WO2025160321A1

WO2025160321A1 - Compositions and methods for treating neurodegenerative disease

Info

Publication number: WO2025160321A1
Application number: PCT/US2025/012841
Authority: WO
Inventors: Gregory Cooksey Rigdon; Michael Friedrich ACKERMANN; Stephen E. Butts
Original assignee: Sirtsei Pharmaceuticals Inc
Current assignee: Sirtsei Pharmaceuticals Inc
Priority date: 2024-01-24
Filing date: 2025-01-24
Publication date: 2025-07-31
Anticipated expiration: 2026-07-24

Abstract

The present invention relates to methods of treating neurodegenerative disease in human subjects by administering an activator of sirtuin 6 (SIRT6) and a nicotinamide adenine dinucleotide (NAD)+ precursor. Exemplary neurodegenerative diseases include, but are not limited to, those where the subject has decreased levels and/or activity of SIRT6, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Description

COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE

DISEASE

STATEMENT OF PRIORITY

[0001] This application claims the benefit, under 35 U.S.C. §119(e), of U.S. Provisional Application No. 63/624,355, filed January 24, 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 neurodegenerative disease in human subjects by administering an activator of SIRT6 and an NAD+ precursor.

BACKGROUND OF THE INVENTION

[0003] Neurodegenerative diseases, such as Alzheimer's disease, Huntington’s disease, amyotrophic lateral sclerosis and Parkinson’s disease, are one of the largest issues that affect the modern healthcare system. These diseases often present early with mild cognitive or physical impairments, but can quickly worsen as the patient ages. Many studies have focused on the molecular changes that occur in the brain during the progression of these age-related diseases. The group of proteins called sirtuins have been linked to such neurodegenerative diseases. They are shown to play a neuroprotective role in ageing patients, and their expression is commonly decreased in those who are suffering from Alzheimer’s disease and/or dementia.

[0004] There is a need in the art for effective therapeutics for neurodegenerative diseases.

SUMMARY OF THE INVENTION

[0005] Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylase/deacylase that is known to have various roles in age-related functions such as telomere maintenance, DNA repair, genome integrity, energy metabolism, inflammation and life span regulation. SIRT6 is also shown to be decreased in the serum of Alzheimer’s disease patients compared to patients with mild cognitive impairment or geriatric controls (Pradhan et al., 2022).

[0006] Similarly, NAD+ itself has been shown to be involved in ageing. Its level decreases over the lifespan of an organism and NAD+ depletion has been linked to neurodegeneration. Though administration of NAD+ itself has proven challenging, NAD+ precursors have worked well in reducing DNA damage, enhancing neuronal survival, and improving cognitive function in aging animal models.

[0007] Accordingly, the present invention is based on the determination that the combination of SIRT6 and/or SIRT6 activators with NAD+ and/or NAD+ precursors provides a significant therapeutic effect for neurodegenerative disease.

[0008] Thus, one aspect of the invention relates to a method of treating a neurodegenerative disease in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 and/or SIRT6 activator with an NAD+ and/or NAD+ precursor, thereby treating the neurodegenerative disease. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating a neurodegenerative disease

[0009] These and other aspects of the invention are set forth in more detail in the description of the invention below.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0010] 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.

[0011] 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.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

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

Definitions

[0014] 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.

[0015] 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”).

[0016] 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.

[0017] 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.

[0018] 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.”

[0019] 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 subject’s condition and/or to alleviate, mitigate or decrease in at least one clinical symptom and/or to delay the progression of the condition. [0020] As used herein, the term “prevent,” “prevents,” or “prevention” (and grammatical equivalents thereof) means to delay or inhibit the onset 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 or delays the onset of the condition.

[0021] A “treatment effective” amount as used herein is an amount that is sufficient to provide some improvement or benefit to the subject. Alternatively stated, a “treatment effective” amount is an amount that will provide some alleviation, mitigation, decrease or stabilization in at least one clinical symptom in the subject. 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.

[0022] 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 the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0023] “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,' 21^st ed. 2005). Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution.

[0024] A “vector” is any nucleic acid molecule for the cloning of and/or transfer of a nucleic acid into a cell. A vector may be a replicon to which another nucleotide sequence may be attached to allow for replication of the attached nucleotide sequence. A “replicon” can be any genetic element (e.g., plasmid, phage, cosmid, chromosome, viral genome) that functions as an autonomous unit of nucleic acid replication in vivo, i.e., capable of replication under its own control. The term “vector” includes both viral and nonviral (e.g., plasmid) nucleic acid molecules for introducing a nucleic acid into a cell in vitro, ex vivo, and/or in vivo. A large number of vectors known in the art may be used to manipulate nucleic acids, incorporate response elements and promoters into genes, etc. For example, the insertion of the nucleic acid fragments corresponding to response elements and promoters into a suitable vector can be accomplished by ligating the appropriate nucleic acid fragments into a chosen vector that has complementary cohesive termini. Alternatively, the ends of the nucleic acid molecules may be enzymatically modified or any site may be produced by ligating nucleotide sequences (linkers) to the nucleic acid termini. Such vectors may be engineered to contain sequences encoding selectable markers that provide for the selection of cells that contain the vector and/or have incorporated the nucleic acid of the vector into the cellular genome. Such markers allow identification and/or selection of host cells that incorporate and express the proteins encoded by the marker. A “recombinant” vector refers to a viral or non-viral vector that comprises one or more heterologous nucleotide sequences (i.e., transgenes), e.g., two, three, four, five or more heterologous nucleotide sequences.

[0025] Viral vectors have been used in a wide variety of gene delivery applications in cells, as well as living animal subjects. Viral vectors that can be used include, but are not limited to, retrovirus, lentivirus, adeno-associated virus, poxvirus, alphavirus, baculovirus, vaccinia virus, herpes virus, Epstein-Barr virus, and adenovirus vectors. Non-viral vectors include plasmids, liposomes, electrically charged lipids (cytofectins), nucleic acid-protein complexes, and biopolymers. In addition to a nucleic acid of interest, a vector may also comprise one or more regulatory regions, and/or selectable markers useful in selecting, measuring, and monitoring nucleic acid transfer results (delivery to specific tissues, duration of expression, etc.).

[0026] By the term “express” or “expression” of a polynucleotide coding sequence, it is meant that the sequence is transcribed, and optionally, translated. Typically, according to the present invention, expression of a coding sequence of the invention will result in production of a polypeptide useful to the invention (e.g., a SIRT6 polypeptide).

Methods of Use

[0027] A first aspect of the invention relates to a method of treating a neurodegenerative disease in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of SIRT6 and/or a SIRT6 activator with NAD+ and/or an NAD+ precursor, thereby treating the neurodegenerative disease. In some embodiments, the neurodegenerative disease is characterized by decreased levels and/or activity of SIRT6 (e.g., the subject in need thereof has 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decreased levels and/or activity of SIRT6 relative to a control subject that does not have the neurodegenerative disease). In some embodiments, the neurodegenerative disease is Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, Down’s syndrome, corticobasal degeneration, Pick’s disease, multisystem atrophy, progressive supranuclear palsy, inclusion body myositis, prion protein cerebral amyloid angiopathy, argyrophilic grain disease, tangle predominant dementia, chronic traumatic encephalopathy, or traumatic brain injury.

[0028] In some embodiments, the method of treating a neurodegenerative disease further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating a neurodegenerative disease. In some embodiments, the additional therapeutic includes, but is not limited to, an amino acid supplement, an antioxidant, a steroid (e.g., a corticosteroid), an antibody (e.g., aducanumab, lecanemab, or donanemab), an immunomodulator (e.g., glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, monomethyl fumarate, fmgolimod, siponimod, ozanimod, ponesimod, or cladribine), a muscle relaxant (e.g., baclofen, tizanidine, or cyclobenzaprine), an antipsychotic or atypical antipsychotic (e.g., haloperidol, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, brexpiprazole, or ziprasidone), tetrab enazine, an anti dy ski netic (e.g., amantadine), levodopa, a cholinesterase inhibitor (e.g., donepezil, rivastigmine, or galantamine), a glutamate regulator (e.g., memantine), an orexin receptor antagonist (e.g., suvorexant), an antidepressant (e g., citalopram, fluoxetine, paroxetine, sertraline, nortriptyline, or trazodone), an anxiolytic (e.g., lorazepam, temazepam, or oxazepam), a sleep aid or insomnia therapeutic (e.g., zolpidem, zaleplon, chloral hydrate, or melatonin), or any combination thereof. In some embodiments, the additional therapeutic is an anti-amyloid therapeutic.

[0029] Assessment of certain neurodegenerative diseases can be performed by scales or assessments known in the art, including assessments such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Unified Parkinson’s Disease Rating Scale (UPDRS), the Unified Huntington's Disease Rating Scale (UHDRS), the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), the Expanded Disability Status Scale (EDSS), and the like. Compounds

[0030] 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.

[0031] The methods of the invention may be carried out with any SIRT6 activator known in the art or later developed. Examples of SIRT6 activators include, without limitation, quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800, MDL-811, UBCS038 (You et al., Angew. Chem. Int. Ed. 56: 1007 (2017)), UBCS039, UBCS040, UBCS058, UBCS060, UBCS068, myristic acid, OEA, CL5D, 10b, 5-C1-PZA, BHJH-TM3, 15f, 17a (catechin gallate), 19b (OSSJ28167), 20b, 21b, 22a (A127-(CONHPr)-B178), and 23. The compounds are described in more detail in Fiorentino et al., J. Med. Chem. 64:9732 (2021) and Akter et al., Int. J. Mol. Sci. 22:4180 (2021), each incorporated by reference herein in its entirety. The methods of the invention may be carried out with SIRT6 by itself (e.g., in the form of SIRT6 protein or a polynucleotide encoding SIRT6) or in addition to a SIRT6 activator.

[0032] A further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof: wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,

R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X,

A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R³ and R³ do not exist, R³ and R³ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or

R³ and R³ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, 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 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 (C 1 -C6 alkyl) aminocarbonyl group, a di (C 1 -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 alkoxy carbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonyl amino 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, substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group. [0033] In some embodiments, the compound of Formula 1 is any compound selected from the following group:

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

(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]-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]-r, 3-dione;

(2S, 5 ’R)-7-chloro-3’, 4-dimethoxy-6-[5-[(lS)-l -methoxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-5’ -methylspiro [benzofuran-2,4 ’ -cy cl ohex-2-ene] - 1 ’ ,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-chl oro-3 ’,4-dimethoxy-6-[3-(l -methoxy ethyl)-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’ - 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’-methyl-spiro [benzofuran-2,4 ’ -cyclohex -2-ene] - 1’ , 3 -di one;

(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]-l’,3-dione.

[0034] In some embodiments, the compound of Formula 1 is a compound of Formula 1’ or a pharmacologically acceptable salt thereof: wherein:

R¹ is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X

R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X.

A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, or a single bond, wherein when it is a single bond, one or the other of R³ and R³ is not present,

R³ and R³ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a carbamoyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, an 8-10 membered condensed aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, or

R³ and R³ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, 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 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 (C 1 -C6 alkyl) aminocarbonyl group, a di (C 1 -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 alkoxy carbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonyl amino group, a C1-C6 alkyl carbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

[0035] In some embodiments of the compound of Formula 1 or Formula 1’, R¹ is a C1-C6 alkyl group, R² is a C1-C6 alkyl group, A is a 5-membered aromatic heterocyclic ring, and R³ and R³ are each independently a hydrogen or a C1-C6 alkyl group.

[0036] In some embodiments of the compound of Formula 1 or Formula 1’, R¹ is a methyl group, an ethyl group, or a hydroxy ethyl group.

[0037] In some embodiments of the compound of Formula 1 or Formula 1’, R² is a methyl group. [0038] In some embodiments of the compound of Formula 1 or Formula 1’, A is a 5-membered aromatic heterocyclic ring, R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, and R³ is a hydrogen atom.

[0039] In some embodiments, the compound of Formula 1 is a compound of a Formula 1” or a pharmacologically acceptable salt thereof:

wherein R¹ is a methyl group or an ethyl group;

R² is a methyl group;

[0040] A is any ring selected from the following group: indicates a binding group; and

R³ is a methyl group or an ethyl group.

[0041] 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]-l ’,3-dione;

(2S, 5 ’R)-7-chl oro-3 ’,4-dimethoxy-6-(2 -methoxy ethoxy)-5’-methyl-spiro [benzofuran-2,4’ - cy clohex-2-ene] - 1’ , 3 -dione;

(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(l-methylpyrazol-3-yl) spiro [benzofuran-2,4’- cy clohex-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]-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 ’ -cy cl ohex -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 ’ -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]- 1, 3, 4-oxadiazol -2 -yl]-3’,4-dimethoxy-5 ’-methylspiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1’ , 3 -di one;

(2S, 5 ’R)-7-chloro-6-[5-[(lR)- 1 -hydroxy ethyl]- 1,3, 4-oxadiazol -2 -yl]-3’,4-dimethoxy-5 ’-methylspiro [benzofuran-2,4 ’ -cy clohex-2-ene] - 1’ , 3 -di one;

(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]-l’, 3-dione;

(2S, 5 ’R)-7-chloro-4-ethoxy-6-[5-[( IS)- 1 -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-hydroxy ethyl)-l, 2, 4-oxadiazol-5-yl]-3’,4-dimethoxy-5 ’-methyl-spiro

[benzofuran-2,4 ’ -cy cl ohex-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;

(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-chloro-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-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 ’ -cy cl ohex-2-ene] - 1 ’ ,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]-r, 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] - 1’ , 3 -di one;

(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 clohex-2-ene] - 1’ , 3 -di one;

[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 -di one;

(2S, 5 ’R)-7-chl oro-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 -di one;

(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-chloro-3’,4,6-trimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-l’,3- dione.

[0042] 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.

[0043] 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.

[0044] 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. [0045] 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]-l’,3- dione or a pharmacologically acceptable salt thereof.

[0046] 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.

[0047] 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, R³ is not present. wherein * indicates a binding group.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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-l-pentyloxy group, and a 3 -methyl- 1-pentyloxy group. Preferably, it is a methoxy group, an ethoxy group, a 1 -propoxy group, or a 2-propoxy group.

[0058] 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.

[0059] 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.

[0060] The “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] The “C1-C6 alkoxycarbonyl 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. [0070] The “C3-C6 cycloalkoxy carbonyl 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.

[0071] 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.

[0072] The “mono (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and it is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.

[0073] 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.

[0074] 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

[0075] The “di (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.

[0076] 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.

[0077] 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.

[0078] The “C1-C6 alkoxy carbonylamino group” in the present specification is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, and for example, it is a methoxy carbonylamino group, an ethoxy carbonylamino group, or a propoxycarbonyl amino group.

[0079] 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.

[0080] The “di (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0081] 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.

[0082] 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.

[0083] 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.

Pharmaceutical compositions

[0084] The term “pharmaceutically acceptable salt” indicates a salt of the compounds that can be used as a pharmaceutical. When the compounds have 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.

[0085] The pharmaceutically acceptable “basic salt” of the compounds 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. [0086] The pharmaceutically acceptable “acidic salt” of the compounds 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).

[0087] The compounds 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.

[0088] 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 such as a cis isomer and a trans isomer, tautomers, or optical isomers such as a d isomer and an 1 isomer, while the compounds include those all 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.

[0089] 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, ³⁵ S, and the like).

[0090] In addition, the present invention also encompasses a prodrug of the described compounds. 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 Prog. Med., Vol. 5, pp. 2157 to 2161 (1985) or the like. As the prodrug, more specifically, when an amino group is present in the compound, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, it is a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butylated, or the like) and the like are included, and when a hydroxyl group is present in the compound, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, it is a compound in which the hydroxyl group 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 methyl ami dated, or the like.), and the like are included.

[0091] The SIRT6 activator 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.

Administration methods

[0092] Administration of the compounds of the present invention may be carried out by any form of oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, or the like, or by any form of parenteral administration by an injection for intra-articular, intravenous, intramuscular, or the like, a suppository, an eye drop, an eye ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant, or the like.

[0093] In some embodiments, 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. The solid composition may contain, according to a conventional method, one or more of an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizer. The tablet or pill may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary.

[0094] In some embodiments, a liquid composition for oral administration, a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like is used. To such a liquid composition, it is possible to add a generally used inert diluent such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, one or more of a solubilizer, an adjuvant such as a wetting agent, a sweetening agent, a flavoring agent, a fragrance, and a preservative.

[0095] In some embodiments, an injection for parenteral administration, a sterile aqueous or nonaqueous 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 nonaqueous 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, fdtration 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.

[0096] In some embodiments, an external preparation, an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, an eye drop, an eye ointment, and the like are used. These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, 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.

[0097] A transmucosal agent such as an inhalant and a transnasal agent are used in solid, liquid, or semisolid form, and it may be produced according to a conventionally known method. For example, a known excipient, and furthermore, one or more of a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be added as appropriate. With these transmucosal agents, devices appropriate for inhalation or insufflation may be used as the method of administration. For example, the compound may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. A dry powder inhaler or the like may be for single or multiple administration, and a dry powder or powder containing capsule may be also used. Alternatively, an appropriate ejector may be used. For example, it may be in the form of a pressurized aerosol spray or the like using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.

[0098] In the case of normal oral administration, the appropriate daily dose is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg of body weight. In some embodiments, the appropriate daily dose is about 1 to 500 mg, e.g., about 5 to 200 mg, e.g., about 10-100 mg, e.g., about 15-30 mg. This is administered in one dose or separated into two or more doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg/kg of body weight, which is administered once or separated into several times a day. In addition, as a transmucosal agent, about 0.001 to 100 mg/kg 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.

[0099] In some embodiments, the SIRT6 and/or 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 NAD+ 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 NAD+ 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 NAD+ precursor. In some embodiments, the NAD+ is administered by intravenous injection.

[0100] In some embodiments, the SIRT6 is a variant of, and 80% or more identical to, the amino acid sequence of the human SIRT6 protein (e.g., is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the human SIRT6 protein). In some embodiments, the SIRT6 is encoded by a polynucleotide that is 80% or more identical to the polynucleotide sequence of the human SIRT6 gene (e.g., is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more identical to the polynucleotide sequence of the human SIRT6 gene). In some embodiments, the SIRT6 is encoded by a polynucleotide and the polynucleotide is a component of a vector (e.g., a viral vector such as an AAV vector) which is administered to the subject. Both amino acid sequences of SIRT6 polypeptide and polynucleotide sequence of genes encoding SIRT6 polypeptides are known in the art and are available in sequence databases such as GenBank (e.g., GenBank Accession Number NM_016539). [0101] In the methods of the present invention, the compounds may be administered in combination with additional various therapeutic agents or preventive agents for diseases that are considered to exhibit the efficacy thereof. The combination may be administered simultaneously, separately, concurrently, and continuously or at desired time intervals. The co-administered agents may be blended or formulated separately. The therapeutic agent may be, for example, one that is known to treat the targeted, or another, neurodegenerative disease. In an embodiment, the therapeutic agent is one that treats Multiple Sclerosis, Traumatic Brain Injury, Parkinson’s Disease, Alzheimer’s Disease, Post-Traumatic Stress Disorder, Major Depressive Disorder, Schizophrenia, or Bipolar Disorder.

[0102] 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 at risk for anhedonia or that would benefit from the delivery of 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.

[0103] The foregoing examples are illustrative of the present invention and are not to be construed as limiting thereof. Although the invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.

Claims

What is Claimed:

1. A method of treating a neurodegen erative disease in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sirtuin 6 (SIRT6) activator and a nicotinamide adenine dinucleotide (NAD+) precursor, thereby treating the neurodegenerative disease.

2. The method of claim 1, wherein the subject has decreased levels and/or activity of SIRT6 (e.g., has 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decreased levels and/or activity of SIRT6) relative to a subject that does not have a neurodegenerative disease.

3. The method of claim 1 or 2, wherein the neurodegenerative disease is Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, Down’s syndrome, corticobasal degeneration, Pick’s disease, multisystem atrophy, progressive supranuclear palsy, inclusion body myositis, prion protein cerebral amyloid angiopathy, argyrophilic grain disease, tangle predominant dementia, chronic traumatic encephalopathy, or traumatic brain injury.

4. The method of any one of claims 1-3, wherein the SIRT6 activator and the NAD+ precursor are administered in the same composition.

5. The method of any one of claims 1-3, wherein the SIRT6 activator and the NAD+ precursor are administered in separate compositions.

6. The method of any one of claims 1-5, further comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent for treating a neurodegenerative disease.

7. The method of any one of claims 1-6, wherein the NAD+ precursor is nicotinamide riboside, nicotinic acid riboside, nicotinic acid, nicotinamide, nicotinamide mononucleotide, tryptophan, or any combination thereof.

8. The method of any one of claims 1-7, wherein the SIRT6 activator is quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800, MDL-811, UBCS038, UBCS039, UBCS040, UBCS058, UBCS060, UBCS068, myristic acid, OEA, CL5D, 10b, or any combination thereof.

9. The method of any one of claims 1-7, wherein the SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt thereof: wherein:

R² is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X, A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8-10 membered condensed aromatic heterocyclic ring, a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, wherein when A is a cyano group, R³ and R³ do not exist,

R³ and R³ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 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, or

R³ and R³ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from a substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic oxy group optionally substituted with the same or different one to two substituents selected from the substituent group Y, 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 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 alkoxy carbonylamino 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, substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group, thereby improving memory function, cognition function, and/or learning function in the subject.

10. The method of claim 9, wherein the 5-membered aromatic heterocyclic ring or the 5- membered aromatic heterocyclic group in A, R³, or R³ is any one selected from the group:

11. The method of claim 9 or 10, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R³, or R³ is any one selected from the group:

12. The method of any one of claims 9-11, wherein the 8-10 membered condensed aromatic heterocyclic ring or the 8-10 membered condensed aromatic heterocyclic group in A, R³, or R³ is any one selected from the group:

13. The method of any one of claims 9-12, wherein the 5-7 membered unsaturated heterocyclic ring or 5-7 membered unsaturated heterocyclic group in A, R³, or R³ is any one selected from the group:

14. The method of any one of claims 9-13, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group:

15. The method any one of claims 9-14, 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 ’ -cyclohex -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-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-chl oro-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;

(2 S, 5 ’R)-7-chl oro-3 ’ ,4-dimethoxy-5 ’ -methyl -6-(8-methyl - 1 -oxa-2, 8 -di azaspiro [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’-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]-l ’,3-dione.

16. The method of any one of claims 9-15, wherein the compound of Formula 1 is a compound of Formula 1’ or a pharmacologically acceptable salt thereof:

wherein:

R³ and R³ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 alkoxy group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkenyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C2-C6 alkynyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, an amino group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C1-C6 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, or

R³ and R³ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring as a ring that binds to each other and condenses with A, and the ring is optionally substituted with the same or different one to two substituents selected from the substituent group X, Substituent group X is a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, a phenyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group Y, 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 cycloalkoxycarbonyl group, a carboxy group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkylcarbonyl group, a phenylcarbonyl group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a carbamoyl group, a mono (C1-C6 alkyl) aminocarbonyl group, a di (C1-C6 alkyl) aminocarbonyl group, a mono (C1-C6 alkyl) aminosulfonyl group, a di (C1-C6 alkyl) aminosulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di (C1-C6 alkyl) amino group, a C1-C6 alkoxycarbonylamino group, a mono (C1-C6 alkyl) aminocarbonylamino group, a di (C1-C6 alkyl) aminocarbonylamino group, a C1-C6 alkylcarbonylamino group, a phenylcarbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 5 -membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted with the same or different one to two substituents selected from the substituent group Y, or a C1-C6 alkylsulfonylamino group, and substituent group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxy group.

17. The method of claim 16, wherein R¹ is a methyl group, an ethyl group, or a hydroxyethyl group.

18. The method of claim 16 or 17, wherein R² is a methyl group.

19. The method of any one of claims 16-18, wherein the 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group in A, R³, or R³ is any one selected from the group:

20. The method of any one of claims 16-19, wherein the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group in A, R³, or R³ is any one selected from the group:

21 . The method of any one of claims 16-20, wherein the 5-7 membered unsaturated heterocyclic ring or the 5-7 membered unsaturated heterocyclic group in A, R³, or R³ is any one selected from the group:

22. The method of any one of claims 16-21, wherein the 4-7 membered saturated heterocyclic ring or the 4-7 membered saturated heterocyclic group in A, R¹, R², or R³ is any one selected from the group:

23. The method of any one of claims 16-22, wherein A is a 5-membered aromatic heterocyclic ring, R³ is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, and R³ is a hydrogen atom.

24. The method of any one of claims 16-23, wherein A is any ring selected from the following group, and in the case of two binding groups, R³ is not present: wherein * indicates a binding group.

25. The method of any one of claims 16-18, wherein the compound of Formula 1 is a compound of a Formula 1” or a pharmacologically acceptable salt thereof: d") wherein R¹ is a methyl group or an ethyl group;

R² is a methyl group;

A is any ring selected from the following group:

* indicates a binding group; and

R³ is a methyl group or an ethyl group.

26. The method of any one of claims 16-24 wherein the compound of Formula 1’ is any compound selected from the following group: (2S, 5 ’R)-7-chloro-6-(2 -hydroxy ethoxy)-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-6-(2 -methoxy ethoxy)-5’-methyl-spiro [benzofuran- 2,4’ -cyclohex-2-ene] - 1 ’ ,3 -di one;

(2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(l-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’ -cy clohex-2-ene] - 1 ’ ,3 -di one;

(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 ’ -cy cl ohex-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]-l’,3-dione;

(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]- 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]-l’,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 -hydroxy ethyl)-!, 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]-r, 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 ’-cyclohex -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-chl oro-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-l,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 -methoxy ethyl)- 1,2, 4-oxadi azol-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;

(2 S, 5 ’R)-7-chl oro-3 ’ ,4-dimethoxy-5 ’ -methyl -6-( 1 H-pyrazol -5 -yl) spiro [b enzofuran- 2,4’-cyclohex-2-ene]-l’,3-dione;

(2S, 5 ’R)-7-chl oro-3 ’ ,4-dimethoxy-6-[ 1 -(2-methoxy ethyl) pyrazol-3 -y 1 ] -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’-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-chl oro-3 ’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’ -methyl-spiro [benzofuran-2, 4 ’ -cy cl ohex -2-ene] - 1’ , 3 -di one; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro [benzofuran-2, 4’-cy cl ohex -2-ene]-!’, 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’-cycl ohex -2-ene]- 1’, 3-dione.

27. The method of claim 26, 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]- 1’, 3-dione or a pharmacologically acceptable salt thereof.

28. The method of claim 26, 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.

29. The method of claim 26, 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.

30. The method of claim 26, 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’ -cy cl ohex- 2-ene]-l’, 3-dione or a pharmacologically acceptable salt thereof.

31. The method of claim 26, 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’-cycl ohex-2-ene]- 1’, 3-dione or a pharmacologically acceptable salt thereof.