD+ precursor may be administered at the same time as the SIRT6 activator or at different time, e.g., on a different administration schedule.

[0133] Improvements in bone density and / or cartilage thickness may be assessed by one or more conventional tests e.g., a magnetic resonance imaging (MRI), X-ray imaging, central dual energy x-ray absorptiometry (DXA), quantitative ultrasound, etc.). Improvements in joint mobility and / or function may be assessed by one or more conventional tests, such as with a goniometer and / or a Beighton score. The period of time following treatment for assessing improvements may be at least about 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes or longer such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. The effect of the treatment may be monitored for even more extended periods of time, such as at least about 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or about 52 weeks or longer.

[0134] In the methods of the present invention, the SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may be administered in combination with various therapeutic agents or preventive agents of use in subjects with a joint and / or bone disease. The therapeutic agent may be, for example, one that treats a joint and / or bone disease (e.g., an age-related and / or inflammation-related joint and / or bone disease) or one that reduces chronic pain associated with ajoint and / or bone disease. For example, a SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may be used in combination with acetaminophen, nonsteroidal anti-inflammatory drugs, steroid (e.g., corticosteroid), hyaluronic acid, alendronate, risendronate, ibandronate, zoledronic acid, antibody treatments (e.g., denosumab, romosozumab), raloxifene, teriparatide, abaloparatide, calcitonin, and / or a cyclin-dependent kinase inhibitor. The combination may be administered simultaneously, separately, concurrently, and continuously or at desired time intervals. The coadministered agents may be blended or formulated separately.

[0135] In the methods of the present invention, the SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, may be administered in combination with physical therapy and / or a surgery. In some embodiments, the surgery is a surgery to repair damaged cartilage tissue. In some embodiments, the surgery is an osteochondral explant, e.g., a cartilage allograft. In some embodiments, the SIRT6 activator is administered within about 1 to about 12 hours after surgery (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or about 12 hours after surgery). In some embodiments, the SIRT6 activator, optionally with NAD+ and / or an NAD+ precursor, is administered within about 1 to about 14 days after surgery (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14 days after surgery).

[0136] In some embodiments, the SIRT6 activator and the NAD+ and / or NAD+ precursor are administered in the same composition. In some embodiments, the SIRT6 and / or SIRT6 activator, and the NATH and / or NAD+ precursor are administered in separate compositions. In some embodiments, the additional therapeutic agent is administered in the same composition as the SIRT6 and / or SIRT6 activator, and / or the NATH and / or NAD+ precursor. In some embodiments, the additional therapeutic agent is administered in a separate composition as the SIRT6 and / or SIRT6 activator, and / or the NAD+ and / or NATH precursor. In some embodiments, the NAD+ is administered by intravenous injection.

[0137] The methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals. The term “mammal” as used herein includes, but is not limited to, humans, primates, non -human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. Optionally, the subject is “in need of’ the methods of the present invention, e.g., because the subject has or is believed to be at risk for a joint and / or bone disease or that would benefit fromtreatment with a compound as described herein. As a further option, the subject can be a laboratory animal and / or an animal model of disease. Preferably, the subject is a human.

[0138] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

What is claimed is:

1. A method of treating a joint and / or bone disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sirtuin 6 (SIRT6) activator, thereby treating the joint and / or bone disease.

2. The method of claim 1, wherein the joint and / or bone disease is an age-related joint and / or bone disease.

3. The method of claim 2, wherein the age-related joint and / or bone disease is osteoporosis, osteoarthritis, and / or osteopenia.

4. The method of claim 1, wherein the joint and / or bone disease is an inflammation-related joint and / or bone disease.

5. The method of claim 4, wherein the inflammation-related joint and / or bone disease is periodontal disease and / or inflammatory arthritis (e.g., rheumatoid arthritis).

6. A method of slowing progression of a reduction in bone mass in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby slowing progression of a reduction in bone mass.

7. The method of claims 6, wherein the reduction in bone mass is caused by increased bone resorption and / or decreased bone formation.

8. A method of increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby increasing osteoblast formation, decreasing osteoclast formation, and / or reducing osteocyte death.

9. A method of slowing progression of a reduction in joint mobility and / or function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby slowing progression of a reduction in joint mobility and / or function.

10. A method of slowing progression of a reduction in cartilage in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby slowing progression of a reduction in cartilage.

11. A method of reducing chondrocyte senescence and / or death in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby reducing chondrocyte senescence and / or death.

12. The method of any one of claims 1-11, further comprising administering to the subject a therapeutically effective amount of nicotinamide adenine dinucleotide (NAD+) and / or an NAD+ precursor.

13. The method of claim 12, wherein the SIRT6 activator and the NAD+ and / or NAD+ precursor are administered in the same composition.

14. The method of claim 12, wherein the SIRT6 activator and the NAD+ and / or NAD+ precursor are administered in separate compositions.

15. The method of any one of claims 12-14, wherein the NAD+ precursor is nicotinamide riboside, nicotinic acid riboside, nicotinic acid, nicotinamide, nicotinamide mononucleotide, tryptophan, or any combination thereof.

16. The method of any one of claims 1-14, wherein the SIRT6 activator is quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7), UBCS039 (CAS No. 358721-70-7), UBCS040 (l-(4,5-Dihydropyrrolo[l,2-a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[l,2-rz]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[l,2- r / ]quinoxaline), UBCS068 (l-(5-((3-(Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[l,2- rz]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide, CL5D (CAS No. 2488745-53-3), 10b (2-(l-benzofuran-2-yl)-A-(diphenylmethyl) quinoline-4-carboxamide), or SP-624 (forvisirvat).

17. The method of any one of claims 1-14, wherein the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereofwherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring,a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R3and R3do not exist;R3and R3are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y,a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkyl sulfonylamino group; and substituent group Yis a C 1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

18. The method of claim 17, wherein the 5-membered aromatic heterocyclic ring or the 5- membered aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

19. The method of claim 17 or 18, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

20. The method of any one of claims 17-19, wherein the 8-10 membered condensed aromatic heterocyclic ring or the 8-10 membered condensed aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

21. The method of any one of claims 17-20, wherein the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group in A, R3, or R3is any one selected from the group:

22. The method of any one of claims 17-21, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R1, R2, or R3is any one selected from the group:

23. The method any one of claims 17-22, wherein the compound of Formula 1 is any compound selected from the following group:(2S,5’R)-7-chloro-6-(5-ethyl-l,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1’ , 3 -di one;(2S, 5 ’R)-7-chl oro-3 ’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl- 1,3,4- oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chl oro-3 ’,4-dimethoxy-5’-methyl-6-[5-(l -methyl -4-piperidyl)-l, 3,4- oxadiazol-2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione;(2S, 5 ’R)-7-chloro-3’, 4-dimethoxy-6-[5-[(l S)-l -methoxy ethyl]- 1,3, 4-oxadiazol -2-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4 ’ -cy cl ohex-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]-l’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(l-methoxyethyl)-l,2,4-oxadiazol-5-yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-[3-(l-hydroxy-l-methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4- dimethoxy-5 ’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(lH-pyrazol-5-yl) spiro [benzofuran- 2,4’ -cy cl ohex-2-ene]-l’,3-di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[l-(2-methoxyethyl) pyrazol-3-yl]-5 ’-methyl-spiro [benzofuran-2,4’-cy cl ohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’ -methyl-spiro [benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1’ ,3 -dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5 ’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-l 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 -di one.

24. The method of any one of claims 17-23, wherein the compound of Formula 1 is a compound of Formula 1' or a pharmaceutically acceptable salt thereof:wherein:R1is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;R2is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X;A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R3and R3is not present;R3and R3are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X,a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy carbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, orR3and R3may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X; substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a Cl- C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group,a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy carbonyl group, a C3-C6 cycloalkoxy carbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y,a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group; and substituent group Y is a C 1 -C6 alkyl group, a C 1 -C6 alkoxy group, a halogen atom, or a hydroxy group.

25. The method of claim 24, wherein R1is a methyl group, an ethyl group, or a hydroxyethyl group.

26. The method of claim 24 or 25, wherein R2is a methyl group.

27. The method of any one of claims 24-26, wherein the 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

28. The method of any one of claims 24-27, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R3, or R3is any one selected from the group:

29. The method of any one of claims 24-28, wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7 membered unsaturated heterocyclic group in A, R3, or R3is any one selected from the group:

30. The method of any one of claims 24-29, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R1, R2, or R3is any one selected from the group:

31. The method of any one of claims 24-30, wherein A is a 5-membered aromatic heterocyclic ring; R3is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group; and R3is a hydrogen atom.

32. The method of any one of claims 24-31, wherein A is any ring selected from the following group, and in the case of two binding groups, R3is not present:wherein * indicates a binding group.

33. The method of any one of claims 24-26, wherein the compound of Formula 1 is a compound of a Formula 1" or a pharmaceutically acceptable salt thereof:whereinR1is a methyl group or an ethyl group;R2is a methyl group;A is any ring selected from the following group:wherein * indicates a binding group; and R3is a methyl group or an ethyl group.

34. The method of any one of claims 24-32, wherein the compound of Formula 1' is any compound selected from the following group:(2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran- 2,4’-cyclohex-2-ene]-l’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(2 -methoxy ethoxy)-5’ -methyl -spiro [benzofuran- 2,4’-cyclohex-2-ene]-l’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-(l-methylpyrazol-3-yl) spiro [benzofuran-2,4 ’ -cy cl ohex -2-ene] - 1 ’ ,3 -dione;(2S, 5 ’R)-7-chloro-6-(l -ethylpyrazol-3-yl)-3’,4-dimethoxy-5 ’-methyl-spiro [benzofuran- 2,4’ -cyclohex-2-ene] - 1 ’ ,3 -dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-l,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-l,2,4-oxadiazol-5-yl) spiro [benzofuran-2, 4 ’ -cyclohex -2-ene] - 1’ , 3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-l,2,4-oxadiazol-3-yl) spiro [benzofuran-2, 4 ’ -cy cl ohex -2-ene] - 1’ , 3 -di one;(2S,5’R)-7-chloro-6-[5-(l-hydroxy-l-methyl-ethyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2, 4’ -cyclohex-2-ene]-l’,3-dione;(2S, 5’R)-7-chloro-6-[5-[(l S)-l-hydroxy ethyl]-l, 3, 4-oxadiazol -2 -yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2, 4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-6-[5-[(lR)-l -hydroxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-3 ’, 4-dimethoxy-5’- methyl-spiro [benzofuran-2, 4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-4-ethoxy-6-[5-(l -hydroxy-1 -methyl-ethyl)-l, 3, 4-oxadiazol -2 -yl]-3 ’- methoxy-5 ’ -methyl-spiro [benzofuran-2, 4 ’ -cy clohex-2-ene]- 1 ’ ,3 -di one;(2S,5’R)-7-chloro-4-ethoxy-6-[5-[(lS)-l-hydroxyethyl]-l,3,4-oxadiazol-2-yl]-3’- methoxy-5’ -methyl-spiro [benzofuran-2, 4’ -cy cl ohex-2-ene]-l’,3-di one;(2S,5’R)-7-chloro-6-[3-(l-hydroxyethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2, 4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-4-(2 -hydroxy ethoxy)-3 ’-methoxy-5 ’-methyl -6-(5-methyl- 1,3,4- oxadiazol-2-yl) spiro [benzofuran-2, 4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-4-(2 -hydroxy ethoxy)-3 ’-methoxy-5 ’-methyl -6-(3-methyl- 1,2,4- oxadiazol-5-yl) spiro [benzofuran-2, 4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-4-(2 -hydroxy ethoxy)-3 ’-methoxy-5 ’-methyl -6-(5-methyl- 1,2,4- oxadiazol-3-yl) spiro [benzofuran-2, 4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chl oro-6-(5 -ethyl- 1, 3, 4-oxadiazol -2 -yl)-3’,4-dimethoxy-5 ’-methyl-spiro [benzofuran-2, 4 ’ -cy cl ohex -2-ene] - 1’ , 3 -di one;(2S, 5 ’R)-7-chl oro-3 ’,4-dimethoxy-5 ’-methyl -6-(5-tetrahydropyran-4-yl-l, 3,4- oxadiazol-2-yl) spiro [benzofuran-2, 4’-cyclohex-2-ene]-l ’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-[5-(l -methyl -4-piperidyl)- 1,3,4- oxadiazol-2-yl] spiro [benzofuran-2,4’-cyclohex-2-ene]-r, 3-dione;(2S,5’R)-7-chloro-6-[5-(4-fluoro-l-methyl-4-piperidyl)-l,3,4-oxadiazol-2-yl]-3’,4- dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’, 4-dimethoxy-6-[5-[(lS)-l -methoxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,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]-l’, 3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-[3-(l -methoxyethyl)-!, 2, 4-oxadiazol-5-yl]-5 ’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’, 3-dione;(2S, 5 ’R)-7-chloro-6-[3-( 1 -hydroxy- 1 -methyl-ethyl)- 1 ,2,4-oxadiazol-5-yl]-3 ’ ,4- dimethoxy-5’ -methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(lH-pyrazol-5-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-l’,3-dione;(2S,5’R)-7-chloro-3’,4-dimethoxy-6-[l-(2-methoxyethyl) pyrazol-3-yl]-5 ’-methyl-spiro [benzofuran-2,4’-cy cl ohex-2-ene]-l’, 3-dione;(2S,5’R)-7-chloro-6-(l,8-dioxa-2-azaspiro [4.5] dec-2-en-3-yl)-3’,4-dimethoxy-5’- methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-5 ’-methyl -6-(8-methyl-l-oxa-2,8-diazaspiro [4.5] dec-2-en-3-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’ -methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione;(2S, 5 ’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5 ’-methyl-spiro [benzofuran-2,4 ’-cy clohex-2-ene]- 1 ’ ,3 -di one;(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl) spiro [benzofuran-2,4’- cyclohex-2-ene]-l ’,3-dione; or(2S, 5 ’R)-7-chl oro-3 ’, 4, 6-trimethoxy-5 ’-methyl-spiro [benzofuran-2,4’ -cyclohex-2-ene]- 1 ’,3-dione.

35. The method of claim 34, wherein the compound is (2S,5’R)-7-chloro-6-(l-ethylpyrazol-3- yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

36. The method of claim 34, wherein the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’- methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-l ’,3-dione or a pharmacologically acceptable salt thereof.

37. The method of claim 33, wherein the compound is (2S,5’R)-7-chloro-6-(5-ethyl-l,3,4- oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3-dione or a pharmacologically acceptable salt thereof.

38. The method of claim 34, wherein the compound is (2S,5’R)-7-chloro-6-[3-(l-hydroxy-l- methyl-ethyl)-l,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran -2, 4’ -cyclohex - 2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

39. The method of claim 34, wherein the compound is (2S,5’R)-7-chloro-4-ethoxy-3’- methoxy-5’-methyl-6-(5-methyl-l,3,4-oxadiazol-2-yl) spiro [benzofuran-2, 4’ -cyclohex -2-ene]- 1 ’,3-dione or a pharmacologically acceptable salt thereof.

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