Compositions and methods for improving memory and cognition

Abstract

The present invention relates to a method for improving memory function, cognitive function, and learning function by administering a compound of formula 1 to a subject in need of improving the memory function, cognitive function, and learning function. The present invention further relates to a method for delaying or retarding the loss of memory function, cognitive function, and learning function by administering a compound of formula 1 to a subject in need of delaying or retarding the loss of the memory function, cognitive function, and learning function.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 393,049, filed on July 28, 2022, the entire content of which is incorporated herein by reference.

[0002] The present invention relates to a method for improving memory function, cognitive function, and learning function by administering a compound of Formula 1 to a subject in need of improving the memory function, cognitive function, and learning function. The present invention further relates to a method for delaying or slowing the loss of memory function, cognitive function, and learning function by administering a compound of Formula 1 to a subject in need of delaying or slowing the loss of the memory function, cognitive function, and learning function.

Background Art

[0003] Brain function, particularly memory and cognition, is extremely important for people of all ages to carry out their daily lives. Optimal memory and cognition are required for the performance of tasks such as learning and work.

[0004] Memory, cognitive, and learning functions naturally decline with aging due to brain atrophy and shrinkage. The decline can be associated with neurological diseases and brain injuries.

Summary of the Invention

Problems to be Solved by the Invention

[0005] In the art, there is a need for effective treatments for improving memory, cognitive function, and learning function, or for delaying the loss of memory, cognitive function, and learning function.

Means for Solving the Problems

[0006] The present invention is based on the determination that the compounds of the present invention act on the improvement of physiological properties associated with cognition and memory, for example, enhancement of neurotransmission in the hippocampus, improvement of scopolamine-induced cognitive impairment, improvement of cognitive impairment involved in NMDA receptor hypofunction, and increase in long-term potentiation. Furthermore, the compounds of the present invention have been shown to improve concentration and decision-making in clinical trials.

[0007] Accordingly, one aspect of the present invention is a method for improving a memory function, a cognitive function, and / or a learning function in a subject in need of improving the memory function, the cognitive function, and / or the learning function, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof: [Chemical formula] Wherein, R 1 is a C1-C6 alkyl group which may be substituted with the same or different 1-2 substituents selected from substituent X, a C3-C6 cycloalkyl group which may be substituted with the same or different 1-2 substituents selected from substituent X, or a 4-7 membered saturated heterocyclic group which may be substituted with the same or different 1-2 substituents selected from substituent X and R 2 is a C1-C6 alkyl group which may be substituted with the same or different 1-2 substituents selected from substituent X, a C3-C6 cycloalkyl group which may be substituted with the same or different 1-2 substituents selected from substituent X, or a 4-7 membered saturated heterocyclic group which may be substituted with the same or different 1-2 substituents selected from substituent X and A is a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, an 8-10 membered fused aromatic heterocycle, 5- to 7-membered unsaturated heterocyclic ring, 4- to 7-membered saturated heterocyclic ring, benzene ring, -CH=, or a cyano group, provided that when A is a cyano group, R 3 and R 3’ do not exist, and R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, a C1-C6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C1-C6 alkoxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C2-C6 alkenyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C2-C6 alkynyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C3-C6 cycloalkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, an amino group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C1-C6 alkoxycarbonyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a carbamoyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a phenyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a 5-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a 6-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X A 5- to 7-membered unsaturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, or An 8- to 10-membered fused aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, or, R 3 and R 3’ may combine with each other to form, as a ring fused to A, a 5- to 7-membered unsaturated heterocyclic ring, a 4- to 7-membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring, where the ring may be substituted with the same or different 1 to 2 substituents selected from substituent X, Substituent 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 which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 5-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 6-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 4- to 7-membered saturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, A phenoxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, A 5-membered aromatic heterocyclic oxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, A 6-membered aromatic heterocyclic oxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, A 4- to 7-membered saturated heterocyclic oxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent 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 which may be substituted with the same or different 1 to 2 substituents selected from substituent 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 which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, A 5-membered aromatic heterocyclic carbonylamino group which may be substituted with the same or different 1 to 2 substituents selected from substituent Y, A 6-membered aromatic heterocyclic carbonylamino group optionally substituted with one or two identical or different substituents selected from substituent Y, or A C1-C6 alkylsulfonylamino group and Substituent Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxy group. Thereby, the memory function, cognitive function and / or learning function in the subject are improved.

[0008] Another aspect of the present invention is a method for delaying or retarding the decline of memory function, cognitive function and / or learning function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula 1 below or a pharmaceutically acceptable salt thereof:

Chemical formula

[0009] The present invention additionally relates to a method of using the compound of the present invention for improving memory function, cognitive function and / or learning function.

[0010] The present invention further relates to a method of using the compound of the present invention for delaying or retarding the decline of memory function, cognitive function and / or learning function.

[0011] The present invention additionally relates to a method of using the compound of the present invention in the preparation of a medicament for improving memory function, cognitive function and / or learning function.

[0012] The present invention further relates to a method of using the compound of the present invention in the preparation of a medicament for delaying or retarding the decline of memory function, cognitive function and / or learning function.

[0013] These and other aspects of the present invention are described in more detail in the following description of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0014]

Figure 1

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Mode for Carrying Out the Invention

[0015] The present invention will be described in more detail below. This description is not intended to be an exhaustive listing of all the various ways in which the invention may be implemented or of all the features that may be added to the invention. For example, features illustrated with respect to one embodiment may be incorporated within other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Additionally, numerous modifications and additional examples to the various embodiments suggested herein will be apparent to those skilled in the art in light of the present disclosure, but do not depart from the invention. Accordingly, the following specification is for the purpose of exemplifying some particular embodiments of the invention and is not intended to specifically identify all permutations, combinations, and variations thereof.

[0016] 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 invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted. By way of example, when the specification states that a composition includes components A, B, and C, it is specifically intended that any one of A, B, or C, or combinations thereof, can be omitted and excluded.

[0017] Unless defined otherwise, 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 terms used in the description of the invention herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the invention.

[0018] All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety for the teachings relevant to the passages and / or paragraphs to which the reference is made.

[0019] As used in the detailed description of the present invention and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0020] As used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted in the alternative ("or"), and encompasses them.

[0021] Furthermore, the present invention also contemplates that, in some embodiments of the present invention, any feature or combination of features described herein can be excluded or omitted.

[0022] Furthermore, as used herein, when the term "about" is referred to a measurable value, such as the amount, dosage, time, temperature, etc. of a compound or agent of the present invention, it is meant to encompass a variation of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

[0023] As used herein, the transitional phrase "consisting essentially of" should be interpreted to include the recited materials or steps that do not materially affect the basic and novel one or more features of the claimed invention. Therefore, the term "consisting essentially of" used herein should not be interpreted as equivalent to "comprising".

[0024] The terms "treat", "treating", or "treatment of" (or grammatically equivalent terms) mean reducing the severity of a condition of a subject, or at least partially improving or ameliorating it, and / or alleviating, reducing or decreasing at least one clinical symptom, and / or slowing the progression of a disease.

[0025] As used herein, the terms "prevent", "prevents", or "prevention" (and their grammatical equivalents) mean delaying or suppressing the onset of a disease. These terms do not mean to require the complete eradication of the disease, but rather include any kind of prophylactic treatment for reducing the occurrence of the disease or delaying the onset of the disease.

[0026] As used herein, a "therapeutically effective" amount is an amount sufficient to provide some improvement or benefit to a subject. Alternatively, a "therapeutically effective" amount is an amount that provides some alleviation, reduction, decrease, or stabilization in at least one clinical symptom in a subject. One of ordinary skill in the art will understand that the therapeutic effect need not be complete or curative so long as some benefit is provided to the subject.

[0027] As used herein, a "prophylactically effective" amount is an amount sufficient to prevent and / or delay the signs of a disease, disorder, and / or clinical symptom in a subject and / or to prevent and / or delay the severity of the signs of a disease, disorder, and / or clinical symptom in a subject as compared to what would occur in the absence of the method of the present invention. One of ordinary skill in the art will understand that the level of prevention need not be complete so long as some benefit is provided to the subject.

[0028] As used herein, "pharmaceutically acceptable" means a substance that is not biologically or otherwise undesirable, i.e., the substance can be administered to an individual with the compositions of the present invention without substantially causing harmful biological effects or interacting in a harmful manner with any of the other components of the composition in which it is contained. As will be well known to those skilled in the art, such substances will of course be selected to minimize any degradation of the active ingredients and to minimize any harmful side effects in the subject (see, e.g., Remington's Pharmaceutical Science: 21st Edition, 2005). Exemplary pharmaceutically acceptable carriers for the compositions of the present invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free saline.

[0029] "Simultaneously" means close enough in time to produce a combined effect (i.e., simultaneously can be all at once or can be two or more events that occur within a short period of time before and after each other). In some embodiments, administering two or more compounds "simultaneously" means that the two compounds are administered closely enough so that the presence of one changes the biological effect of the other in a timely manner. The two compounds can be in the same or different formulations or can be administered sequentially. Simultaneous administration can be effected by mixing the compounds prior to administration or by administering the compounds in two different formulations, e.g., at the same time but at different anatomical sites or using different routes of administration.

[0030] Memory is a process by which data or information is encoded, stored, and retrieved when needed. The memory processing system in the brain consists of a sensory processor, short-term memory (or working memory), and long-term memory. As used herein, the memory function refers to the level of memory that can be quantified in a memory performance test. Increases or decreases in the memory function can be quantified by repeatedly performing such tests.

[0031] Cognition refers to the mental act or process of acquiring knowledge and understanding through thought, experience, and the senses. It encompasses all aspects of intellectual functions and processes, such as perception, attention, thinking, intelligence, knowledge formation, memory, and working memory, judgment and evaluation, reasoning and calculation, problem-solving, and decision-making, understanding, as well as language generation. As used herein, the cognition function refers to the level of cognition that can be quantified in a cognition performance test. Increases or decreases in the cognition function can be quantified by repeatedly performing such tests.

[0032] Learning is a process of acquiring new understanding, knowledge, behavior, skills, values, and preferences. As used herein, the learning function refers to the learning level that can be quantified in a learning performance test. Increases or decreases in the learning function can be quantified by repeatedly performing such tests.

[0033] One aspect of the present invention relates to a method for improving a memory function, a cognition function, and / or a learning function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof:

Chemical formula

[0034] A further aspect of the present invention relates to a method for delaying or retarding the decline of a memory function, cognitive function and / or learning function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula 1 below or a pharmaceutically acceptable salt thereof: [Chemical formula] Here, R 1 is a C1-C6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C3-C6 cycloalkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, or a 4- to 7-membered saturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X and R 2 is a C1-C6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, a C3-C6 cycloalkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, or a 4- to 7-membered saturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X and A is a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, an 8- to 10-membered fused aromatic heterocyclic ring, a 5- to 7-membered unsaturated heterocyclic ring, a 4- to 7-membered saturated heterocyclic ring, a benzene ring, -CH=, or a cyano group, where when A is a cyano group, R 3 and R 3’ do not exist, and R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an oxo group, A C1-C6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A C1-C6 alkoxy group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A C2-C6 alkenyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A C2-C6 alkynyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, An amino group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A C1-C6 alkoxycarbonyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A carbamoyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A phenyl group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A 5-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A 6-membered aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A 5- to 7-membered unsaturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X, or An 8- to 10-membered condensed aromatic heterocyclic group which may be substituted with the same or different 1 to 2 substituents selected from substituent X wherein, or R 3 and R 3’may form a 5- to 7-membered unsaturated heterocyclic ring, a 4- to 7-membered saturated heterocyclic ring, or a C3-C6 cycloalkyl ring that is bonded to each other and condensed with A, where the ring may be substituted with the same or different 1 to 2 substituents selected from substituent X. Substituent 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 that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 5-membered aromatic heterocyclic group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 6-membered aromatic heterocyclic group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 4- to 7-membered saturated heterocyclic group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 halocycloalkoxy group, a phenoxy group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 5-membered aromatic heterocyclic oxy group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 6-membered aromatic heterocyclic oxy group that may be substituted with the same or different 1 to 2 substituents selected from substituent Y, a 4- to 7-membered saturated heterocyclic oxy group that may be substituted with the same or different 1 to 2 substituents selected from substituent 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 which may be substituted with the same or different one or two substituents selected from substituent 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 which may be substituted with the same or different one or two substituents selected from substituent Y, a 5-membered aromatic heterocyclic carbonylamino group which may be substituted with the same or different one or two substituents selected from substituent Y, a 6-membered aromatic heterocyclic carbonylamino group which may be substituted with the same or different one or two substituents selected from substituent Y, or a C1-C6 alkylsulfonylamino group and substituent Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxy group, whereby, in the subject, the decline of the memory function, the cognitive function and / or the learning function is retarded or slowed down.

[0035] The method of the present invention can be used for any subject that requires improving a memory function, a cognitive function, and / or a learning function, or that requires delaying or slowing down a decline in a memory function, a cognitive function, and / or a learning function. In some embodiments, the subject has normal (e.g., average) memory, cognitive, and / or learning functions compared to the general population. The subject may be a person seeking improvement in memory, cognition, and / or learning in order to enhance performance at school, at work, or in other situations. The subject may be a person who does not have a factor, such as a neurological disorder or a brain injury, that has caused or is causing a decline in memory, cognitive, and / or learning functions. The subject may be a person who does not have an age-related decline in memory, cognitive, and / or learning functions.

[0036] In some embodiments, the subject has a reduced memory function, cognitive function, and / or learning function as compared to the general population. The reduction may be due to aging. In some embodiments, the reduction is not due to aging. The reduction may be due to a factor, such as neuropathy or brain injury.Examples of factors associated with impaired memory, cognition, and / or learning include, but are not limited to, Alzheimer’s disease, attention deficit disorder, dementia with Lewy bodies disease, early onset dementia, epilepsy-related cognitive dysfunction, fronto-temporal dementia, mild cognitive impairment, normal pressure hydrocephalus, Parkinson’s disease-related cognitive dysfunction, posterior cortical atrophy, primary progressive aphasia, stroke-related cognitive dysfunction, traumatic brain injury, other psychiatric and / or neurologic disorder-related cognitive impairments (e.g., multiple sclerosis, schizophrenia, amyotrophic lateral sclerosis, Huntington’s disease, chronic depression), and chemotherapy-related cognitive impairment (chemo-brain).

[0037] The memory, cognitive, and learning functions can be measured by the well-known tests in the art, such as, but not limited to, the Stroop test, the Rey Auditory Verbal Learning Test (RAVLT), the Wechsler Adult Intelligence Scale (WAIS) test, Memex 100, the Mini-Mental Status, Activities of Daily Living, Clinical Dementia Rating, or combinations thereof. These tests may be repeated to quantify the changes in memory, cognition, and learning over time.

[0038] In some embodiments, the method of the invention can improve the memory, cognitive, and / or learning functions by at least 5%, such as at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, relative to the baseline before treatment. In some embodiments, the method of the invention can slow the loss of memory, cognitive, and / or learning functions by at least 5%, such as at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to a subject not receiving treatment. In some embodiments, the method of the invention can delay the loss of memory, cognitive, and / or learning functions by at least 1 month, such as at least 3 months, at least 6 months, at least 1 year, or more, relative to a subject not receiving treatment.

[0039] In some embodiments, the compound of Formula 1 is any one compound selected from the following group: (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]deca-2-en-3-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]deca-2-en-3-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; or, (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione.

[0040] In some embodiments, the compound of formula 1 is a compound of formula 1’ or a pharmaceutically acceptable salt thereof:

Chem.

[0041] In some embodiments of the compound of Formula 1 or Formula 1', R 1 is a C1-C6 alkyl group, R2 is a C1-C6 alkyl group, A is a 5-membered aromatic heterocyclic ring, and R 3 and R 3’ are each independently a hydrogen atom or a C1-C6 alkyl group.

[0042] In some embodiments of the compound of Formula 1 or Formula 1', R 1 is a methyl group, an ethyl group or a hydroxyethyl group.

[0043] In some embodiments of the compound of Formula 1 or Formula 1', R 2 is a methyl group.

[0044] In some embodiments of the compound of Formula 1 or Formula 1', A is a 5-membered aromatic heterocyclic ring, R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group or a methoxy C1-C3 alkyl group, and R 3’ is a hydrogen atom.

[0045] In some embodiments, the compound of Formula 1 is a compound of Formula 1'' or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0046] In some embodiments, the compound of Formula 1' is any compound selected from the following group: (2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl)-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3’-methoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3’-methoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(2-hydroxyethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazol-2-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-4-(difluoromethoxy)-3’-methoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]deca-2-en-3-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]deca-2-en-3-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxypyrimidin-5-yl)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(6-methoxy-3-pyridyl)-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(3-pyridyl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; or, (2S,5’R)-7-chloro-3’,4,6-trimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione.

[0047] In one embodiment, the compound is (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4-dimethoxy-5’-methyl-spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmaceutically acceptable salt thereof.

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

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

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

[0052] In certain embodiments, the 5-membered aromatic heterocycle for A is the same as those described above, but more preferably, it represents the following 5-membered ring. (In this case, R 3’It should be noted that it does not exist.)

Chem.

[0053] In this specification, the "5-membered aromatic heterocyclic ring" is a monocyclic 5-membered aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. For example, rings as shown below can be mentioned.)

Chem.

[0054] In this specification, the "6-membered aromatic heterocyclic ring" is a monocyclic 6-membered aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. For example, rings as shown below can be mentioned.)

Chem.

[0055] In this specification, the "8- to 10-membered fused aromatic heterocyclic ring" is an 8- to 10-membered fused aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. For example, rings as shown below can be mentioned.)

Chem.

[0056] In this specification, the "5- to 7-membered unsaturated heterocyclic ring" refers to a ring in which a monocyclic 5- to 7-membered saturated heterocyclic ring is partially oxidized, or a ring in which an aromatic heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom is partially reduced. For example, rings as shown below can be mentioned.)

Chem.

[0057] In this specification, the "4- to 7-membered saturated heterocyclic ring" refers to a monocyclic 4- to 7-membered saturated heterocyclic ring containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. For example, rings such as those shown below can be mentioned.

Chemical formula

[0058] The "halogen atom" in this specification refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom.

[0059] The "C1-C6 alkyl group" in this specification refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof are a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, and a 2,3-dimethyl-1-butyl group, and it is preferably a methyl group or an ethyl group.

[0060] The "C2-C6 alkenyl group" in this specification refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, which may have one or more 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.

[0061] As used herein, the term "C2-C6 alkynyl group" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, which may have one or more or two or more carbon-carbon triple bonds. For example, it may be an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 1-pentynyl group, 2-pentynyl group or 1-hexynyl group, preferably an ethynyl group or 1-propynyl group.

[0062] As used herein, the term "C1-C6 alkoxy group" refers to a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include a methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, 2-methyl-1-propoxy group, 2-methyl-2-propoxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-2-butoxy group, 3-methyl-2-butoxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl-1-pentyloxy group and 3-methyl-1-pentyloxy group. Preferably, it is a methoxy group, ethoxy group, 1-propoxy group or 2-propoxy group.

[0063] As used herein, the term "C3-C6 cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, preferably a cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.

[0064] As used herein, the term "hydroxy C1-C6 alkyl group" refers to a group in which a hydroxyl group is bonded to a C1-C6 alkyl group. For example, it may be a hydroxymethyl group or hydroxyethyl group.

[0065] As used herein, the term "C1-C6 alkoxy C1-C6 alkyl group" refers to a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, methoxyethyl group, ethoxymethyl group and ethoxyethyl group.

[0066] As used herein, the term "C1-C6 haloalkyl group" refers to a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include fluoromethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-bromoethyl group, 2-chloroethyl group, 2-iodoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, trichloroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 3-chloropropyl group, and 4-fluorobutyl group. It is preferably a trifluoromethyl group.

[0067] As used herein, the term "C3-C6 halocycloalkyl group" refers to a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include fluorocyclopropyl group, fluorocyclobutyl group, fluorocyclopentyl group, and fluorocyclohexyl group.

[0068] As used herein, the term "C1-C6 haloalkoxy group" refers to a group in which a halogen atom is bonded to a C1-C6 alkoxy group. Examples thereof include fluoromethoxy group, difluoromethoxy group, dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 2-fluoroethoxy group, 2-bromoethoxy group, 2-chloroethoxy group, 2-iodoethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, trichloroethoxy group, pentafluoroethoxy group, 3-fluoropropoxy group, 3-chloropropoxy group, and 4-fluorobutoxy group. It is preferably a trifluoromethoxy group.

[0069] As used herein, the term "C3-C6 cycloalkoxy group" refers to a group in which a 3-C6 cycloalkyl group is bonded to an oxygen atom, and it is preferably a cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, or cyclohexyloxy group.

[0070] As used herein, the term "C3-C6 halocycloalkoxy group" refers to a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, examples of which include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.

[0071] As used herein, the term "5-membered aromatic heterocyclic oxy group" refers to a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0072] As used herein, the term "6-membered aromatic heterocyclic oxy group" refers to a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom.

[0073] As used herein, the term "4-7 membered saturated heterocyclic oxy group" refers to a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom.

[0074] As used herein, the term "C1-C6 alkoxycarbonyl group" refers to a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, examples of which include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

[0075] As used herein, the term "C3-C6 cycloalkoxycarbonyl group" refers to a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, which is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.

[0076] As used herein, the term "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group is bonded to a carbonyl group, examples of which include a methylcarbonyl group, an ethylcarbonyl group, or a propylcarbonyl group.

[0077] As used herein, the term "mono(C1-C6 alkyl)aminocarbonyl group" refers to a group in which one C1-C6 alkyl group is bonded to the amino group of the aminocarbonyl group, and it is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group or a propylaminocarbonyl group.

[0078] As used herein, the term "di(C1-C6 alkyl)aminocarbonyl group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminocarbonyl group, and it is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group or a dipropylaminocarbonyl group.

[0079] As used herein, the term "mono(C1-C6 alkyl)aminosulfonyl group" refers to a group in which one C1-C6 alkyl group is bonded to the amino group of the aminosulfonyl group, and it is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group or a propylaminosulfonyl group.

[0080] As used herein, the term "di(C1-C6 alkyl)aminosulfonyl group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group or a dipropylaminosulfonyl group.

[0081] As used herein, the term "mono(C1-C6 alkyl)amino group" refers to a group in which one C1-C6 alkyl group is bonded to the amino group, and it is preferably a methylamino group, an ethylamino group or a propylamino group.

[0082] As used herein, the term "di(C1-C6 alkyl)amino group" refers to a group in which two C1-C6 alkyl groups are bonded to the amino group, and it is preferably a dimethylamino group, a diethylamino group or a dipropylamino group.

[0083] As used herein, the term "C1-C6 alkoxycarbonylamino group" refers to a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group. For example, it may be a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.

[0084] As used herein, the term "mono(C1-C6 alkyl)aminocarbonylamino group" refers to a group in which a mono(C1-C6 alkyl)aminocarbonyl group is bonded to an amino group, which is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.

[0085] As used herein, the term "di(C1-C6 alkyl)aminocarbonylamino group" refers to a group in which a di(C1-C6 alkyl)aminocarbonyl group is bonded to an amino group, which is preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.

[0086] As used herein, the term "5-membered aromatic heterocyclic carbonylamino group" refers to a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0087] As used herein, the term "6-membered aromatic heterocyclic carbonylamino group" refers to a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0088] As used herein, the term "C1-C6 alkylsulfonylamino group" refers to a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, which is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.

[0089] "Pharmaceutically acceptable salt" refers to a salt that can be used as a pharmaceutical. When the compound has an acidic group or a basic group, the compound can be converted into a basic salt or an acidic salt by reacting with a base or an acid to form its salt.

[0090] The pharmaceutically acceptable "basic salts" of the compound are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt and picoline salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt, which are preferably alkali metal salts.

[0091] The pharmaceutically acceptable "acidic salts" of the compound are preferably inorganic acid salts such as hydrohalic acid salts (e.g., hydrofluoric acid salt, hydrochloride, hydrobromic acid salt and hydroiodic acid salt), nitrate, perchlorate, sulfate, and phosphate; organic acid salts such as lower alkanesulfonate salts such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonate salts such as benzenesulfonate and p-toluenesulfonate; acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt, which are most preferably hydrohalides (especially hydrochloride).

[0092] The compounds of the present invention or their pharmaceutically acceptable salts can become hydrates by absorbing moisture, adhering to adsorbed water, or being left in the air or recrystallized. The present invention also includes such various hydrates, solvates and crystalline polymorphs of the compounds.

[0093] The compounds of the present invention, their pharmaceutically acceptable salts or solvates may have various isomers, such as geometric isomers (e.g., cis and trans isomers), tautomers, or optical isomers (e.g., d- and l-isomers), depending on the type and combination of substituents. However, unless otherwise specified, the compounds include all of these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known separation means.

[0094] The compounds of the present invention also include labeled compounds, i.e., compounds in which one or more atoms of the compound are substituted with isotopes (e.g., 2H, 3H, 13C, 14C, 35S, etc.).

[0095] In addition, the present invention also includes prodrugs. The prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. of the compound by hydrolysis or under physiological conditions. Examples of groups that form such prodrugs include those described in Prog. Med., Vol. 5, pp. 2157-2161 (1985), etc. More specifically, as prodrugs, when an amino group is present in the compound, the amino group is acylated, alkylated or phosphorylated compounds (for example, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated or tert-butylated, etc. of the compound), etc. are mentioned. When a hydroxyl group is present in the compound, the hydroxyl group is acylated, alkylated, phosphorylated or borated compounds (for example, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated, etc. of the compound), etc. are mentioned. In addition, when a carboxy group is present in the compound, the carboxy group is esterified or amidated compounds (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, methylamidated compounds, etc. of the compound), etc. are mentioned.

[0096] The compounds of the present invention may be produced by synthetic methods known in the art, and are described in WO2017 / 170623 and WO2019 / 065928, which are incorporated herein by reference in their entirety.

[0097] Administration of the compounds of the present invention may be carried out by any oral administration such as tablets, pills, capsules, granules, powders, solutions, etc., or by any form of parenteral administration such as injections for intra-articular, intravenous, intrathecal, intraventricular, intramuscular, nasal, intravenous, intrathecal, intraventricular, intramuscular, intranasal, etc., suppositories, eye drops, eye ointments, transdermal absorption solutions, ointments, transdermal patches, transmucosal absorption solutions, transmucosal patches, inhalants, etc.

[0098] As solid compositions for oral administration, tablets, powders, granules, etc. are used. Such solid compositions are composed of one or more active ingredients and at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, etc. The solid composition may contain one or more inert additives, for example, lubricants (e.g., magnesium stearate), disintegrants (e.g., sodium carboxymethyl starch), stabilizers, and solubilizers, according to conventional methods. The tablets or pills may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary.

[0099] As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. are used. It is possible to add an inert diluent generally used, for example, purified water or ethanol, to such liquid compositions. The liquid composition may contain, in addition to the inert diluent, one or more of solubilizers, adjuvants (e.g., wetting agents), sweeteners, flavors, and preservatives.

[0100] For parenteral administration, injection preparations such as sterile aqueous solutions, non-aqueous solutions, suspensions, or emulsions are used. Examples of such aqueous solvents include distilled water for injection and physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), alcohols (such as ethanol, polysorbate 80), and the like. Such injection compositions may further contain one or more of tonicity agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These injection compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, application of a bactericide, or radiation irradiation. In addition, these injection compositions can be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent before use.

[0101] For external use, ointments, patches, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, etc. are used. These external preparations generally include commonly used ointment bases, lotion bases, aqueous solutions or non-aqueous solutions, suspensions, emulsions, and the like. For example, as the ointment base or lotion base, polyethylene glycol, propylene glycol, white petrolatum, beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. are used.

[0102] Transmucosal agents, such as inhalants and nasal agents, are used in solid, liquid, or semi-solid forms and can be manufactured according to commonly known methods. For example, one or more known excipients, and further, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. In these transmucosal agents, as the administration method, a device suitable for inhalation or pneumoperitoneum can be used. For example, the compound can be administered alone, or as a powder of a formulated mixture, or as a solution or suspension combined with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered-dose inhalers. Dry powder inhalers, etc. can be for single-dose or multiple-dose use, and dry powder or powder-containing capsules can also be used. Alternatively, a suitable ejector can be used. For example, it can be in the form of a pressurized aerosol spray using a suitable gas, such as chlorofluorocarbon, hydrofluorocarbon, or carbon dioxide gas.

[0103] In the case of ordinary oral administration, a suitable daily dose is about 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg. In some embodiments, a suitable daily dose is about 0.1 mg to about 500 mg, for example, about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg. This is administered in one dose or divided into two or more doses. In the case of intravenous administration, a suitable daily dose is about 0.0001 to 10 mg / kg based on body weight, and it is administered once a day or divided into several times a day. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg based on body weight is administered once a day or divided into several times a day. The dose is appropriately determined according to individual cases considering symptoms, age, gender, etc.

[0104] In the method of the present invention, the compound can be administered in combination with various therapeutic or prophylactic agents for diseases for which it is considered to exhibit its efficacy. The combination can be administered simultaneously, separately, in parallel, and continuously or at desired time intervals. The agents to be administered in combination may be blended or may be formulated separately. The therapeutic agent may be, for example, one that treats conditions that cause problems with memory, cognition, or learning, and includes benzodiazepines, anticholinergic drugs, antihistamines, opioids, proton pump inhibitors, antidepressants, antihypertensive drugs, sleep apnea treatment drugs, therapeutic agents that increase neurotransmitter levels (e.g., donepezil, galantamine, rivastigmine), memantine, aducanumab, and suvorexant.

[0105] The method of the present invention is used in both veterinary and medical applications. Suitable subjects include birds, reptiles, amphibians, fish, and mammals. The term "mammal" as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, etc.). Human subjects include neonates, infants, juveniles, and adults. Optionally, the subject is "in need of" the method of the present invention, for example, because the subject has or is at risk of having a disorder as described herein, or because the subject would benefit from the delivery of a compound as described herein. As a further option, the subject may be an experimental animal and / or a disease model animal. Preferably, the subject is a human.

[0106] Although the present invention has been described, it will be described in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the present invention.

[0107] Example 1

[0108] Physiological activity of Compound 1

[0109] Compound 1 (SP-624; DS-7830a; (2S,6’R)-7-chloro-2’,4-dimethoxy-6’-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[1-benzofuran-2,1’-cyclohex[a]ene]-3,4’-dione) was tested in multiple cognitive models. [Chemical formula]

[0110] Ex vivo electrophysiological experiments conducted on hippocampal slices of Sprague Dawley rats demonstrated that Compound 1 acts presynaptically to increase the frequency of miniature excitatory post-synaptic potentials (mEPSPs) in the hippocampus, enhance short-term plasticity (Figures 1 and 2), and tend to increase short-lasting long-term potentiation (Figure 3), suggesting that neurotransmitter release in the hippocampus is promoted. The effect of Compound 1 on enhancing mEPSPs may depend on the influx of extracellular calcium. The results suggest that the influx of extracellular calcium is mainly involved in P / Q-type and N-type calcium channels, and not in L-type calcium channels or protein kinase A. These findings indicate an enhancement of neuronal transmission in the hippocampus, a brain region involved in memory and cognitive functions.

[0111] To investigate the effect of Compound 1 on scopolamine-induced cognitive impairment in Long-Evans rats, a novel object recognition test (which evaluates visual learning and memory) was conducted. Donepezil was used as a positive control. Administration of 0.1 mg / kg scopolamine SC decreased the novelty discrimination index (NDI), an indicator of cognitive function (Figures 4 - 6). Administration of 0.1 and 1 mg / kg Compound 1 PO significantly improved the NDI decreased by scopolamine. This suggests that Compound 1 improves scopolamine-induced cognitive impairment.

[0112] To examine the effect of SP-624 on sub-chronic PCP-induced cognitive impairment in Wistar rats, a novel object recognition test was conducted. Clozapine was used as a positive control. Administration of 5 mg / kg sub-chronic PCP twice a day for 7 days by IP injection significantly decreased the NDI compared to sub-chronic vehicle treatment (Figures 7 - 9). Treatment with 0.1 and 1 mg / kg Compound 1, but not 0.01 mg / kg, significantly attenuated the sub-chronic PCP-induced cognitive deficit in NDI. This result suggests that Compound 1 improves cognitive impairment associated with decreased function of the NMDA receptor.

[0113] A freely behaving rodent model of long-term potentiation (LTP), a form of synaptic plasticity that has been frequently studied, was used. LTP is a persistent increase in the strength of synaptic connections between neurons and is a cellular mechanism widely considered to underlie the processes of learning and memory. Compound 1 increased LTP at 0.01 and 0.1 mg / kg IV compared to vehicle control (Figures 10 - 11). The results indicate that Compound 1 can have a positive effect on cognition.

[0114] Example 2

[0115] Clinical trial of Compound 1

[0116] A Phase 2 multi-site, double-blind, randomized, placebo-controlled trial was conducted to verify the safety and efficacy of SP-624 in the treatment of adults with major depressive disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). After successful completion of the screening phase, subjects were randomly assigned in a 1:1 ratio to one of two treatment groups, and received Compound 1 (SP-624) or placebo over a 4-week treatment period (Treatment Group #1: SP-624 20 mg / day, Treatment Group #2: placebo).

[0117] Prior to starting the 4-week treatment period, subjects completed a screening / baseline period of up to 28 days, during which all screening evaluations were performed and any current antidepressant medications were discontinued. All screening evaluations were completed prior to discontinuing any current antidepressant medications. Subjects returned for a Baseline Visit to complete efficacy and safety evaluations. During the treatment period, subjects returned to the study site to complete efficacy and safety evaluations at the end of Weeks 1, 2, 3, and 4. After the final dose of study drug, subjects completed a 2-week follow-up period and returned for visits at the end of Weeks 5 and 6. After completion of Week 5, subjects may be treated with antidepressants at the discretion of the physician.

[0118] Each dose of Compound 1 was supplied as two capsules, each containing 10 mg of active pharmaceutical ingredient (API). Placebo capsules of the same form and color as the active capsules were used.

[0119] The primary efficacy endpoint was the change from baseline to week 4 in the total score of the Montgomery-Asberg Depression Rating Scale (MADRS).

[0120] The secondary efficacy endpoints included the following: Change in the total MADRS score from baseline to weeks 1, 2, and 3, Change in the total score of the Clinical Global Impression-Severity (CGI-S) from baseline to weeks 1, 2, 3, and 4, Change in the total MADRS score and total CGI-S score from baseline to week 5, and change from week 4 to week 5, Change in the total score of the 17-item Hamilton Depression Rating Scale (HAM D-17) from baseline to weeks 2 and 4, Change in the Sheehan Disability Scale (SDS) from baseline to weeks 2 and 4, Change in the Quick Inventory of Depressive Symptomology-Self Report (QIDS-SR) from baseline to weeks 2 and 4, and Change in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) from baseline to weeks 2 and 4.

[0121] The demographics of the study population are shown in Table 1 below.

[0122]

Table 1

[0123] In this study, several measurements related to cognitive function were conducted. The first one is item number 10 of QIDS-SR, "Concentration / Decision-making". The response scale is as follows: 0 - No change in normal concentration or decision-making ability; 1 - Sometimes becoming indecisive or having a scattered attention; 2 - Mostly having difficulty concentrating or making decisions; 3 - Not having enough concentration to read or unable to make even trivial decisions. The results are shown in Figure 12 and Table 2 below. The data indicates that there was a significant improvement in the scores of the subjects administered with Compound 1 by the 4th week of administration.

[0124] [Table 2]

[0125] The second measurement of cognitive function is item number 17 of HAM-D, "Retardation" (slowness of thinking and conversation, decreased concentration, decreased motor activity). The response scale is as follows: 0 - Normal speech and thinking; 1 - Slight retardation during the interview (mild psychomotor retardation); 2 - Obvious retardation during the interview (moderate, some difficulty in the interview, and significant retardation in thinking); 3 - Difficulty in the interview (severe psychomotor retardation, for a very long time); 4 - Complete stupor (extreme retardation, almost impossible to conduct the interview). The results are shown in Figure 13 and Table 3 below. The data indicates that there was a significant improvement in the scores of the subjects administered with Compound 1 by the 4th week of administration.

[0126] [Table 3]

[0127] The third cognitive function measurement is the MADRS item number 6 "Concentration disorder" (difficulty in summarizing thoughts, lack of concentration, evaluated according to the strength, frequency and degree of resulting weakness). The response scale is as follows: 0 - no problem with concentration, 1 - blank, 2 - sometimes difficult to summarize thoughts, 3 - blank, 4 - difficult to concentrate and sustain thoughts, thereby reducing the ability to read or continue a conversation, 5 - blank, 6 - extremely difficult, unable to read or converse. The results are shown in Figure 14 and Table 4 below. The data indicates that there was a significant improvement in the core in subjects administered Compound 1 at all measurement times up to week 5.

[0128]

Table 4

[0129] The foregoing examples illustrate the present invention and should not be construed as limiting the present invention. Although the present invention has been described in detail with reference to preferred embodiments, there are variations and modifications within the scope and spirit of the present invention as set forth and defined in the appended claims.

Claims

1. In subjects requiring improvement of memory function, cognitive function and / or learning function, an agent used to improve said memory function, cognitive function and / or learning function, comprising a therapeutically effective amount of the compound of the following formula 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 Here, R 1 teeth, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, R 2 teeth, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, A 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 8-10 member condensed aromatic heterocycle, 5- to 7-membered unsaturated hetero rings, 4- to 7-membered saturated hetero rings, Benzene ring, -CH=, or, A cyano group, where A is a cyano group, R 3 and R 3’ It does not exist. and R 3 and R 3’ Each is independent of the others. hydrogen atom, halogen atom, Cyano group, Hydroxyl group, Oxo group, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxy group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkynyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X. An amino group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxycarbonyl group which may be substituted with one or two identical or different substituents selected from substituent X, A carbamoyl group which may be substituted with one or two identical or different substituents selected from substituent X, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 5-7 member unsaturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, An 8-10 membered condensed aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, Or, R 3 and R 3’ These may form a 5-7 membered unsaturated heterocycle, a 4-7 membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused with A, where the ring may be substituted with one or two identical or different substituents selected from substituent X. The substituent X is halogen atom, Cyano group, Hydroxyl group, Oxo group, C1-C6 alkyl groups, Hydroxy C1-C6 alkyl groups, C1-C6 alkyl C1-C6 alkyl groups C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C3-C6 cycloalkoxy groups, C3-C6 halocycloalkoxy groups, A phenoxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxycarbonyl groups, C3-C6 cycloalkoxycarbonyl group, Carboxy group, C1-C6 alkylcarbonyl groups, C3-C6 cycloalkylcarbonyl group, A phenylcarbonyl group which may be substituted with one or two identical or different substituents selected from substituent Y, Carbamoyl group, Mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, Mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, Mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino groups, Mono(C1-C6 alkyl)aminocarbonylamino group, Di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino groups, A phenylcarbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkylsulfonylamino groups And, The substituent Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxyl group. This improves memory function, cognitive function and / or learning function in the subject. The aforementioned agent.

2. In subjects requiring delay or slowing of the decline of memory, cognitive, and / or learning functions, an agent used to delay or slow the decline of said memory, cognitive, and / or learning functions, wherein the agent comprises a therapeutically effective amount of the compound of formula 1 below or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 Here, R 1 is A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, R 2 teeth, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, A 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 8-10 member condensed aromatic heterocycle, 5- to 7-membered unsaturated hetero rings, 4- to 7-membered saturated hetero rings, Benzene ring, -CH=, or, A cyano group, where A is a cyano group, R 3 and R 3’ It does not exist. And, R 3 and R 3’ Each is independent of the others. hydrogen atom, halogen atom, Cyano group, Hydroxyl group, Oxo group, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxy group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkynyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X. An amino group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxycarbonyl group which may be substituted with one or two identical or different substituents selected from substituent X, A carbamoyl group which may be substituted with one or two identical or different substituents selected from substituent X, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 5-7 member unsaturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, An 8-10 membered condensed aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, Or, R 3 and R 3’ These may form a 5-7 membered unsaturated heterocycle, a 4-7 membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring bonded to each other and condensed with A, where the ring may be substituted with one or two identical or different substituents selected from substituent X. The substituent X is halogen atom, Cyano group, Hydroxyl group, Oxo group, C1-C6 alkyl groups, Hydroxy C1-C6 alkyl groups, C1-C6 alkyl C1-C6 alkyl groups C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C3-C6 cycloalkoxy groups, C3-C6 halocycloalkoxy groups, A phenoxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxycarbonyl groups, C3-C6 cycloalkoxycarbonyl group, Carboxy group, C1-C6 alkylcarbonyl groups, C3-C6 cycloalkylcarbonyl group, A phenylcarbonyl group which may be substituted with one or two identical or different substituents selected from substituent Y, Carbamoyl group, Mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, Mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, Mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino groups, Mono(C1-C6 alkyl)aminocarbonylamino group, Di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino groups, A phenylcarbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkylsulfonylamino groups And, The substituent Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxyl group. This slows down or delays the decline in memory function, cognitive function and / or learning function in the subject. The aforementioned agent.

3. The agent according to claim 1 or 2, wherein the subject does not have nerve damage or brain injury.

4. The agent according to claim 1 or 2, wherein the subject has normal memory function, cognitive function and / or learning function compared to the general population.

5. The agent according to claim 1 or 2, wherein the subject has reduced memory function, cognitive function, and / or learning function compared to the general population.

6. The agent according to claim 5, wherein the aforementioned declined memory function, cognitive function and / or learning function is due to aging.

7. A, R 3 or R 3’ In the above, the 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group is the following group: 【Transformation 3】 The agent according to claim 1 or 2, which is one selected from the following.

8. A, R 3 or R 3’ In the above, the 6-membered aromatic heterocyclic ring or the 6-membered aromatic heterocyclic group is the following group: 【Chemistry 4】 The agent according to claim 1 or 2, which is one selected from the following.

9. A, R 3 or R 3’ In the above, the 8-10 member condensed aromatic heterocycle or the 8-10 member condensed aromatic heterocycle group is the following group: 【Transformation 5】 The agent according to claim 1 or 2, which is one selected from the following.

10. A, R 3 or R 3’ In the above, the 5- to 7-membered unsaturated heterocycle or 5- to 7-membered unsaturated heterocyclic group belongs to the following group: 【Transformation 6】 The agent according to claim 1 or 2, which is one selected from the following.

11. A, R 1 , R 2 or R 3 In the above, the 4- to 7-membered saturated heterocycle or the 4- to 7-membered saturated heterocycle group is one of the following groups: 【Transformation 7】 The agent according to claim 1 or 2, which is one selected from the following.

12. The compounds in Formula 1 belong to the following group: (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazole-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazole-2-yl]spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazole-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazole-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazole-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazole-5-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazole-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]deca-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]deca-2-en-3-yl)spiro[benzofuran-2,4'-cyclohexa-2-en]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidine-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; or, (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione The agent according to claim 1 or 2, which is selected from any of the following.

13. The agent according to claim 1 or 2, wherein the compound of formula 1 is the compound of formula 1' below or a pharmaceutically acceptable salt thereof: 【Transformation 8】 Here, R 1 but, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, R 2 but, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A 4- to 7-membered saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, A 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 8-10 member condensed aromatic heterocycle, 5- to 7-membered unsaturated hetero rings, 4- to 7-membered saturated hetero rings, Benzene ring, or, A single bond, where A is a single bond, R 3 and R 3’ Neither one nor the other exists. And, R 3 and R 3’ Each is independent of the others. hydrogen atom, halogen atom, Cyano group, Hydroxyl group, A C1-C6 alkyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxy group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C2-C6 alkynyl group which may be substituted with one or two identical or different substituents selected from substituent X, A C3-C6 cycloalkyl group which may be substituted with one or two identical or different substituents selected from substituent X. An amino group which may be substituted with one or two identical or different substituents selected from substituent X, A C1-C6 alkoxycarbonyl group which may be substituted with one or two identical or different substituents selected from substituent X, A carbamoyl group which may be substituted with one or two identical or different substituents selected from substituent X, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent X, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 5-7 member unsaturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X, An 8-10 membered condensed aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent X. And, Or, R 3 and R 3’ These may form a 5-7 membered unsaturated heterocycle, a 4-7 membered saturated heterocycle, or a C3-C6 cycloalkyl ring as a ring bonded to each other and condensed with A, where the ring may be substituted with one or two identical or different substituents selected from substituent X. The substituent X is halogen atom, Cyano group, Hydroxyl group, Oxo group, C1-C6 alkyl groups, Hydroxy C1-C6 alkyl groups, C1-C6 alkyl C1-C6 alkyl groups C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, A phenyl group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C3-C6 cycloalkoxy groups, C3-C6 halocycloalkoxy groups, A phenoxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, A 4-7 member saturated heterocyclic oxy group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkoxycarbonyl groups, C3-C6 cycloalkoxycarbonyl group, Carboxy group, C1-C6 alkylcarbonyl groups, C3-C6 cycloalkylcarbonyl group, A phenylcarbonyl group which may be substituted with one or two identical or different substituents selected from substituent Y, Carbamoyl group, Mono(C1-C6 alkyl)aminocarbonyl group, di(C1-C6 alkyl)aminocarbonyl group, Mono(C1-C6 alkyl)aminosulfonyl group, di(C1-C6 alkyl)aminosulfonyl group, amino group, Mono(C1-C6 alkyl)amino group, di(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonylamino groups, Mono(C1-C6 alkyl)aminocarbonylamino group, Di(C1-C6 alkyl)aminocarbonylamino group, C1-C6 alkylcarbonylamino groups, A phenylcarbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A five-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, A six-membered aromatic heterocyclic carbonylamino group which may be substituted with one or two identical or different substituents selected from substituent Y, C1-C6 alkylsulfonylamino groups And, The substituent Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, or a hydroxyl group.

14. R 1 The agent according to claim 13, wherein the group is a methyl group, an ethyl group, or a hydroxyethyl group.

15. R 2 The agent according to claim 13, wherein is a methyl group.

16. A, R 3 or R 3’ The 5-membered aromatic heterocyclic ring or the 5-membered aromatic heterocyclic group in the above is the following group: 【Chemistry 9】 The agent according to claim 13, which is one of the following selected from.

17. A, R 3 or R 3’ The 6-membered aromatic heterocycle or the 6-membered aromatic heterocyclic group in the above is the following group: 【Chemistry 10】 The agent according to claim 13, which is one of the following selected from:

18. A, R 3 or R 3’ The 5-7 member unsaturated heterocycle or 5-7 member unsaturated heterocyclic group in the above is one of the following groups: 【Chemistry 11】 The agent according to claim 13, which is one of the following selected from.

19. A, R 1 , R 2 or R 3 The 4- to 7-membered saturated heterocycle or the 4- to 7-membered saturated heterocycle group in the above is the following group: 【Chemistry 12】 The agent according to claim 13, which is one of the following selected from:

20. A is a 5-membered aromatic heterocycle, and R 3 However, R is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group or a methoxy C1-C3 alkyl group, and 3’ The agent according to claim 13, wherein is a hydrogen atom.

21. A is based on the following: 【Chemistry 13】 Here, * indicates a bonding group. The agent according to claim 13, wherein the ring is selected from any of the rings, and in the case of two bonding groups, R3' is absent.

22. The agent according to claim 13, wherein the compound of formula 1 is the compound of formula 1'' below or a pharmaceutically acceptable salt thereof: 【Chemistry 14】 Here, R 1 is a methyl group or an ethyl group; R 2 is a methyl group; A is based on the following: 【Chemistry 15】 * indicates a bonding group. It is one of the rings selected from; and, R 3 However, it is either a methyl group or an ethyl group.

23. The agent according to claim 13, 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'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazole-3-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1-ethylpyrazole-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazole-5-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl)-1,2,4-oxadiazole-3-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazole-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazole-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazole-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazole-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazole-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazole-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazole-5-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazole-3-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazole-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazole-2-yl]spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[5-(4-fluoro-1-methyl-4-piperidyl)-1,3,4-oxadiazole-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazole-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazole-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazole-5-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazole-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-(1,8-dioxa-2-azaspiro[4.5]deca-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]deca-2-en-3-yl)spiro[benzofuran-2,4'-cyclohexa-2-en]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxypyrimidine-5-yl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione; or, (2S,5'R)-7-chloro-3',4,6-trimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione.

24. The agent according to claim 23, wherein the compound is (2S,5'R)-7-chloro-6-(1-ethylpyrazole-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

25. The agent according to claim 23, wherein the compound is (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

26. The agent according to claim 23, wherein the compound is (2S,5'R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazole-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

27. The agent according to claim 23, wherein the compound is (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

28. The agent according to claim 23, wherein the compound is (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-yl)spiro[benzofuran-2,4'-cyclohexa-2-ene]-1',3-dione or a pharmaceutically acceptable salt thereof.

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