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 thereof. The present invention also relates to a method of delaying or slowing the loss of memory, cognitive and learning functions by administering a compound of Formula 1 to a subject in need thereof.

Description

[0001] Priority declaration

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 393,049, filed on July 28, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] 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 thereof. The present invention also relates to a method for delaying or slowing down the loss of memory function, cognitive function and learning function by administering a compound of formula 1 to a subject in need thereof. Background Art

[0004] Brain function, especially memory and cognition, is essential for daily life for people of all ages. Tasks such as learning and work performance require optimal memory and cognition.

[0005] Memory, cognition, and learning function naturally decline with age due to brain atrophy and shrinkage. Declines can also be associated with neurological disorders and brain damage.

[0006] Griseofulvin derivatives with anti-inflammatory activity have been developed and disclosed for use in the treatment of inflammatory diseases, including central inflammatory diseases, such as neurodegenerative diseases. See WO 2017 / 170623 and WO 2019 / 065928.

[0007] There is a need in the art for effective treatments to improve memory, cognitive function, and learning function, or to delay the loss of memory, cognitive function, and learning function. Summary of the invention

[0008] The present invention is based on the following determination: the compounds of the present invention can improve physiological characteristics related to cognition and memory, such as enhancing neuronal transmission in the hippocampus, improving cognitive impairment induced by scopolamine, alleviating cognitive deficits associated with NMDA receptor hypofunction, and improving long-term potentiation. In addition, the compounds of the present invention have been shown in clinical studies to improve the ability to focus and make decisions.

[0009] Therefore, one aspect of the present invention relates to a method for improving the memory function, cognitive function and / or learning function of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby improving the memory function, cognitive function and / or learning function of the subject:

[0010]

[0011] in:

[0012] R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0013] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0014] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0015] R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0016] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0017] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0018] A is a 5-membered aromatic heterocyclic ring,

[0019] 6-membered aromatic heterocycle,

[0020] 8-10 membered fused aromatic heterocyclic ring,

[0021] 5-7 membered unsaturated heterocyclic ring,

[0022] 4-7 membered saturated heterocyclic ring,

[0023] benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist,

[0024] R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxydimethylene group,

[0025] C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0026] C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different,

[0027] C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0028] C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0029] C3-C6 cycloalkyl group optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0030] an amino group optionally substituted by the same or different one to two substituents selected from substituent group X,

[0031] a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0032] a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0033] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0034] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0035] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0036] a 5- to 7-membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0037] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0038] an 8-10 membered fused aromatic heterocyclic group optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, or

[0039] R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0040] The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxydeoxy 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,

[0041] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y,

[0042] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0043] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0044] a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0045] C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy,

[0046] a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y,

[0047] a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0048] a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0049] a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0050] C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl,

[0051] a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0052] carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino,

[0053] a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0054] a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0055] a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or

[0056] C1-C6 alkylsulfonylamino,

[0057] Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

[0058] Another aspect of the present invention relates to a method for delaying or slowing down the decline of memory function, cognitive function and / or learning function of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby delaying or slowing down the decline of memory function, cognitive function and / or learning function of the subject:

[0059]

[0060] in:

[0061] R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0062] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0063] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0064] R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0065] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0066] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0067] A is a 5-membered aromatic heterocyclic ring,

[0068] 6-membered aromatic heterocycle,

[0069] 8-10 membered fused aromatic heterocyclic ring,

[0070] 5-7 membered unsaturated heterocyclic ring,

[0071] 4-7 membered saturated heterocyclic ring,

[0072] benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist,

[0073] R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxydimethylene group,

[0074] C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0075] C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different,

[0076] C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0077] C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0078] C3-C6 cycloalkyl group optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0079] an amino group optionally substituted by the same or different one to two substituents selected from substituent group X,

[0080] a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0081] a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0082] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0083] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0084] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0085] a 5- to 7-membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0086] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0087] an 8-10 membered fused aromatic heterocyclic group optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, or

[0088] R 3 and R 3’may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0089] The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxydeoxy 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,

[0090] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y,

[0091] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0092] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0093] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0094] C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy,

[0095] a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y,

[0096] a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0097] a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0098] a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0099] C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl,

[0100] a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0101] carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino,

[0102] a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0103] a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0104] a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or

[0105] C1-C6 alkylsulfonylamino,

[0106] Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

[0107] The present invention also relates to the use of the compound of the present invention for improving memory function, cognitive function and / or learning function.

[0108] The present invention also relates to the use of the compound of the present invention for delaying or slowing down the decline of memory function, cognitive function and / or learning function.

[0109] The present invention also relates to the use of the compound of the present invention in preparing a drug for improving memory function, cognitive function and / or learning function.

[0110] The present invention also relates to the use of the compound of the present invention in the preparation of a drug for delaying or slowing down the decline of memory function, cognitive function and / or learning function.

[0111] These and other aspects of the invention will be described in more detail in the following description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] Figure 1 The paired pulse ratio (PPF index defined as the slope of fEPSP2 / fEPSP1) at the interstimulus interval of 50-400ms is shown in rats after infusion with compound 1 (10nM) or vehicle (0.01% DMSO) or positive control (30μM dopamine). The response is from the stratum radiatum of the CA1 region of the hippocampus when using Schaffer collateral stimulation. The statistical difference corresponds to the difference in the measured values ​​between the 10nM compound 1 and vehicle groups;

[0113] Figure 2 Paired pulse ratios at 50-400 ms interstimulus intervals are shown in rats infused with Compound 1 (100 nM) or vehicle (0.01% DMSO) or positive control (30 μM dopamine). Responses were from the stratum radiatum of the CA1 region when Schaffer collateral stimulation was used. Statistical differences correspond to the difference in measured values ​​between the 100 nM Compound 1 and vehicle groups;

[0114] Figure 3 The time course of the average slope of the field response evoked after induction of short-lasting long-term potentiation (S-LTP) by a single 1-second train of 100-Hz stimulation of hippocampal CA1 synapses in rats infused with compound 1 (10 nM), vehicle (0.01% DMSO) or positive control (30 μM dopamine) is shown. Time point 0 represents the delivery of HFS. The slope of fEPSP is normalized to the baseline and plotted against time;

[0115] Figure 4 The total exploration time in the acquisition test of the novel object recognition test in rats is shown. The total exploration time of two identical objects in the acquisition test was measured manually and expressed as mean ± SEM (n = 8). After one-way ANOVA, there was no statistical difference in the total exploration time between different groups (P = 0.115);

[0116] Figure 5 The effect of compound 1 in the novel object recognition test in rats is shown. NDI was calculated using the following formula: novel object interaction time / total interaction time × 100 (%). Data are expressed as mean ± SEM (n = 8). Significant differences from the control group are indicated by ***P < 0.001 (Student's t-test). Significant differences from the scopolamine-treated vehicle group are indicated by ##P < 0.01 (Dunnett's test). Significant differences from the scopolamine-treated vehicle group are indicated by means (Student's t-test);

[0117] Figure 6 The exploration time of familiar objects and novel objects in the retention test in the novel object recognition test of rats is shown. The exploration time of each object in the retention test was measured manually and expressed as the mean ± SEM (n = 8). The significant difference in the interaction with the familiar object is indicated by **P < 0.01, *P < 0.05 (paired t test);

[0118] Figure 7The total exploration time in the acquisition test of the novel object recognition test in rats is shown. The total exploration time of two identical objects in the acquisition test was measured manually and expressed as the mean ± SEM (n = 10). After one-way ANOVA, there was no statistical difference in the total exploration time between different groups (P = 0.340);

[0119] Figure 8 The effect of compound 1 in the novel object recognition test in rats is shown. NDI was calculated using the following formula: novel object interaction time / total interaction time × 100 (%). Data are expressed as mean ± SEM (n = 10). Significant differences from the control group are indicated by ***P < 0.001 (Student's t-test). Significant differences from the PCP-treated group are indicated by ##P < 0.01, #P < 0.05 (Dunnett's test). Significant differences from the PCP-treated group are indicated by means (Student's t-test);

[0120] Fig. 9 The exploration time of familiar objects and novel objects in the retention test in the novel object recognition test of rats is shown. The exploration time of each object in the retention test was measured manually and expressed as the mean ± SEM (n = 10). The significant difference of the interaction with the familiar object is indicated by ***P < 0.001, **P < 0.01 (paired t test);

[0121] Fig.10 The time course of the average amplitude of fEPSP in the stratum radiatum after long-term potentiation (LTP) was induced by 100 Hz stimulation (10 bursts of 10 stimuli, 0.1 ms stimulus duration, 10 s inter-burst interval) of the Schaffer collateral / commissural pathways in rats after administration of compound 1 (0.1 mg / kg, 0.01 mg / kg, 0.001 mg / kg) or vehicle (0.01% DMSO) or positive control (10 mg / kg memantine) is shown. The amplitude of fEPSP was normalized to the baseline and plotted against time;

[0122] Fig.11 The mean stratum radiatum fEPSP amplitudes of rats after administration of compound 1 (0.1 mg / kg, 0.01 mg / kg, 0.001 mg / kg) or vehicle (0.01% DMSO) or positive control (10 mg / kg memantine) during 3 baseline periods (Baseline 1, Baseline 2, Baseline 3), 60 minutes after HFT delivery (0-60 minutes after HFT), and 24 hours after HFT delivery (24 hours after HFT) are shown;

[0123] Fig.12The results of the Quick Inventory of Depression Symptoms-Self-Rating (QIDS-SR) Item 10 - Concentration / Decision-making are shown;

[0124] Fig.13 Results of Hamilton Depression Rating Scale (Ham-D) Item 17 - retardation are shown;

[0125] Fig.14 Results for Montgomery-Asberg Depression Rating Scale (MADRS) Item 6 - Difficulty Concentrating are shown. DETAILED DESCRIPTION

[0126] The present invention will be explained in more detail below. This specification is not intended to be a detailed catalog of all different ways of implementing the present invention or all features that can be added to the present invention. For example, the features illustrated for one embodiment can be incorporated into other embodiments, and the features illustrated for a specific embodiment can be deleted from the embodiment. In addition, it will be apparent to those skilled in the art that many changes and additions to the various embodiments proposed herein will be made in accordance with this disclosure without departing from the present invention. Therefore, the following description is intended to illustrate some specific embodiments of the present invention, rather than to list exhaustively all permutations, combinations and variations thereof.

[0127] Unless otherwise indicated in the context, it is expressly contemplated that the various features of the invention described herein may be used in any combination. In addition, the present invention also contemplates that any feature or combination of features set forth herein may be excluded or omitted in some embodiments of the present invention. For illustrative purposes, if the specification states that a composite comprises components A, B, and C, it is expressly contemplated that any one or combination of A, B, or C may be omitted or abandoned, either individually or in any combination.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention belongs. The terms used in the description of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention.

[0129] All publications, patent applications, patents, nucleotide sequences, amino acid sequences, and other references mentioned herein are incorporated by reference in their entirety.

[0130] As used in the description of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0131] As used herein, "and / or" means and encompasses any and all possible combinations of one or more of the associated listed items, as well as combinations that are not construed in the alternative ("or").

[0132] Furthermore, the present invention contemplates that any feature or combination of features set forth herein may be excluded or omitted in some embodiments of the present invention.

[0133] In addition, the term "about" as used herein when referring to a measurable value, such as an amount of a compound or agent of the invention, dosage, time, temperature, etc., is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

[0134] As used herein, the transitional phrase "consisting essentially of" should be interpreted to encompass the recited materials or steps as well as materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. Therefore, the term "consisting essentially of" as used herein should not be interpreted as being equivalent to "comprising".

[0135] The term "treat" (or grammatically equivalent terms) means to reduce or at least partially improve or alleviate the severity of a subject's condition, and / or to alleviate, alleviate or reduce at least one clinical symptom, and / or delay the progression of a condition.

[0136] As used herein, the term "prevention" (and grammatical equivalents thereof) means delaying or inhibiting the onset of a disease. The term is not meant to require complete elimination of the disease, but rather encompasses any type of preventive treatment to reduce the incidence of a disorder or delay the onset of a disorder.

[0137] As used herein, a "therapeutically effective" amount is an amount sufficient to provide some improvement or benefit to a subject. In other words, a "therapeutically effective" amount is an amount that provides some relief, alleviation, reduction, or stabilization of at least one clinical symptom of a subject. It will be understood by those skilled in the art that the therapeutic effect need not be complete or curative, but only that some benefit is provided to the subject.

[0138] As used herein, a "prophylactically effective" amount is an amount sufficient to prevent and / or delay the onset of a disease, disorder, and / or clinical symptom in a subject and / or to reduce and / or delay the severity of the onset of a disease, disorder, and / or clinical symptom in a subject relative to what would occur if the methods of the invention were not used. It will be understood by those skilled in the art that the level of prevention need not be complete, but only as long as some benefit is provided to the subject.

[0139] 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 causing substantial adverse biological effects or interacting in a harmful manner with any other component of the composition comprising the substance. As is well known to those skilled in the art, the substance should be reasonably selected to minimize any degradation of the active ingredient and to minimize any side effects to the subject (e.g., see 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 physiological saline solutions.

[0140] "Simultaneous" means close enough in time to produce a combined effect (in other words, simultaneous can be simultaneous, or it can be two or more events that occur within a short period of time of each other). In some embodiments, the "simultaneous" administration of two or more compounds means that the administration time of the two compounds is close enough that the presence of one compound changes the biological effect of the other compound. The two compounds can be administered in the same or different formulations or in sequence. Simultaneous administration can be performed by mixing the compounds before administration, or by administering the compounds in two different formulations, for example, at the same time point but at different anatomical sites or using different administration routes.

[0141] Memory is the process of encoding, storing and extracting data or information when needed. The memory processing system in the brain is composed of sensory processors, short-term (or working) memory and long-term memory. Memory function as used herein refers to the memory level that can be quantified in a memory performance test. The improvement and reduction of memory function can be quantified by repeated use of this test.

[0142] Cognition refers to the mental activity or process of obtaining knowledge and understanding through thinking, experience and judgment. It covers all aspects of intellectual function and process, including perception, attention, thinking, intelligence, formation of knowledge, memory and working memory, judgment and evaluation, reasoning and calculation, problem solving and decision-making, understanding and language generation. As used herein, cognitive function refers to the cognitive level that can be quantified in cognitive performance test. The raising and reducing of cognitive function can be quantified by repeated use of such test.

[0143] Learning is the process of acquiring new understanding, knowledge, behavior, skills, values ​​and preferences. As used herein, learning function refers to the level of learning that can be quantified in a learning performance test. Improvements and decreases in learning function can be quantified by repeated use of such tests.

[0144] One aspect of the present invention relates to a method for improving the memory function, cognitive function and / or learning function of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby improving the memory function, cognitive function and / or learning function of the subject,

[0145]

[0146] in:

[0147] R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0148] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0149] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0150] R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0151] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0152] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0153] A is a 5-membered aromatic heterocyclic ring,

[0154] 6-membered aromatic heterocyclic ring,

[0155] 8-10 membered fused aromatic heterocyclic ring,

[0156] 5-7 membered unsaturated heterocyclic ring,

[0157] 4-7 membered saturated heterocyclic ring,

[0158] benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist,

[0159] R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or an oxydene group,

[0160] C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0161] C1-C6 alkoxy optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0162] C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0163] C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0164] C3-C6 cycloalkyl group optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0165] an amino group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0166] C1-C6 alkoxycarbonyl optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0167] a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0168] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0169] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0170] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0171] a 5- to 7-membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0172] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0173] an 8-10 membered fused aromatic heterocyclic group optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, or

[0174] R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0175] The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde 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,

[0176] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y,

[0177] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0178] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0179] a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0180] C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy,

[0181] a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y,

[0182] a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0183] a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0184] a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0185] C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl,

[0186] a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0187] carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino,

[0188] a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0189] a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0190] a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or

[0191] C1-C6 alkylsulfonylamino,

[0192] Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

[0193] Another aspect of the present invention relates to a method for delaying or slowing down the decline of memory function, cognitive function and / or learning function of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby delaying or slowing down the decline of memory function, cognitive function and / or learning function of the subject,

[0194]

[0195] in:

[0196] R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0197] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0198] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0199] R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0200] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0201] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0202] A is a 5-membered aromatic heterocyclic ring,

[0203] 6-membered aromatic heterocyclic ring,

[0204] 8-10 membered fused aromatic heterocyclic ring,

[0205] 5-7 membered unsaturated heterocyclic ring,

[0206] 4-7 membered saturated heterocyclic ring,

[0207] benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist,

[0208] R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or an oxydene group,

[0209] C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0210] C1-C6 alkoxy optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0211] C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0212] C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0213] C3-C6 cycloalkyl group optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0214] an amino group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0215] C1-C6 alkoxycarbonyl optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0216] a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0217] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0218] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0219] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0220] a 5- to 7-membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0221] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0222] an 8-10 membered fused aromatic heterocyclic group optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, or

[0223] R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0224] The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde 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,

[0225] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y,

[0226] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0227] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0228] a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0229] C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy,

[0230] a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y,

[0231] a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0232] a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0233] a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0234] C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl,

[0235] a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0236] carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino,

[0237] a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0238] a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0239] a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or

[0240] C1-C6 alkylsulfonylamino,

[0241] Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

[0242] Method of the present invention can be used for needing to improve memory function, cognitive function and / or learning function or needing to delay or slow down any object of the decline of memory function, cognitive function and / or learning function. In some embodiments, relative to the general population, the object has normal (for example, general level) memory function, cognitive function and / or learning function. The object can be the people who seek to improve memory, cognition and / or learning to improve the achievement in school, work or other situations. The object can be the people who do not have the factors such as neurological disorders or brain damage that are reducing or have reduced memory function, cognitive function and / or learning function. The object can be the people who do not have the decline of memory function, cognitive function and / or learning function caused by aging.

[0243] In some embodiments, relative to the general population, the object has reduced memory function, cognitive function and / or learning function. This reduction may be caused by aging. In some embodiments, this reduction is not caused by aging. This reduction may be caused by factors such as neurological disorders or brain damage. The example of factors related to memory, cognitive and / or learning ability reduction includes but is not limited to Alzheimer's disease, attention deficit disorder, Lewy body dementia, early onset dementia, cognitive dysfunction associated with epilepsy, frontotemporal dementia, mild cognitive impairment, normal pressure hydrocephalus, cognitive dysfunction associated with Parkinson's disease, posterior cortical atrophy, primary progressive aphasia, cognitive dysfunction associated with stroke, traumatic brain injury, other cognitive dysfunctions associated with mental and / or neurological disorders (e.g., multiple sclerosis, schizophrenia, amyotrophic lateral sclerosis, Huntington's disease, chronic depression) and cognitive dysfunction associated with chemotherapy (chemo-brain).

[0244] Memory function, cognitive function and learning function can be measured by tests known in the art, including but not limited to the Stroop test, the Rey Auditory Verbal Learning Test (RAVLT), the Wechsler Adult Intelligence Scale (WAIS) test, the Memex 100, the Mini-Mental State Examination scale, the Activities of Daily Living Scale, the Clinical Dementia Rating, or a combination thereof. These tests can be repeated to quantify changes in memory, cognition and learning abilities over time.

[0245] In some embodiments, relative to the baseline before treatment, the method of the present invention can improve memory function, cognitive function and / or learning function by at least 5%, such as at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more. In some embodiments, relative to an untreated subject, the method of the present invention can slow down the loss of memory function, cognitive function and / or learning function by at least 5%, such as at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more. In some embodiments, relative to an untreated subject, the method of the present invention can delay the loss of memory function, cognitive function and / or learning function by at least one month, such as at least three months, six months, one year or more.

[0246] In some embodiments, the compound of Formula 1 is any compound selected from the following group:

[0247] (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;

[0248] (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;

[0249] (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidinyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0250] (2S,5'R)-7-Chloro-6-[5-(4-fluoro-1-methyl-4-piperidinyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0251] (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;

[0252] (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;

[0253] (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;

[0254] (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;

[0255] (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;

[0256] (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;

[0257] (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;

[0258] (2S,5'R)-7-Chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0259] (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0260] (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;

[0261] (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridinyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or

[0262] (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

[0263] In some embodiments, the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt thereof:

[0264]

[0265] in:

[0266] R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0267] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0268] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0269] R 2is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different,

[0270] C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or

[0271] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0272] A is a 5-membered aromatic heterocyclic ring,

[0273] 6-membered aromatic heterocycle,

[0274] 8-10 membered fused aromatic heterocyclic ring,

[0275] 5-7 membered unsaturated heterocyclic ring,

[0276] 4-7 membered saturated heterocyclic ring,

[0277] benzene ring or a single bond, where A is a single bond, R 3 and R 3’ If one or the other does not exist, R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, or a hydroxyl group,

[0278] C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0279] C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different,

[0280] C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0281] C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X,

[0282] C3-C6 cycloalkyl group optionally substituted by one to two substituents selected from substituent group X which are the same or different,

[0283] an amino group optionally substituted by the same or different one to two substituents selected from substituent group X,

[0284] a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X,

[0285] a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0286] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0287] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0288] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0289] a 5- to 7-membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0290] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X,

[0291] an 8-10 membered fused aromatic heterocyclic group optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, or

[0292] R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X,

[0293] The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde 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,

[0294] A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y,

[0295] a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0296] a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0297] a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0298] C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy,

[0299] a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y,

[0300] a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0301] a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0302] a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0303] C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl,

[0304] a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0305] carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino,

[0306] a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0307] a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y,

[0308] a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or

[0309] C1-C6 alkylsulfonylamino, and

[0310] Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

[0311] In some embodiments of the compound of Formula 1 or Formula 1', R 1 is a C1-C6 alkyl group, R 2 is a C1-C6 alkyl group, A is a 5-membered aromatic heterocyclic ring, and R 3 and R 3’ Each is independently hydrogen or C1-C6 alkyl.

[0312] In some embodiments of the compound of Formula 1 or Formula 1', R 1 It is methyl, ethyl or hydroxyethyl.

[0313] In some embodiments of the compound of Formula 1 or Formula 1', R 2 It's methyl.

[0314] In some embodiments of the compound of Formula 1 or Formula 1′, A is a 5-membered aromatic heterocycle, R 3 is methyl, ethyl, hydroxy C1-C3 alkyl or methoxy C1-C3 alkyl, and R 3’ It's a hydrogen atom.

[0315] In some embodiments, the compound of Formula 1 is a compound of Formula 1″ or a pharmaceutically acceptable salt thereof:

[0316]

[0317] Where R 1 is methyl or ethyl;

[0318] R 2 It is methyl;

[0319] A is any ring selected from the following group:

[0320]

[0321] * denotes a binding group; and

[0322] R 3 It is methyl or ethyl.

[0323] In some embodiments, the compound of Formula 1' is any compound selected from the following group:

[0324] (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0325] (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0326] (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;

[0327] (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;

[0328] (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;

[0329] (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;

[0330] (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;

[0331] (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;

[0332] (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;

[0333] (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;

[0334] (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0335] (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;

[0336] (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;

[0337] (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;

[0338] (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;

[0339] (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;

[0340] (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;

[0341] (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;

[0342] (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidinyl)-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0343] (2S,5'R)-7-Chloro-6-[5-(4-fluoro-1-methyl-4-piperidinyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0344] (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;

[0345] (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;

[0346] (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;

[0347] (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;

[0348] (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;

[0349] (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;

[0350] (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;

[0351] (2S,5'R)-7-Chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0352] (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0353] (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;

[0354] (2S,5'R)-7-chloro-3',4-dimethoxy-6-(6-methoxy-3-pyridinyl)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione;

[0355] (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-pyridyl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; or

[0356] (2S,5'R)-7-Chloro-3',4,6-trimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] In certain embodiments, the 5-membered aromatic heterocycle of A is the same as described above, but more preferably, it represents the following 5-membered ring. (It should be noted that in this case, R 3’does not exist. )

[0363]

[0364] Wherein * represents a binding group.

[0365] In the present specification, a "5-membered aromatic heterocycle" is a monocyclic 5-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. For example, it includes the following rings.

[0366]

[0367] In the present specification, a "6-membered aromatic heterocycle" is a monocyclic 6-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. For example, it includes the following rings.

[0368]

[0369] In the present specification, the "8- to 10-membered fused aromatic heterocycle" refers to an 8- to 10-membered fused aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. For example, the rings shown below are included.

[0370]

[0371] In the present specification, a "5- to 7-membered unsaturated heterocycle" is a ring in which a monocyclic 5- to 7-membered saturated heterocycle is partially oxidized or a ring in which an aromatic heterocycle is partially reduced, and the ring contains 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. For example, the ring shown below is included.

[0372]

[0373] In the present specification, a "4- to 7-membered saturated heterocyclic ring" is a monocyclic 4- to 7-membered saturated heterocyclic ring containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. For example, the ring shown below is included.

[0374]

[0375] The "halogen atom" in the present specification is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.

[0376] The "C1-C6 alkyl" in this specification is a straight or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl and 2,3-dimethyl-1-butyl, preferably methyl or ethyl.

[0377] "C2-C6 alkenyl" in this specification is a straight or branched alkenyl group having 2 to 6 carbon atoms, and it may have one or two or more carbon-carbon double bonds. For example, it is vinyl, 2-propenyl (allyl), 2-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 2-hexenyl or 3-methyl-2-pentenyl, preferably vinyl or allyl.

[0378] "C2-C6 alkynyl" in this specification is a straight or branched alkynyl group having 2 to 6 carbon atoms, and it may have one or two or more carbon-carbon triple bonds. For example, it is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl or 1-hexynyl, preferably ethynyl or 1-propynyl.

[0379] "C1-C6 alkoxy" in this specification is a group in which an oxygen atom is bonded to a C1-C6 alkyl group. Examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexoxy, 2-hexoxy, 3-hexoxy, 2-methyl-1-pentoxy and 3-methyl-1-pentoxy. Preferably, it is methoxy, ethoxy, 1-propoxy or 2-propoxy.

[0380] The "C3-C6 cycloalkyl group" in the present specification is a cycloalkyl group having 3 to 6 carbon atoms, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0381] The "hydroxy C1-C6 alkyl group" in the present specification is a group in which a hydroxy group is bonded to a C1-C6 alkyl group. For example, it is a hydroxymethyl group or a hydroxyethyl group.

[0382] The "C1-C6 alkoxy C1-C6 alkyl group" in the present specification is a group in which a C1-C6 alkoxy group is bonded to a C1-C6 alkyl group. Examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

[0383] The "C1-C6 haloalkyl" in this specification is a group in which a halogen atom is bonded to a C1-C6 alkyl group. Examples thereof include fluoromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, trichloroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl and 4-fluorobutyl. It is preferably trifluoromethyl.

[0384] The "C3-C6 halogenated cycloalkyl group" in the present specification is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.

[0385] The "C1-C6 haloalkoxy group" in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxy group, a 2-bromoethoxy group, a 2-chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a trichloroethoxy group, a pentafluoroethoxy group, a 3-fluoropropoxy group, a 3-chloropropoxy group, and a 4-fluorobutoxy group. It is preferably a trifluoromethoxy group.

[0386] The "C3-C6 cycloalkoxy group" in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group or a cyclohexyloxy group.

[0387] The "C3-C6 halocycloalkoxy group" in the present specification is a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropyloxy group, a fluorocyclobutyloxy group, a fluorocyclopentyloxy group and a fluorocyclohexyloxy group.

[0388] The "5-membered aromatic heterocycle-oxy group" in the present specification is a group in which a 5-membered aromatic heterocycle is bonded to an oxygen atom.

[0389] The "6-membered aromatic heterocycle-oxy group" in the present specification is a group in which a 6-membered aromatic heterocycle is bonded to an oxygen atom.

[0390] The "4- to 7-membered saturated heterocyclic-oxy ​​group" in the present specification is a group in which a 4- to 7-membered saturated heterocyclic ring is bonded to an oxygen atom.

[0391] The "C1-C6 alkoxycarbonyl group" in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

[0392] The "C3-C6 cycloalkoxycarbonyl group" in the present specification is a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group or a cyclohexyloxycarbonyl group.

[0393] The "C1-C6 alkylcarbonyl group" in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group or a propylcarbonyl group.

[0394] The "mono(C1-C6 alkyl)aminocarbonyl group" in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group or a propylaminocarbonyl group.

[0395] The "di(C1-C6 alkyl)aminocarbonyl group" in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminocarbonyl group, and is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group or a dipropylaminocarbonyl group.

[0396] The "mono(C1-C6 alkyl)aminosulfonyl group" in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminosulfonyl group, and is preferably a methylaminosulfonyl group, an ethylaminosulfonyl group or a propylaminosulfonyl group.

[0397] The "di(C1-C6 alkyl)aminosulfonyl group" in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group or a dipropylaminosulfonyl group.

[0398] The "mono(C1-C6 alkyl)amino group" in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, and is preferably a methylamino group, an ethylamino group or a propylamino group.

[0399] The "di(C1-C6 alkyl)amino group" in the present specification is a group in which two C1-C6 alkyl groups are bonded to an amino group, and is preferably a dimethylamino group, a diethylamino group or a dipropylamino group.

[0400] The "C1-C6 alkoxycarbonylamino group" in the present specification is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, and is, for example, a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.

[0401] The "mono(C1-C6 alkyl)aminocarbonylamino group" in the present specification is a group in which a mono(C1-C6 alkyl)aminocarbonyl group is bonded to an amino group, and preferably is a methylaminocarbonylamino group, an ethylaminocarbonylamino group or a propylaminocarbonylamino group.

[0402] The "di(C1-C6 alkyl)aminocarbonylamino group" in the present specification is a group in which a di(C1-C6 alkyl)aminocarbonyl group is bonded to an amino group, and preferably a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group or a dipropylaminocarbonylamino group.

[0403] The "5-membered aromatic heterocyclic carbonylamino group" in the present specification is a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0404] The "6-membered aromatic heterocyclic carbonylamino group" in the present specification is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.

[0405] The "C1-C6 alkylsulfonylamino group" in the present specification is a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and preferably a methylsulfonylamino group, an ethylsulfonylamino group or a propylsulfonylamino group.

[0406] "Pharmaceutically acceptable salt" means a salt that can be used as a drug. When a compound has an acidic group or a basic group, it can be converted into a basic salt or an acidic salt by reacting it with a base or an acid to form a salt thereof.

[0407] Pharmaceutically acceptable "basic salts" of the compound preferably include alkali metal salts, such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts, such as magnesium salts and calcium salts; organic base salts, such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidinium salts, pyridine salts, 4-pyrrolidinylpyridine salts and methylpyridine salts; and amino acid salts, such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate and aspartate salts, preferably alkali metal salts.

[0408] Pharmaceutically acceptable "acid salts" of the compounds preferably include inorganic acid salts, such as hydrohalides (e.g., hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), nitrates, perchlorates, sulfates and phosphates; organic salts, such as lower alkanesulfonates (e.g., methanesulfonates, trifluoromethanesulfonates and ethanesulfonates), arylsulfonates (e.g., benzenesulfonates and p-toluenesulfonates), acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates and the like; and amino acid salts, such as glycine, lysine, arginine, ornithine, glutamate and aspartate, with hydrohalides (especially hydrochlorides) being most preferred.

[0409] The compounds of the present invention or their pharmaceutically acceptable salts may absorb moisture, attach to adsorbed water, or become hydrates by exposure to air or recrystallization. The present invention also includes these various hydrates, solvates and crystalline polymorphs of the compounds.

[0410] According to the type and combination of substituents, the compound of the present invention, its pharmaceutically acceptable salt or solvate may have various isomers, such as geometric isomers, such as cis isomers and trans isomers, tautomers, or optical isomers, such as d isomers and l isomers, and unless otherwise specified, the compound includes all isomers, stereoisomers and mixtures of these isomers and stereoisomers mixed in any ratio. These isomeric mixtures can be resolved by known resolution methods.

[0411] Compounds of the invention also include labels, i.e., one or more atoms of the compound are replaced by isotopes (e.g., 2 H. 3 H. 13 C. 14 C. 35 S, etc.) substituted compounds.

[0412] In addition, the present invention also includes prodrugs. Prodrugs are compounds having amino, hydroxyl, carboxyl, etc. groups that can be converted into compounds by hydrolysis or under physiological conditions, and the groups that form such prodrugs are groups described in Prog. Med. Vol. 5, pp. 2157-2161 (1985), etc. As a prodrug, more specifically, when there is an amino group in the compound, it includes compounds in which the amino group is acylated, alkylated or phosphorylated (for example, compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated or tert-butylated, etc.), and, when there is a hydroxyl group in the compound, it includes compounds in which the hydroxyl group is acylated, alkylated, phosphorylated or boronated (for example, compounds in which the hydroxyl group is acetylated, palmitoylated, propionylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated, etc.), etc. In addition, when a carboxyl group is present in the compound, it includes compounds in which the carboxyl group is esterified or amidated (for example, compounds in which the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated or methylamidated, etc.) and the like.

[0413] The compounds of the present invention can be produced by synthetic methods known in the art and as described in WO 2017 / 170623 and WO 2019 / 065928, the entire contents of which are incorporated herein by reference.

[0414] Administration of the compounds of the present invention can be carried out by oral administration in any form such as tablets, pills, capsules, granules, powders, solutions, or by parenteral administration in any form such as injections for intra-articular, intravenous, intrathecal, intracerebroventricular, intramuscular, intranasal, etc., suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0415] As solid compositions for oral administration, tablets, powders, granules, etc. are used. This solid composition consists of one or more active ingredients and at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminum silicate, etc. According to conventional methods, the solid composition may contain one or more inert additives, such as lubricants, such as magnesium stearate; disintegrants, such as sodium carboxymethyl starch; stabilizers and solubilizers. If necessary, the tablets or pills may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine.

[0416] As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. are used. Conventional inert diluents, such as purified water or ethanol, can be added to such liquid compositions. In addition to the inert diluent, the liquid composition may also contain one or more solubilizing agents, adjuvants, such as wetting agents, sweeteners, flavoring agents, flavoring agents, and preservatives.

[0417] As injections for parenteral administration, sterile aqueous or non-aqueous solutions, suspensions or emulsions are used. Aqueous solvents include, for example, distilled water for injection, physiological saline, etc. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80, etc. Such injection compositions may also contain one or more tonicity agents, preservatives, wetting agents, emulsions, dispersants, stabilizers or solubilizers. These injection compositions may be sterilized, for example, by filtering through a bacterial retention filter, applying a bactericide or irradiating. In addition, these injection compositions may be used by producing a sterile solid composition and dissolved or suspended in sterile water or a sterile injection solvent before use.

[0418] As external preparations, ointments, plasters, creams, gels, pastes, sprays, lotions, eye drops, eye ointments, etc. are used. These external preparations contain common ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, etc. For example, as ointment or lotion bases, polyethylene glycol, propylene glycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauryl alcohol polyoxyethylene ether, sorbitan sesquioleate, etc. are used.

[0419] Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semisolid forms and can be prepared according to conventional known methods. For example, known excipients can be appropriately added, and in addition, one or more pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can also be added. For these transmucosal agents, a device suitable for suction or insufflation can be used as a method of application. For example, known devices such as metered-dose inhalation devices and atomizers can be used to administer the compound alone or as a powder for preparing a mixture, or as a solution or suspension combined with a pharmaceutically acceptable carrier. For single or multiple administrations, dry powder inhalers, etc. can be used, and capsules containing dry powder or powder can also be used. Alternatively, a suitable ejector can be used. For example, it can be a form such as a pressurized aerosol spray using suitable gases such as chlorofluoroalkanes, hydrofluoroalkanes or carbon dioxide.

[0420] In the case of normal oral administration, a suitable daily dose is about 0.001 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight. In some embodiments, a suitable daily dose is about 0.1 mg to about 500 mg, for example, about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450 or 500 mg. This can be administered in a single dose, or divided into two or more doses for administration. When administered intravenously, a suitable daily dose is about 0.0001 to 10 mg / kg body weight, which can be administered once a day or in divided doses. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg body weight is administered once a day or in divided doses. The dose should be appropriately determined according to individual circumstances in consideration of symptoms, age, sex, etc.

[0421] In the methods of the present invention, the compounds may be administered in combination with therapeutic or prophylactic agents for various diseases for which they are believed to exert their efficacy. The combination may be administered simultaneously, separately, together, sequentially, or at desired intervals. The co-administered agents may be blended or formulated separately. The therapeutic agent may, for example, be a therapeutic agent for treating a condition causing memory, cognition, or learning problems, including benzodiazepines, antidepressants, antipsychotics, proton pump inhibitors, antidepressants, treatments for high blood pressure, treatments for sleep apnea, treatments that increase neurotransmitter levels (e.g., donepezil, galantamine, rivastigmine), memantine, aducanumab, and suorexin.

[0422] The method of the present invention has uses in both veterinary and medical applications. Suitable objects include birds, reptiles, amphibians, fish and mammals. As used herein, the term "mammal" includes but is not limited to humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, etc.), etc. Human subjects include neonates, infants, teenagers and adults. Optionally, the object "needs" the method of the present invention, for example, because the object has or is believed to have a risk of suffering from a disease (including a disease described herein), or will benefit from the delivery of the compound described herein. As another option, the object can be an experimental animal and / or an animal model of the disease. Preferably, the object is a person.

[0423] Having described the present invention, it will be explained in more detail in the following examples, which are for illustrative purposes only and are not intended to limit the present invention.

[0424] Example 1

[0425] Biological activity of compound 1

[0426] Compound 1 (SP-624; DS-7830a; (2S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[1-benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione) was tested in multiple cognitive models.

[0427]

[0428] In vitro electrophysiological experiments in hippocampal slices of Sprague Dawley rats demonstrated that compound 1 acts presynaptically, increasing the frequency of miniature excitatory postsynaptic potentials (mEPSPs) in the hippocampus and enhancing short-term plasticity ( Figure 1-2 ), and tend to increase short-lasting long-term potentiation ( Figure 3 ), suggesting facilitation of neurotransmitter release in the hippocampus. The effect of compound 1 in enhancing mEPSPs may be dependent on the influx of extracellular calcium. The results showed that the influx of extracellular calcium mainly involved P / Q-type and N-type calcium channels, but not L-type calcium channels or protein kinase A. These findings suggest enhancement of neuronal transmission in the hippocampus, a brain region involved in memory and cognitive function.

[0429] A novel object recognition test (assessing visual learning and memory) was performed to investigate the effect of Compound 1 on cognitive impairment induced by scopolamine in Long-Evans rats. Donepezil was used as a positive control. Subcutaneous injection of scopolamine at a dose of 0.1 mg / kg reduced the novel object discrimination index (NDI), a measure of cognitive function ( Figure 4-6 ). Oral administration of compound 1 at doses of 0.1 and 1 mg / kg significantly improved the NDI that was reduced by scopolamine. This suggests that compound 1 improves cognitive impairment induced by scopolamine.

[0430] A novel object recognition test was performed to investigate the effect of SP-624 on cognitive impairment induced by subchronic PCP in Wistar rats. Clozapine was used as a positive control. Subchronic PCP at a dose of 5 mg / kg twice daily intraperitoneally for 7 consecutive days significantly reduced NDI ( Figure 7-9 ). Treatment with 0.1 mg / kg and 1 mg / kg, but not 0.01 mg / kg, of compound 1 significantly reduced subchronic PCP-induced cognitive deficits in terms of NDI. This result suggests that compound 1 improves cognitive deficits associated with NMDA receptor hypofunction.

[0431] The long-term potentiation (LTP) model in freely behaving rodents is a common form of synaptic plasticity. LTP is a sustained increase in the strength of synaptic connections between neurons and is a cellular mechanism widely considered to underlie learning and memory processes. Compared to vehicle controls, intravenous administration of compound 1 at doses of 0.01 mg / kg and 0.1 mg / kg increased LTP ( Figure 10-11 ). This result suggests that compound 1 can have a positive effect on cognition.

[0432] Example 2

[0433] Clinical trial of compound 1

[0434] A Phase 2, multicenter, double-blind, randomized, placebo-controlled study was conducted to investigate the safety and efficacy of SP-624 in the treatment of adult subjects with major depressive disorder (MDD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). After successful completion of the screening phase, subjects were randomized 1:1 to one of two treatment groups and received either Compound 1 (SP-624) or placebo during a four-week treatment period (Treatment Group #1: SP-624, 20 mg / day; Treatment Group #2: placebo).

[0435] Prior to starting the 4-week treatment period, subjects completed a 28-day screening / baseline period during which all screening assessments were performed and any current depression medications were discontinued. All screening assessments were completed before any current depression medications were discontinued. Subjects returned for a baseline visit to complete efficacy and safety assessments. During the treatment period, subjects returned to the study center at the end of Weeks 1, 2, 3, and 4 to complete efficacy and safety assessments. After taking the last dose of study medication, subjects completed a two-week follow-up period and returned at the end of Weeks 5 and 6. After completing the Week 5 visit, subjects could receive antidepressant medication based on their physician's recommendation.

[0436] Each dose of Compound 1 was provided in the form of two capsules, each containing 10 mg of active pharmaceutical ingredient (API). Matching placebo capsules of the same shape and color as the active capsules were used.

[0437] The primary efficacy endpoint was the change from baseline to week 4 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score.

[0438] Secondary efficacy endpoints include:

[0439] Changes in MADRS total score from baseline to week 1, week 2, and week 3,

[0440] Changes in Clinical Global Impression-Severity (CGI-S) total scores from baseline to Week 1, Week 2, Week 3, and Week 4,

[0441] Changes from baseline to week 5 and from week 4 to week 5 in MADRS total score and CGI-S total score,

[0442] Changes from baseline to weeks 2 and 4 in the total score of the 17-item Hamilton Depression Rating Scale (HAM D-17),

[0443] Changes from baseline to weeks 2 and 4 on the Sheehan Disability Scale (SDS),

[0444] Change from baseline to Week 2 and Week 4 on the Quick Inventory of Depression Symptoms-Self-Rating (QIDS-SR), and

[0445] Changes from baseline to weeks 2 and 4 on the Brief Well-Being and Quality of Life Satisfaction Questionnaire (Q-LES-Q-SF).

[0446] The demographic data of the study population are shown in Table 1 .

[0447] Table 1. Demographic data, safety population

[0448]

[0449] The study included several measures related to cognitive function. The first was item 10 of the QIDS-SR - Concentration / Decision-making. The answer scale was: 0 - There was no change in my usual ability to concentrate or make decisions; 1 - Occasionally I felt indecisive or found myself distracted; 2 - Most of the time, I had difficulty concentrating or making decisions; 3 - I could not concentrate well enough to read or even make small decisions. The results were Fig.12 and are shown in Table 2. The data show that by the 4th week of treatment, the scores of the subjects administered Compound 1 were all improved to a greater extent.

[0450] Table 2. QIDS-SR-Item 10 (Focus / Decision Making)-Mean Change from Baseline (mITT, Female)

[0451]

[0452] The second cognitive function measure was HAM-D Item 17 - Slowness (slowed thinking and language, impaired concentration, reduced motor activity). The answer scale was: 0 - normal language and thinking; 1 - mild slowness during interview (mild psychomotor slowness); 2 - marked slowness during interview (moderate, some difficulty in interview, obvious pauses and slow thinking); 3 - difficult interview (severe psychomotor slowness, very long pauses); 4 - complete confusion (extreme slowness, almost unable to interview). The results were Fig.13 and are shown in Table 3. The data show that by week 4 of treatment, subjects administered Compound 1 had a greater improvement in their scores.

[0453] Table 3. HAM-D-Item 17 (Retardation)-Mean Change from Baseline (mITT, Female)

[0454]

[0455] The third cognitive function measure was MADRS Item 6 - Difficulty in Concentration (difficulty concentrating thoughts, up to complete inability to concentrate, assessed based on the intensity, frequency and degree of inattention produced). The answer scale was: 0 - no difficulty concentrating thoughts; 1 - blank; 2 - occasional difficulty concentrating thoughts; 3 - blank; 4 - difficulty concentrating and maintaining thoughts, which reduces the ability to read or hold a conversation; 5 - blank; 6 - great difficulty reading or holding a conversation. The results were Fig.14 and are shown in Table 4. The data show that at all measurement times in Week 5, the scores of subjects administered Compound 1 were significantly improved.

[0456] Table 4. MADRS-Item 6 (Difficulty Concentrating)-Mean Change from Baseline (mITT, Female)

[0457]

[0458] 1 P values, differences in least-squares mean estimates with 95% CIs based on mixed models for repeated measures.

[0459] *The Week 5 assessment was completed 1 week after the last dose of study drug. The Week 5 summary includes subjects who received the full four weeks of study drug and returned for the Week 5 assessment.

[0460] The foregoing examples are intended to illustrate the present invention by way of example and should not be construed as limiting the present invention. Although the present invention has been described in detail with reference to preferred embodiments, various changes and modifications exist within the scope and spirit of the present invention, as described and defined in the appended claims.

Claims

1. A method for improving the memory function, cognitive function and / or learning function of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby improving the memory function, cognitive function and / or learning function of the subject, in: R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, A is a 5-membered aromatic heterocyclic ring, 6-membered aromatic heterocyclic ring, 8-10 membered fused aromatic heterocyclic ring, 5-7 membered unsaturated heterocyclic ring, 4-7 membered saturated heterocyclic ring, benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist, R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or an oxydene group, C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different, C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X, C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from substituent group X, an amino group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X, a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, an 8-10 membered fused aromatic heterocyclic group optionally substituted by the same or different one to two substituents selected from Substituent Group X, or R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X, The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y, a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino, a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or C1-C6 alkylsulfonylamino, Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

2. A method for delaying or slowing down the decline of memory function, cognitive function and / or learning function of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby delaying or slowing down the decline of memory function, cognitive function and / or learning function of the subject, in: R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, A is a 5-membered aromatic heterocyclic ring, 6-membered aromatic heterocyclic ring, 8-10 membered fused aromatic heterocyclic ring, 5-7 membered unsaturated heterocyclic ring, 4-7 membered saturated heterocyclic ring, benzene ring, -CH= or cyano, wherein when A is cyano, R 3 and R 3’ does not exist, R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or an oxydene group, C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different, C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X, C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from substituent group X, an amino group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X, a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, an 8-10 membered fused aromatic heterocyclic group optionally substituted by the same or different one to two substituents selected from Substituent Group X, or R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X, The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y, a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino, a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or C1-C6 alkylsulfonylamino, Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

3. The method of claim 1 or 2, wherein the subject does not have a neurological disorder or brain damage.

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

5. The method of claim 1 or 2, wherein the subject has reduced memory function, cognitive function and / or learning function relative to the general population.

6. The method according to claim 5, wherein the reduced memory function, cognitive function and / or learning function is caused by aging.

7. The method according to any one of claims 1 to 6, wherein A, R 3 or R 3’ The 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group is any one selected from the following groups:

8. The method according to any one of claims 1 to 7, wherein A, R 3 or R 3’ The 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group is any one selected from the following groups:

9. The method according to any one of claims 1 to 8, wherein A, R 3 or R 3’ The 8-10 membered fused aromatic heterocycle or 8-10 membered fused aromatic heterocyclic group is any one selected from the following groups:

10. The method according to any one of claims 1 to 9, wherein A, R 3 or R 3’ The 5- to 7-membered unsaturated heterocyclic ring or 5- to 7-membered unsaturated heterocyclic group is any one selected from the following groups:

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

12. The method according to any one of claims 1 to 11, wherein the compound of Formula 1 is any compound selected from the following group: (2S,5'R)-7-Chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidinyl)-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-piperidinyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-Chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (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-pyridinyl)-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.

13. The method according to any one of claims 1 to 12, wherein the compound of Formula 1 is a compound of Formula 1' or a pharmaceutically acceptable salt thereof: in: R 1 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, R 2 is a C1-C6 alkyl group optionally substituted by one to two substituents selected from the substituent group X which are the same or different, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from Substituent Group X, or a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, A is a 5-membered aromatic heterocyclic ring, 6-membered aromatic heterocyclic ring, 8-10 membered fused aromatic heterocyclic ring, 5-7 membered unsaturated heterocyclic ring, 4-7 membered saturated heterocyclic ring, benzene ring or a single bond, wherein when it is a single bond, R 3 and R 3’ One or the other does not exist, R 3 and R 3’ are each independently a hydrogen atom, a halogen atom, a cyano group, or a hydroxyl group, C1-C6 alkyl optionally substituted by one to two substituents selected from substituent group X which are the same or different, C1-C6 alkoxy optionally substituted by one to two substituents selected from Substituent Group X which are the same or different, C2-C6 alkenyl optionally substituted by the same or different one to two substituents selected from substituent group X, C2-C6 alkynyl optionally substituted by the same or different one to two substituents selected from substituent group X, C3-C6 cycloalkyl optionally substituted by the same or different one to two substituents selected from substituent group X, an amino group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a C1-C6 alkoxycarbonyl group optionally substituted by the same or different one to two substituents selected from Substituent Group X, a carbamoyl group optionally substituted by the same or different one to two substituents selected from the substituent group X, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 5-7 membered unsaturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, a 4- to 7-membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group X, an 8-10 membered fused aromatic heterocyclic group optionally substituted by the same or different one to two substituents selected from Substituent Group X, or R 3 and R 3’ may form a 5-7 membered unsaturated heterocyclic ring, a 4-7 membered saturated heterocyclic ring or a C3-C6 cycloalkyl ring as a ring bonded to each other and fused to A, and the ring is optionally substituted by the same or different one to two substituents selected from the substituent group X, The substituent group X is a halogen atom, a cyano group, a hydroxyl group, an oxyde group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, A phenyl group optionally substituted by one to two substituents which are the same or different and are selected from the substituent group Y, a 5-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4-7 membered saturated heterocyclic group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 halocycloalkoxy, a phenoxy group optionally substituted by the same or different one to two substituents selected from substituent group Y, a 5-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 4- to 7-membered saturated heterocyclic-oxy ​​group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, carboxyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, a phenylcarbonyl group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, carbamoyl, mono(C1-C6 alkyl)aminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, mono(C1-C6 alkyl)aminosulfonyl, di(C1-C6 alkyl)aminosulfonyl, amino, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C1-C6 alkoxycarbonylamino, mono(C1-C6 alkyl)aminocarbonylamino, di(C1-C6 alkyl)aminocarbonylamino, C1-C6 alkylcarbonylamino, a phenylcarbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 5-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, a 6-membered aromatic heterocyclic carbonylamino group optionally substituted by one to two substituents which are the same or different and are selected from substituent group Y, or C1-C6 alkylsulfonylamino, and Substituent Group Y is a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom or a hydroxyl group.

14. The method according to claim 13, wherein R 1 It is methyl, ethyl or hydroxyethyl.

15. The method according to claim 13 or 14, wherein R 2 It's methyl.

16. The method according to any one of claims 13 to 15, wherein A, R 3 or R 3’ The 5-membered aromatic heterocycle or 5-membered aromatic heterocyclic group is any one selected from the following groups:

17. The method according to any one of claims 13 to 16, wherein A, R 3 or R 3’ The 6-membered aromatic heterocycle or 6-membered aromatic heterocyclic group is any one selected from the following groups:

18. The method according to any one of claims 13 to 17, wherein A, R 3 or R 3’ The 5- to 7-membered unsaturated heterocyclic ring or 5- to 7-membered unsaturated heterocyclic group is any one selected from the following groups:

19. The method according to any one of claims 13 to 18, wherein A, R 1 , R 2 or R 3 The 4-7 membered saturated heterocyclic ring or 4-7 membered saturated heterocyclic group is any one selected from the following groups:

20. The method according to any one of claims 12 to 18, wherein A is a 5-membered aromatic heterocycle, R 3 is methyl, ethyl, hydroxy C1-C3 alkyl or methoxy C1-C3 alkyl, and R 3’ It's a hydrogen atom.

21. The method according to any one of claims 13 to 20, wherein A is any ring selected from the following groups, and, in the case of two binding groups, R 3’ Does not exist: Wherein * represents a binding group.

22. The method according to any one of claims 13-15, wherein the compound of Formula 1 is a compound of Formula 1″ or a pharmaceutically acceptable salt thereof: Where R 1 is methyl or ethyl; R 2 It is methyl; A is any ring selected from the following group: * denotes a binding group; and R 3 It is methyl or ethyl.

23. The method according to any one of claims 13-21, wherein the compound of formula I' 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-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-Chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-(1-methyl-4-piperidinyl)-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-piperidinyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-ethoxy-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-4-(difluoromethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-6-[3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1H-pyrazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-6-[1-(2-methoxyethyl)pyrazol-3-yl]-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-Chloro-6-(1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(8-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione; (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-pyridinyl)-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.

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

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

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

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

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

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