JP2019199438A - Agent for improving defective structure of proteolipid protein 1, and agent for prevention or treatment of disease or symptom caused by defective structure of proteolipid protein 1, and use therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide means for substantially improving structural deficiency of proteolipid protein 1 (PLP1). A proteolipid protein containing a compound represented by the formula (I-1-1) or (I-2-1), a stereoisomer thereof, a salt thereof, or a solvate thereof as an active ingredient. 1 (PLP1) structural failure improver. A pharmaceutical composition for use in the prophylaxis or treatment of a disease or symptom caused by structural failure of PLP1, comprising the compound, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient. [Selection diagram] None

Description

  The present invention relates to an agent for improving proteolipid protein 1 structural failure, a prophylactic or therapeutic agent for diseases or symptoms caused by structural failure of proteolipid protein 1, and uses thereof.

  It is considered that many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis are associated with abnormal protein tertiary structure and subsequent endoplasmic reticulum stress (Non-Patent Document). 1 and 2). In these neurodegenerative diseases, changes over several decades accumulate and occur, making it difficult to visualize the disease state. In addition, abnormalities in protein tertiary structure and endoplasmic reticulum stress are caused by various causes, and it is difficult to establish an effective treatment.

  A normal protein localized mainly in the cell membrane forms a tertiary structure of the protein in the endoplasmic reticulum and is transported to the cell membrane via the Golgi apparatus. In contrast, an abnormal protein having a certain type of mutation does not form a normal tertiary structure, resulting in structural failure. The abnormal protein that causes structural failure remains in the endoplasmic reticulum, resulting in endoplasmic reticulum stress. Due to endoplasmic reticulum stress, chaperone protein expression induction, protein synthesis decrease, endoplasmic reticulum-related degradation, and the like occur. If abnormal proteins cannot be processed by these responses, the cells undergo apoptosis (Non-patent Document 2). In addition, loss of protein function may occur due to the protein not reaching the cell membrane or intracellular organelle that should be reached.

  Thus, structural failure of certain proteins can be one of the factors that cause endoplasmic reticulum stress. For example, Pelizaeus-Merzbacher disease (hereinafter also referred to as “PMD”), which develops due to abnormal myelination, is the first disease for which the relationship between endoplasmic reticulum stress and neurodegenerative diseases has been clarified. PMD is caused mainly by proteolipid protein 1 (hereinafter also referred to as “PLP1”) due to structural failure caused by mutation such as substitution, deletion, or duplication (Non-patent Document 3). In previous studies, when PMD patient cells were differentiated into iPS and oligodendrocytes, PLP1 with severe mutations remained around the nucleus and was not distributed throughout the cytoplasm, resulting in an enhanced endoplasmic reticulum stress response. (Non-Patent Document 4).

  PMD is a type of hereditary neuroleukoplasia and is an intractable disease known as a childhood-onset neurodegenerative disease. Many patients with PMD exhibit severe psychomotor developmental delay and regression, such as lack of cervical or sitting positions or no speech. The number of patients with PMD is estimated to be about 100 in Japan, and is reported to be 1 in 200,000 to 500,000 in Europe and America (Non-patent Document 5).

Hetz C, Saxena S., ER stress and the unfolded protein response in neurodegeneration., Nature reviews Neurology, 2017, Vol. 13, p. 477-91 Hetz C, Mollereau B., Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases., Nat Rev Neurosci., 2014, 15, p. 233-49 Osaka H, Inoue K., Pathophysiology and emerging therapeutic strategies in Pelizaeus-Merzbacher disease., Expert Opinion on Orphan Drugs, 2015, Vol. 3, p. 1447-5 Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M et al., Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes., Stem Cell Reports., 2014 Year, Volume 2, p. 648-61 Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K et al., Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies., Journal of Neurology., 2014, 261, p. 752-8

  Various treatment methods have been developed for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis that can be associated with endoplasmic reticulum stress. However, even if the disease or symptom can be related to endoplasmic reticulum stress, no fundamental treatment method has been established for the disease or symptom caused by the structural failure of PLP1. For example, for PMD, currently, anticonvulsants for paralysis or coping treatment for complications are applied as the main treatment methods (Non-patent Document 5). Thus, for PMD, there has been no drug that has demonstrated the effectiveness of prevention or treatment.

  In order to develop a preventive or therapeutic means for a disease or symptom caused by structural failure of PLP1, it is necessary to find a drug having an improving effect on the structural failure of PLP1. However, no drug has been known that has a substantial improvement effect on PLP1 structural failure.

  Therefore, an object of the present invention is to provide means for substantially improving the structural failure of PLP1.

  The present inventors have studied various means for solving the above problems. The present inventors have found that certain compounds can substantially improve PLP1 structural dysfunction by screening known drug libraries. Based on the above findings, the present inventors have completed the present invention.

That is, the present invention includes the following aspects and embodiments.
(1) The following formula (I-1):
[Where:
n is an integer from 1 to 6,
R ¹¹ Independently of each other when there are a plurality, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or non-substituted Substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted Heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Siku Alkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted Or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted Properly is unsubstituted heteroaryl alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ¹² Is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Cycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or Unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl , Substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Alkoxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N11 And R ^N12 Are independently of one another hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Of cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted Or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino. ]
Or formula (I-2):
[Where:
R ^{twenty one} , R ^{twenty two} , R ^{twenty three} , R ^{twenty four} And R ^{twenty five} Independently of one another, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted Or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or Is unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted hetero Reel alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ²⁶ Is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Cycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or Unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl , Substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Alkoxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N21 And R ^N22 Are independently of one another hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Of cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted Or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N23 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryl Alkyloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl or substituted or unsubstituted amino,
R ^N24 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryl Alkyloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Or acyl or substituted or unsubstituted amino. ]
Or a stereoisomer or a salt thereof, or a solvate thereof as an active ingredient.
(2) n is 6,
R ¹¹ Are both hydrogen,
R ¹² Is hydrogen,
R ^N11 And R ^N12 Independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ The agent for improving structural failure of proteolipid protein 1 (PLP1) according to the embodiment (1), which is acyl or substituted or unsubstituted amino.
(3) R ^{twenty one} , R ^{twenty two} And R ^{twenty three} Are both hydroxyl,
R ^{twenty four} And R ^{twenty five} Are both hydrogen,
R ²⁶ Is hydroxyl, substituted or unsubstituted C ₁ ~ C ₆ Alkoxy, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxy, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxy, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxy or substituted or unsubstituted C ₁ ~ C ₂₀ Acyloxy,
R ^N21 And R ^N22 Independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ Acyl, or substituted or unsubstituted amino;
R ^N23 Is hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ Acyl, or substituted or unsubstituted amino;
R ^N24 Is hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ The agent for improving structural failure of proteolipid protein 1 (PLP1) according to the embodiment (1), which is acyl or substituted or unsubstituted amino.
(4) The following formula:
The proteolipid protein 1 (PLP1) according to any one of the above embodiments (1) to (3), which comprises a compound represented by formula (I), a stereoisomer or a salt thereof, or a solvate thereof as an active ingredient: Improvers of structural failure.
(5) The proteolipid protein 1 (PLP1) according to any one of the embodiments (1) to (4) for improving endoplasmic reticulum stress caused by structural failure of the proteolipid protein 1 (PLP1) An agent for improving structural failure.
(6) The following formula (I-1):
[Where:
n is an integer from 1 to 6,
R ¹¹ Independently of each other when there are a plurality, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or non-substituted Substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted Heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Siku Alkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted Or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted Properly is unsubstituted heteroaryl alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ¹² Is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Cycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or Unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl , Substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Alkoxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N11 And R ^N12 Are independently of one another hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Of cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted Or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino. ]
Or formula (I-2):
[Where:
R ^{twenty one} , R ^{twenty two} , R ^{twenty three} , R ^{twenty four} And R ^{twenty five} Independently of one another, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted Or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or Is unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted hetero Reel alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ²⁶ Is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Cycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or Unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl , Substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Alkoxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N21 And R ^N22 Are independently of one another hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Of cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted Or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N23 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryl Alkyloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl or substituted or unsubstituted amino,
R ^N24 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted Or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryl Alkyloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Or acyl or substituted or unsubstituted amino. ]
Or a stereoisomer or salt thereof, or a solvate thereof as an active ingredient is used for the prevention or treatment of a disease or symptom caused by structural failure of proteolipid protein 1 (PLP1) For medicine.
(7) n is 6,
R ¹¹ Are both hydrogen,
R ¹² Is hydrogen,
R ^N11 And R ^N12 Independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ The medicament according to the embodiment (6), which is acyl or substituted or unsubstituted amino.
(8) R ^{twenty one} , R ^{twenty two} And R ^{twenty three} Are both hydroxyl,
R ^{twenty four} And R ^{twenty five} Are both hydrogen,
R ²⁶ Is hydroxyl, substituted or unsubstituted C ₁ ~ C ₆ Alkoxy, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxy, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxy, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxy or substituted or unsubstituted C ₁ ~ C ₂₀ Acyloxy,
R ^N21 And R ^N22 Independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ Acyl, or substituted or unsubstituted amino;
R ^N23 Is hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ Acyl, or substituted or unsubstituted amino;
R ^N24 Is hydrogen, substituted or unsubstituted C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₂ ~ C _Five Alkenyl, substituted or unsubstituted C ₂ ~ C _Five Alkynyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkenyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyl, substituted or unsubstituted C ₁ ~ C _Five Alkoxycarbonyl, substituted or unsubstituted C _Three ~ C ₆ Cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ ~ C ₁₅ Aryloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkyloxycarbonyl, substituted or unsubstituted C ₇ ~ C ₂₀ Arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C _Five Alkyloxycarbonyl, substituted or unsubstituted C ₁ ~ C ₂₀ The medicament according to the embodiment (6), which is acyl or substituted or unsubstituted amino.
(9) The following formula:
The pharmaceutical in any one of said embodiment (6)-(8) containing the compound represented by these, its stereoisomer, those salts, or those solvates as an active ingredient.
(10) The medicament according to any one of the embodiments (6) to (9), for improving endoplasmic reticulum stress caused by structural failure of proteolipid protein 1 (PLP1).
(11) One or more diseases or symptoms selected from the group consisting of hereditary neuroleukoplasia, cerebral ischemia and manic depression, wherein the disease or symptoms resulting from structural failure of proteolipid protein 1 (PLP1) The medicament according to any one of the embodiments (6) to (10), wherein
(12) The medicament according to the embodiment (11), wherein the hereditary neuroleukoplasia is Pelizaeus-Merzbacher disease.

  According to the present invention, it is possible to provide means for substantially improving the structural failure of PLP1.

  Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

Figure 1 shows HEK293 cells transiently transfected with normal PLP1 and green fluorescent protein (GFP) fusion plasmid and severe mutant (A242V) PLP1 (PLP1 ^A242V ) and GFP fusion plasmid. It is a fluorescence micrograph of HEK293 cells transiently transfected. (A): HEK293 cells (PLP1-WT) transiently transfected with ^{normal PLP1} and GFP fusion plasmid, (B): Transiently transfected ^{PLP1 A242V} and GFP fusion plasmid HEK293 cells (PLP1-A242V). FIG. 2 is a graph comparing the GFP fluorescence intensity of the whole cell, cytoplasm, and cell membrane for a plurality of normal (PLP1-WT) and mutant (PLP1-A242V) clones. FIG. 3 is a graph showing a part of the results of primary screening of each drug in the drug library by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein. The vertical axis represents the relative value of the fluorescence intensity of the test group to which the drug was added relative to the fluorescence intensity of the control. The dotted line in the horizontal axis direction indicates the value of the fluorescence intensity that is determined to be effective. Figure 4 is the GFP fluorescence intensity analysis of mutant PLP1-GFP fusion protein in the cell membrane, co of the cells after the addition of agents No. 537 and 938 of the drug library PLP1 ^A242V stable expression strain of MO3.13 cells It is a focused laser microscope image (600 times). (A) and (B): cells added with drug No. 537, (C): cells added with drug No. 537. FIG. 5 is a graph showing the results of secondary screening of drug Nos. 537 and 938 in the drug library by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein. (A): fluorescence intensity of the mutant PLP1-GFP fusion protein localized in the cell membrane, (B): fluorescence intensity of the mutant PLP1-GFP fusion protein present in the whole cell. FIG. 6 is a graph showing the results of analysis of endoplasmic reticulum stress response after addition of drug No. 537 or 938 in the drug library. A vertical axis | shaft shows the fluorescence intensity by a luciferase activity.

  Hereinafter, preferred aspects and embodiments of the present invention will be described in detail.

<1. Improving the structural failure of proteolipid protein 1>
As used herein, “proteolipid protein 1 (PLP1)” means the most abundant protein constituting the myelin (myelin) of brain neurons. PLP1 is localized mainly in the cell membrane in myelin of brain neurons, and forms myelin together with myelin basic protein and the like.

  As used herein, “(protein) structural failure” refers to mutations such as substitutions, deletions or duplications that occur in the amino acid sequence (primary structure) of a protein, and / or changes in secondary structure (eg, disulfides) This means that the normal tertiary structure (higher order structure) of the protein and / or the normal function of the protein that can be expressed thereby is lost due to, for example, loss of binding.

  In the present specification, “endoplasmic reticulum stress” means a phenomenon caused by accumulation of abnormal protein that causes structural failure in the endoplasmic reticulum. Due to endoplasmic reticulum stress, endoplasmic reticulum stress responses such as chaperone protein expression induction, reduced protein synthesis and endoplasmic reticulum-related degradation occur. If abnormal proteins cannot be processed by these responses, the cells undergo apoptosis (Non-patent Document 2). In addition, loss of protein function may occur due to the protein not reaching the cell membrane or intracellular organelle that should be reached.

  A number of diseases or conditions that can be associated with endoplasmic reticulum stress are known. These diseases or conditions may be able to be prevented or treated by improving the structural failure of certain proteins that cause endoplasmic reticulum stress. For example, it is known that Pelizaeus-Merzbacher disease (PMD) develops due to structural failure of PLP1 (Non-patent Document 3). However, no fundamental therapeutic method has been established for diseases or symptoms caused by the structural failure of PLP1.

  In order to develop a preventive or therapeutic means for a disease or symptom caused by structural failure of PLP1, it is necessary to find a drug having an improving effect on the structural failure of PLP1. In particular, since PLP1 is a protein that constitutes myelin of cranial nerve cells, a drug that has an improving effect on PLP1 structural failure can be delivered to the brain or the central nervous system through the blood-brain barrier. It may be preferable to have a physical property. However, no drug having such a pharmacokinetic property has a substantial preventive or therapeutic effect on a disease or symptom caused by structural failure of PLP1.

The present inventors have found that by screening known drug libraries, certain compounds expected to be delivered to the brain or central nervous system can substantially improve PLP1 structural dysfunction. Therefore, one embodiment of the present invention is represented by the following formula (I-1):
Or formula (I-2):
Or a stereoisomer or salt thereof, or a solvate thereof as an active ingredient. It is known that certain compounds encompassed by the above formula, their stereoisomers or their salts, or their solvates can cross the blood brain barrier. Therefore, these compounds can be delivered to the brain or the central nervous system to prevent or treat various diseases or symptoms resulting from the structural failure of PLP1 by improving the structural failure of PLP1.

  In formula (I-1), n is an integer of 1-6. n is preferably 6.

In the formula (I-1), when there are a plurality of R ^{11 s} , independently of each other, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Substituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or Unsubstituted alkoxy, substituted Or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy Substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxy Aryloxycarbonyl, substituted or unsubstituted heteroaryl alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ¹¹ is independently from each other when a plurality of R ¹¹ are present, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or non-substituted C ₂ -C ₅ alkenyl substituted, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or non C ₃ -C ₆ cycloalkenyl substituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocyclo alkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted young Properly is 5-15 membered unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, Wakashi substituted Unsubstituted C ₆ -C ₁₅ aryloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, 5 substituted or unsubstituted 15-membered heteroaryloxy carbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino It is preferred that when there are a plurality, it is more preferred that all are hydrogen.

In the formula (I-1), R ¹² is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted. Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted hetero Cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy , Replace Or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted Lower reel alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ¹² is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or non-substituted C ₂ -C ₅ alkynyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered substituted or unsubstituted heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl, substituted or unsubstituted Of C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbo Cycloalkenyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted more it is hydrogen; 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl substituent, preferably a substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino preferable.

In formula (I-1), R ^N11 and R ^N12 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocyclo Alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ^N11 and R ^N12 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member Preferably heteroaryl-C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino; independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl , Substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl , substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, that substituted or unsubstituted 5-15 membered heteroaryl, or heteroaryl -C ₁ -C ₅ alkyl substituted or unsubstituted 5-15 membered More preferably; both are more preferably hydrogen.

In formula (I-2), R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclo Alkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero Arylalkyl, substituted or unsubstituted alkoxy, Or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy Substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxy Xoxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C _{1 to} C _5. alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, 3 substituted or unsubstituted 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5-15 membered substituted or unsubstituted heteroaryl Aryl, substituted Properly is 5-15 membered unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, Wakashi substituted Unsubstituted C ₆ -C ₁₅ aryloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, 5 substituted or unsubstituted 15-membered heteroaryloxy carbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino preferably there; independently of one another, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, location Or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered More preferably heteroaryl-C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy; independently of one another, hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or C ₃ -C ₆ cycloalkoxy unsubstituted heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted young properly Heteroaryl -C ₁ -C ₅ alkyloxy 5-15 membered unsubstituted or further preferably substituted or unsubstituted C ₁ -C ₂₀ acyloxy; R ^21, R ²² and R ²³ are both It is particularly preferred that it is hydroxyl and R ²⁴ and R ²⁵ are both hydrogen.

In the formula (I-2), R ²⁶ represents hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted. Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted hetero Cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy , Replace Or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted Arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted Lower reel alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ²⁶ is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or non-substituted C ₂ -C ₅ alkynyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered substituted or unsubstituted heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl, substituted or unsubstituted Of C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbo Cycloalkenyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted Preferably substituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino; hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered substituted or unsubstituted heterocyclo alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted young Properly is unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or more preferably C ₁ -C ₂₀ acyloxy substituted or unsubstituted; hydrogen, hydroxyl, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted heterocycloalkoxy 3-6 membered substituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl oxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or substituted or Particularly preferably hydroxyl; it is C ₁ -C ₂₀ acyloxy substituents are more preferred.

In formula (I-2), R ^N21 and R ^N22 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocyclo Alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member Preferably heteroaryl-C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino; independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl , Substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, a substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl , substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, that substituted or unsubstituted 5-15 membered heteroaryl, or heteroaryl -C ₁ -C ₅ alkyl substituted or unsubstituted 5-15 membered More preferably; both are more preferably hydrogen.

In formula (I-2), R ^N23 represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ^N23 is selected from hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted preferably a amino; hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalk Le, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ aryl More preferred is alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyl; more preferably hydrogen.

In the formula (I-2), R ^N24 represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, Substituted or unsubstituted acyl, or substituted or unsubstituted amino. R ^N24 is selected from hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted preferably a amino; hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalk Le, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ ~ C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ aryl More preferred is alkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyl; more preferably hydrogen.

In the formulas (I-1) and (I-2), when the group is substituted, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted Heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heteroarylalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Selected from the group consisting of heteroarylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, and substituted or unsubstituted amino it is preferably at least one monovalent group, a halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ ~ C ₅ alkenyl, location Or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and a substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl - C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy substituted or unsubstituted, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy conversion, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, substituted or more preferably unsubstituted C ₁ -C ₂₀ acyloxy, and at least one monovalent group selected from the group consisting of substituted or unsubstituted amino, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, Substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, and It is more preferably at least one monovalent group selected from the group consisting of substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, and particularly preferably hydroxyl. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

The compound represented by the formula (I-1) can include a compound defined by any combination of n, R ¹¹ , R ¹² , R ^N11 and R ^N12 exemplified above.

The compound represented by the formula (I-2) is any one of R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ^N21 , R ^N22 , R ^N23 and R ^N24 exemplified above. Compounds defined by combinations can be included.

Preferably, the compound represented by the formula (I-1) is
n is an integer from 1 to 6,
When a plurality of R ¹¹ are present, independently of each other, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or non-substituted C ₂ -C ₅ alkenyl substituted, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or non C ₃ -C ₆ cycloalkenyl substituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocyclo alkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted young Properly is 5-15 membered unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, Wakashi substituted Unsubstituted C ₆ -C ₁₅ aryloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxycarbonyl, 5 substituted or unsubstituted 15-membered heteroaryloxy carbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino Yes,
R ¹² is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or non-substituted C ₂ -C ₅ alkynyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered substituted or unsubstituted heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl, substituted or unsubstituted Of C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbo Cycloalkenyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl substituent, a substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N11 and R ^N12 are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member a heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

More preferably, the compound represented by the formula (I-1) is
n is 6,
R ¹¹ is both hydrogen,
R ¹² is hydrogen;
R ^N11 and R ^N12 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

More preferably, the compound represented by the formula (I-1) is
n is 6,
R ¹¹ is both hydrogen,
R ¹² is hydrogen;
R ^N11 and R ^N12 are both hydrogen.

Preferably, the compound represented by the formula (I-2) is
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C _{1 to} C _5. alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, 3 substituted or unsubstituted 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5-15 membered substituted or unsubstituted heteroaryl Aryl, substituted Properly is 5-15 membered unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, Wakashi substituted Unsubstituted C ₆ -C ₁₅ aryloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, 5 substituted or unsubstituted 15-membered heteroaryloxy carbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino Yes,
R ²⁶ is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or non-substituted C ₂ -C ₅ alkynyl substituted, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered substituted or unsubstituted heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl, substituted or unsubstituted Of C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkoxycarbonyl, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbo Cycloalkenyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl substituent, a substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member a heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N23 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N24 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

More preferably, the compound represented by the formula (I-2) is
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or C ₃ -C ₆ cycloalkoxy unsubstituted heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or heteroaryl -C ₁ ~ unsubstituted 5-15 membered a C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ²⁶ is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or heterocycloalkoxy 3-6 membered unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy a substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy And
R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
R ^N23 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyl;
R ^N24 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

More preferably, the compound represented by the formula (I-2) is
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ independently of one another are hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ²⁶ is hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryl Oxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
R ^N23 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₅ alkyl;
R ^N24 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino. When the monovalent group is substituted, the substituent is preferably further selected from the monovalent group, and more preferably selected from the unsubstituted monovalent group.

Particularly preferably, the compound represented by the formula (I-2) is
R ²¹ , R ²² and R ²³ are all hydroxyl,
R ²⁴ and R ²⁵ are both hydrogen,
R ²⁶ is hydroxyl,
R ^N21 and R ^N22 are both hydrogen,
R ^N23 is hydrogen,
R ^N24 is hydrogen.

Particularly preferably, the compound represented by the formula (I-1) is represented by the following formula (I-1-1):
Or a stereoisomer or a salt thereof, or a solvate thereof. The compound represented by the formula (I-1-1) includes 2-oxo-1-pyrrolidone acetamide (common name: piracetam) known as a brain function regulator.

Particularly preferably, the compound represented by the formula (I-2) is represented by the following formula (I-2-1):
Or a stereoisomer or a salt thereof, or a solvate thereof. The compound represented by the formula (I-2-1) is (2RS) -2-amino-3-hydroxy-N ′-(2,3,4-trihydroxybenzyl) propanoyl known as a therapeutic agent for Parkinson's disease It includes hydrazide monohydrochloride (common name: benserazide).

  A person skilled in the art can purchase these compounds based on the chemical structure and the compound name, apply an appropriate conversion reaction to the purchased compounds, or prepare the compounds by formula (I- A compound represented by 1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1) can be prepared.

  In each embodiment of the present invention, the compounds represented by formulas (I-1) and (I-2), particularly the compounds represented by formulas (I-1-1) and (I-2-1) It includes not only the compound itself but also its salt. Examples of the salt of the compound represented by the above formula include, but are not limited to, a salt with a cation such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, lactic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid , Ethanedisulfonic acid, propionic acid, tartaric acid, malic acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamine Acid, methanesulfonic acid, ethanesulfur Phosphate, isethionate, salts with organic acid anions such as p- toluenesulfonic acid or naphthalenesulfonic acid. When the compound represented by the above formula is in the form of the salt, the compound is used without substantially reducing the effect of improving the structural failure of PLP1, particularly the structural failure of PLP1, which can cause endoplasmic reticulum stress. can do.

  In each embodiment of the present invention, the compounds represented by formulas (I-1) and (I-2), particularly the compounds represented by formulas (I-1-1) and (I-2-1) It includes not only the compound itself but also a solvate of the compound or a salt thereof. Examples of the solvent that can form a solvate with the compound represented by the above formula, or a salt thereof include, but are not limited to, for example, water, or a lower alcohol (for example, methanol, ethanol, or 2-propanol (isopropyl Alcohols having 1 to 6 carbon atoms), higher alcohols (eg alcohols having 7 or more carbon atoms such as 1-heptanol or 1-octanol), dimethyl sulfoxide (DMSO), acetic acid Organic solvents such as ethanolamine or ethyl acetate are preferred. When the compound represented by the above formula or a salt thereof is in the form of a solvate with the above-mentioned solvent, the effect of improving the structural failure of PLP1, particularly the structural failure of PLP1, which can cause endoplasmic reticulum stress, is substantially reduced. The compound can be used without it.

  The compounds represented by the formulas (I-1) and (I-2), particularly the compounds represented by the formulas (I-1-1) and (I-2-1), are not only the compounds themselves, Protected forms are also included. In the present specification, the “protected form” means a form in which a protecting group is introduced into one or a plurality of functional groups (for example, a hydroxyl group or an amino group). In this specification, the protected form of the compound may be referred to as a protected derivative of the compound. In the present specification, a “protecting group” is a group introduced into a specific functional group in order to prevent an undesirable reaction from progressing, and is quantitatively removed under specific reaction conditions. In other reaction conditions, it means a group that is substantially stable, that is, reaction-inactive. The protecting group capable of forming a protected form of the compound is not limited. For example, in the case of a protecting group for a hydroxyl group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) Or tert-butyldiphenylsilyl (TBDPS)) or alkoxy (for example, methoxymethoxy (MOM) or methoxy (Me)) is an amino-protecting group, t-butoxycarbonyl (Boc), 2-bromobenzyloxy Carbonyl (BrZ) or 9-fluorenylmethoxycarbonyl (Fmoc) is preferred respectively. Protection and deprotection by the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. Even when the compound represented by the above formula is in a protected form by the above-described protecting group, the effect of improving the structural failure of PLP1, particularly the structural failure of PLP1, which can cause endoplasmic reticulum stress, is substantially reduced. In some cases, the compound can be used.

  In each embodiment of the present invention, there is one compound represented by the formulas (I-1) and (I-2), particularly one compound represented by the formulas (I-1-1) and (I-2-1). Alternatively, when a compound has a plurality of tautomers, the compound also includes individual tautomeric forms of the compound.

  In each embodiment of the present invention, compounds represented by formulas (I-1) and (I-2), particularly compounds represented by formulas (I-1-1) and (I-2-1) Where it has one or more stereocenters (chiral centers), the compound also includes the individual enantiomers and diastereomers of the compound, as well as the stereoisomers of the compound, including mixtures thereof such as racemates. Include.

  Due to the above characteristics, the compounds represented by the formulas (I-1) and (I-2), particularly the compounds represented by the formulas (I-1-1) and (I-2-1) It is possible to express a high improvement effect on structural failure of PLP1, particularly on structural failure of PLP1 that can cause endoplasmic reticulum stress.

<2. Pharmaceutical use>
As already explained, compounds represented by formula (I-1) or (I-2), particularly compounds represented by formula (I-1-1) or (I-2-1) are exemplified below. Administration to human or non-human mammalian cells or structures thereof substantially improves PLP1 structural dysfunction in the cells or structures thereof, particularly PLP1 structural dysfunction that can cause endoplasmic reticulum stress can do. Therefore, another aspect of the present invention is a compound represented by formula (I-1) or (I-2), particularly represented by formula (I-1-1) or (I-2-1). PLP1 structural insufficiency, in particular, the structure of PLP1 that can cause endoplasmic reticulum stress, comprising as an active ingredient The present invention relates to a medicament for use in improving dysfunction.

  In each embodiment of the present invention, “PLP1” is usually a human or non-human mammal, such as a human or pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon. Alternatively, it is a protein constituting the myelin of a brain neuron of a warm-blooded animal such as a chimpanzee or a structure thereof, and particularly a protein constituting the myelin of a human brain nerve cell or a structure thereof. By administering a compound represented by the above formula or a medicine containing the compound as an active ingredient to the cells of the organism or the structure thereof, the structural failure of PLP1 present in the cell or the structure thereof can be reduced. It can be substantially improved.

  In each aspect of the invention, the “endoplasmic reticulum” is usually a human or non-human mammal, such as a human or pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, It is an endoplasmic reticulum present in a cell of warm-blooded animals such as baboon or chimpanzee or a structure thereof, and particularly an endoplasmic reticulum present in a human cell or structure thereof. By administering a compound represented by the above formula or a pharmaceutical containing the compound as an active ingredient to the cells of the organism or the structure thereof, in the endoplasmic reticulum existing in the cell or the structure thereof, PLP1 structural dysfunction that can cause endoplasmic reticulum stress can be substantially improved.

  In each embodiment of the present invention, “PLP1 structural dysfunction” refers to mutations such as substitutions, deletions or duplications that occur in the amino acid sequence (primary structure) of the PLP1 protein, and / or secondary structure changes caused thereby (for example, It means that the normal tertiary structure (higher order structure) of the PLP1 protein and / or the normal function of the PLP1 protein that can be expressed thereby is lost due to a disulfide bond deletion or the like. Due to the structural failure of PLP1, various diseases or symptoms exemplified below may occur. In addition, structural failure of PLP1 can cause endoplasmic reticulum stress.

  In each embodiment of the present invention, the “improvement of PLP1 structural dysfunction” is a PLP1 protein that is substantially reduced in the PLP1 protein and / or reduced by losing the normal tertiary structure. It means to restore the normal functioning of. As already explained, the compounds represented by the formulas (I-1) and (I-2), particularly the compounds represented by the formulas (I-1-1) and (I-2-1) A high ameliorating effect can be expressed for structural failure, particularly PLP1 structural failure that can cause endoplasmic reticulum stress. Therefore, the compounds represented by formulas (I-1) and (I-2), particularly the compounds represented by formulas (I-1-1) and (I-2-1), are molecular chaperones for PLP1 protein. Can act as Therefore, the medicament of this embodiment can be used as a molecular chaperone for PLP1 protein.

In each embodiment of the present invention, the effect of improving the structural failure of PLP1 by the compound used as an active ingredient is not limited, but can be determined by, for example, the following means. PLP1 with structural failure stays around the nucleus and is not distributed throughout the cytoplasm, and the endoplasmic reticulum stress response is enhanced (Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M et al., Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes., Stem Cell Reports., 2014, Vol. 2, p. 648-61). Here, when the intracellular localization of PLP1 protein is improved by adding a target compound, the compound can be a candidate for a prophylactic or therapeutic agent for a disease or symptom caused by structural failure of PLP1. Such compounds can also be candidates for molecular chaperone therapeutics. First, a fusion protein (eg, ^{PLP1 A242V-} GFP) of ^{mutant PLP1} and green fluorescent protein (hereinafter also referred to as “GFP”) is transfected into a test cell (eg, HEK293 cell or MO3.13 cell). . Next, each stable cell line is prepared by adding aminoglycosides used for selection of eukaryotic cells. A target compound is added to the obtained ^{PLP1 A242V-} GFP stable expression strain, and changes in GFP fluorescence intensity and subcellular localization before and after the addition of the target compound are ^measured using, for example, In Cell Analyzer (registered trademark) (hereinafter referred to as “ICA”). (Also described) (GE Healthcare). As the primary screening, a compound that increases the fluorescence intensity of the whole cell may be selected. As the secondary screening, for the compounds selected in the primary screening, images of cells before and after compound addition are taken with a confocal laser microscope, and compounds that increase the fluorescence intensity of the cell membrane may be selected. By such means, it is possible to evaluate the effect of improving the structural failure of PLP1, particularly the structural failure of PLP1, which can induce endoplasmic reticulum stress, by the target compound.

  In each embodiment of the present invention, the compound represented by the above formula used as an active ingredient is usually 10 nM or more, for example, in the range of 10 nM to 100 μM, preferably in the range of 10 nM to 10 μM. The effect of improving PLP1 structural dysfunction, particularly PLP1 structural dysfunction capable of causing endoplasmic reticulum stress, can be expressed.

  Compounds represented by formulas (I-1) and (I-2), particularly compounds represented by formulas (I-1-1) and (I-2-1) are both known as active ingredients of pharmaceuticals. Or include such known agents. These drugs known as active ingredients of pharmaceuticals have been sufficiently confirmed in safety. Therefore, the compound represented by the above formula can be applied to the pharmaceutical use of each aspect of the present invention as an active ingredient whose safety has been confirmed.

  That the compounds represented by formulas (I-1) and (I-2), particularly the compounds represented by formulas (I-1-1) and (I-2-1), can cross the blood-brain barrier. It has been known. Therefore, the compound represented by the above formula is delivered to the brain or the central nervous system and is caused by ER stress caused by structural failure of PLP1, in particular, structural failure of PLP1, by improving the structural failure of PLP1. Various diseases or symptoms can be prevented or treated.

  When the compound represented by the formula (I-1) or (I-2), particularly the compound represented by the formula (I-1-1) or (I-2-1) is applied for pharmaceutical use, The compounds include not only the compounds themselves, but also stereoisomers of the compounds, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The compounds represented by the above formula, and pharmaceutically acceptable salts of the stereoisomers thereof, and pharmaceutically acceptable solvates thereof are not limited, but examples thereof include those exemplified above. Salts or solvates are preferred. When the compound represented by the above formula or a stereoisomer thereof is in the form of the above-mentioned salt or solvate, the effect of improving the structural failure of PLP1, particularly the structural failure of PLP1, which can cause endoplasmic reticulum stress, is substantially improved. The compound can be applied to the desired pharmaceutical use without reduction.

  When the compound represented by the formula (I-1) or (I-2), particularly the compound represented by the formula (I-1-1) or (I-2-1) is applied for pharmaceutical use, A compound includes not only the compound itself but also a prodrug form of the compound. As used herein, “prodrug” means a compound that is converted into the parent drug in vivo. The prodrug form of the compound is not limited. For example, when a hydroxyl group is present, an ester of the hydroxyl group and an arbitrary carboxylic acid, sulfonic acid, phosphoric acid, phosphonic acid or phosphinic acid is used. Can be mentioned. For example, when an amino group is present, an amide of the amino group and an arbitrary carboxylic acid can be exemplified. When the compound represented by the above formula is in the above-mentioned prodrug form, the compound represented by the above formula, which is the parent drug, has an effect of improving the structural failure of PLP1, particularly the structural failure of PLP1 that can cause endoplasmic reticulum stress. The pharmacokinetics upon administration of the prodrug form to the subject can be improved without substantially reducing it.

  When the compound represented by the formula (I-1) or (I-2), particularly the compound represented by the formula (I-1-1) or (I-2-1) is applied for pharmaceutical use, the compound May be used alone or in combination with one or more pharmaceutically acceptable ingredients. The medicament of this embodiment can be formulated into various dosage forms commonly used in the art depending on the desired administration method. Therefore, the medicament of this embodiment also comprises a pharmaceutical composition comprising a compound represented by the above formula, a stereoisomer or salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. It can also be provided in the form of a thing. In addition to the above components, the pharmaceutical composition of this embodiment comprises one or more pharmaceutically acceptable media (for example, a solvent such as sterile water or a solution such as physiological saline), an excipient, a binder, Vehicles, solubilizers, preservatives, stabilizers, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffering agents, soothing agents, antioxidants, sweeteners and A flavoring agent etc. may be included.

  A compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutical thereof The pharmaceutical dosage form of this embodiment containing an acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient is not particularly limited, and may be a preparation for use in parenteral administration, It may be a preparation for use in oral administration. In addition, the pharmaceutical dosage form of this embodiment may be a unit dosage form or a multiple dosage form. Examples of preparations for parenteral administration include injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media, lotions, ointments, eye drops, and suppositories. Can be mentioned. Ingredients that can be mixed with injections include, but are not limited to, for example, saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions, solubilizing agents such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), polysorbate 80 ™ or poly Nonionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, benzalkonium chloride or procaine hydrochloride A soothing agent, human serum albumin or Stabilizers such as polyethylene glycol, may be mentioned preservatives, and antioxidants, and the like. The prepared injection is usually filled in an appropriate vial (for example, an ampoule) and stored in an appropriate environment until use.

  Preparations for use in oral administration include, for example, tablets, pills, powders, granules, powders, capsules, soft capsules, microcapsules, elixirs, solutions, syrups, slurries and suspensions. Etc. The tablet may be formulated as a sugar-coated tablet with a sugar coating or a soluble coating, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet, if desired, or as a dosage form of a double tablet or a multilayer tablet It may be formulated.

  Ingredients that can be mixed into tablets or capsules are not limited, but for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, Binders such as gelatin, corn starch, gum tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch or lactose; white sugar, stearin cacao Disintegration inhibitors such as water or hydrogenated oils; absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; humectants such as glycerin or starch; starch, lactose, kaolin, bentonite or colloidal silicic acid Adsorbents such as; refined talc, stearates (eg magnesium stearate), lubricants such as boric acid powder or polyethylene glycol; sweeteners such as sucrose, lactose or saccharin; and peppermint, red oil or cherry And the like. When the preparation is a capsule, it may further contain a liquid carrier such as fats and oils.

  The medicament of this embodiment can also be formulated as a depot preparation. In this case, the medicament of this embodiment in the form of a depot preparation can be administered, for example, subcutaneously or intramuscularly, or administered by intramuscular injection. By applying the medicament of this embodiment to a depot preparation, a compound represented by formula (I-1) or (I-2), particularly represented by formula (I-1-1) or (I-2-1) The effect of improving the structural failure of PLP1 by the compound, particularly the structural failure of PLP1 that can induce endoplasmic reticulum stress, can be expressed continuously over a long period of time.

  A compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutical thereof The medicament of this embodiment containing an acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient can be used in combination with one or more other drugs useful as a medicament. In the pharmaceutical of this embodiment, the other drug used in combination with the compound represented by the above formula is not limited, but for example, one or more other compounds represented by the above formula except the compound and Curcumin etc. can be mentioned. In this case, the medicament of this embodiment includes a compound represented by the above formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more kinds of the other. It becomes the form of the combined use medicine containing this medicine. The concomitant drug comprises a compound represented by the above formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more other drugs. It may be in the form of a combined pharmaceutical composition, including a compound represented by the above formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. It may be in the form of a pharmaceutical composition used in combination with one or more other drugs. When the medicament of this embodiment is in the form of a combined medicament as described above, the compound represented by the above formula, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof And a pharmaceutical combination or kit comprising a plurality of formulations separately formulated with one or more other drugs. It may be provided in the form. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (eg sequentially).

  A compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutical thereof The pharmaceutical of this embodiment containing an acceptable salt, or a pharmaceutically acceptable solvate thereof as an active ingredient, has various structural diseases caused by structural failure of PLP1, particularly endoplasmic reticulum stress caused by structural failure of PLP1, Symptoms and / or disorders can be similarly prevented or treated. Examples of the disease, symptom and / or disorder include, but are not limited to, hereditary neurowhite matter dysplasia (also known as congenital cerebral white matter dysplasia) such as Pelizaeus-Merzbacher disease (PMD), Mention may be made of cerebral ischemia and manic depression (Lindholm, D., Korhonen, L. and Koeks, S., Frontiers in Cell and Developmental Biology, 2017, Vol. 5, p. 1-16). By administering the medicament of this embodiment to a subject in need of prevention or treatment of the disease, symptom or disorder, the disease, symptom or symptom caused by ER stress caused by structural failure of PLP1, particularly PLP1 structural failure The disorder, for example, one or more diseases or symptoms selected from the group consisting of inherited neurodystrophy such as PMD, cerebral ischemia and manic depression can be prevented or treated.

  A compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutical thereof The pharmaceutical of the present embodiment comprising an acceptable salt or a pharmaceutically acceptable solvate thereof as an active ingredient is the PLP1 structural failure, particularly the symptom or disease caused by endoplasmic reticulum stress caused by the structural failure of PLP1. And / or can be applied to various subjects in need of prevention or treatment of disorders. The subject is usually a human or non-human mammal such as a human or a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee. Preferably it is a subject or patient. By administering the medicament of this embodiment to the subject, preventing or treating the disease, symptom and / or disorder caused by structural failure of PLP1 possessed by the subject, particularly endoplasmic reticulum stress caused by structural failure of PLP1 Can do.

  As used herein, “prevention” means substantially preventing the occurrence (onset or onset) of symptoms, diseases and / or disorders. In the present specification, “treatment” means to suppress (e.g., suppress progression), relieve, repair, and / or cure a symptom, disease, and / or disorder that has occurred (onset or onset).

  The compound represented by the formula (I-1) or (I-2), particularly the compound represented by the formula (I-1-1) or (I-2-1), is the symptom, disease and It can be used in the prevention or treatment of the symptoms, diseases and / or disorders in a subject having a disorder (eg, hereditary neuroleukoplasia, cerebral ischemia and manic depression). Therefore, the medicament of this embodiment is a medicament for use in the prophylaxis or treatment of the symptoms, diseases and / or disorders described above (for example, inherited neuroleukodysplasia, cerebral ischemia and manic depression). Preferably, it is a medicament for use in the prevention or treatment of one or more diseases or symptoms selected from the group consisting of hereditary neuroleukoplasia, such as PMD, cerebral ischemia and manic depression Is more preferable. By using the medicament of this embodiment for the prevention or treatment of the above symptoms, diseases and / or disorders caused by structural failure of PLP1, in particular, endoplasmic reticulum stress caused by structural failure of PLP1, the compound represented by the above formula The symptom, disease and / or disorder can be prevented or treated through the ameliorating effect of PLP1 structural dysfunction, particularly PLP1 structural dysfunction capable of causing endoplasmic reticulum stress.

  The compound represented by the formula (I-1) or (I-2), particularly the compound represented by the formula (I-1-1) or (I-2-1), is the symptom, disease and It can be used in the prevention or treatment of the symptoms, diseases and / or disorders in a subject having a disorder (eg, hereditary neuroleukoplasia, cerebral ischemia and manic depression). Therefore, another aspect of the present invention requires the prevention or treatment of the symptoms, diseases and / or disorders described above (eg, hereditary neuroleukoplasia, cerebral ischemia and manic depression) Subject is an effective amount of a compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), and its stereoisomerism Said disease caused by structural failure of PLP1, in particular, endoplasmic reticulum stress caused by structural failure of PLP1, comprising administering to the body or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof Alternatively, it is a method for preventing or treating symptoms. The symptom, disease and / or disorder is preferably one or more diseases or symptoms selected from the group consisting of inherited dysgenesis such as PMD, cerebral ischemia and manic depression. By administering the compound represented by the above formula to a subject in need of prophylaxis or treatment of the symptom, disease and / or disorder caused by structural failure of PLP1, particularly endoplasmic reticulum stress caused by structural failure of PLP1 The symptom, disease and / or disorder can be prevented or treated through the effect of improving the structural failure of PLP1 by the compound represented by the above formula, particularly the structural failure of PLP1 which can cause endoplasmic reticulum stress.

  Another aspect of the invention is a formula for use in the prevention or treatment of the symptoms, diseases and / or disorders described above (eg, hereditary neuroleukoplasia, cerebral ischemia and manic depression). A compound represented by (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutically acceptable product thereof Or a pharmaceutically acceptable solvate thereof. Another aspect of the present invention is the production of a medicament for use in the prevention or treatment of the symptoms, diseases and / or disorders described above (eg, hereditary neuroleukoplasia, cerebral ischemia and manic depression). A compound of formula (I-1) or (I-2), in particular a compound of formula (I-1-1) or (I-2-1), a stereoisomer or The use of their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates. The symptom, disease and / or disorder is preferably one or more diseases or symptoms selected from the group consisting of inherited dysgenesis such as PMD, cerebral ischemia and manic depression. By using the compound represented by the above formula or the pharmaceutical agent of this embodiment for the prevention or treatment of the above-mentioned symptoms, diseases and / or disorders caused by structural failure of PLP1, particularly endoplasmic reticulum stress caused by structural failure of PLP1. The symptom, disease and / or disorder can be prevented or treated through the effect of improving the structural failure of PLP1 by the compound represented by the above formula, particularly the structural failure of PLP1 which can cause endoplasmic reticulum stress.

  A compound represented by formula (I-1) or (I-2), particularly a compound represented by formula (I-1-1) or (I-2-1), a stereoisomer thereof, or a pharmaceutical thereof When a pharmaceutical comprising an acceptable salt, or a pharmaceutically acceptable solvate thereof as an active ingredient, is administered to a subject, particularly a human patient, the exact dosage and usage (eg, dosage, frequency of administration and / or The route of administration) is treated by the attending physician in view of many factors such as the subject's age, sex, symptoms to be prevented or treated, the exact state of the disease and / or disorder (eg severity), and the route of administration. It should be finally determined in consideration of the effective dose, the number of administrations, the administration route, and the like. Therefore, in the medicament of this embodiment, the compound represented by the above formula as an active ingredient is administered to a subject in a therapeutically effective amount and frequency. For example, when the pharmaceutical of this embodiment is administered to a human patient, the dose of the compound represented by the above formula as an active ingredient is usually in the range of 0.001 to 100 mg / kg body weight per administration, Typically, it is in the range of 0.01 to 10 mg / kg body weight per dose, in particular in the range of 0.1 to 10 mg / kg body weight per dose. In addition, the number of administrations of the medicament of this embodiment can be, for example, once a day or multiple times (for example, 2 or 3 times), or once every several days. In addition, the administration route of the medicament of this embodiment is not particularly limited, and may be administered orally, and parenterally (for example, rectal, radial mucosa, intestine, intramuscular, subcutaneous, intramedullary, intrathecal). May be administered directly or intra-ventricularly, intravenously, intravitreally, intraperitoneally, intranasally, or intraocularly). By using the pharmaceutical agent of this embodiment in the above-mentioned dosage and usage, PLP1 structural dysfunction caused by the compound represented by the above formula, in particular, PLP1 structural dysfunction capable of causing endoplasmic reticulum stress is improved. It is possible to prevent or treat the above-mentioned symptoms, diseases and / or disorders caused by endoplasmic reticulum stress caused by structural failure, particularly PLP1 structural failure.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

<I. Overview>
The following experiments were carried out using Pelizaeus-Merzbacher disease (PMD), a neurodegenerative disease of childhood onset, as a model. PMD is an intractable disease that develops mainly due to mutations such as substitution, deletion, or duplication in proteolipid protein 1 (PLP1). In previous studies, PLP1 cells that had severe mutations and had structural defects when differentiated from PMD patient cells into iPS and oligodendrocytes remained around the nucleus and were not distributed throughout the cytoplasm. It was shown that stress response is enhanced (Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M et al., Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes., Stem Cell Reports., 2014, Vol. 2, p. 648-61). Here, when the intracellular localization of PLP1 protein is improved by adding a specific drug, the drug becomes a candidate for the prevention or treatment of a disease or symptom caused by structural failure of PLP1, such as PMD. obtain. Such drugs can also be candidates for molecular chaperone therapeutics.

<II. Materials>
[II-1. Compound]
Among diseases or symptoms caused by endoplasmic reticulum stress, PMD and the like manifest major symptoms in the central nervous system. Accordingly, a commercially available drug library of central nervous system agonists (Perkin Elmer), which is known to be able to cross the blood brain barrier, was used. This drug library contains 275 known drugs.

[II-2. Cells]
Green fluorescent protein of PLP1 normal type and four types of PLP1 variants (A242V, W162R (severe type), I186T, and W162L (mild type)) for the selection of variants to be used in the drug screening experiments shown below The (GFP) fusion plasmid was transfected into human fetal kidney cell-derived HEK293 cells by the lipofectamine method using Lipofectamine (registered trademark) 3000 transfection kit (Invitrogen). Using In Cell Analyzer (registered trademark) (hereinafter also referred to as “ICA”) (GE Healthcare), the GFP fluorescence intensity and subcellular localization of each mutant were compared with the normal results. HEK293 cells transiently transfected with normal PLP1 and GFP fusion plasmid and HEK293 transiently transfected with severe mutant (A242V) PLP1 (PLP1 ^A242V ) and GFP fusion plasmid A fluorescence micrograph of the cells is shown in FIG. In the figure, (A) shows HEK293 cells (PLP1-WT) transiently transfected with a ^{normal PLP1} and GFP fusion plasmid, and (B) shows a ^{PLP1 A242V} and GFP fusion plasmid. HEK293 cells (PLP1-A242V) transiently transfected are shown respectively. FIG. 2 shows a graph comparing the GFP fluorescence intensity of the whole cell, cytoplasm, and cell membrane for a plurality of normal (PLP1-WT) and mutant (PLP1-A242V) clones.

  As shown in Figure 1, in normal cells (PLP1-WT), the fusion protein was expressed in large amounts throughout the cell (A), whereas in mutant cells (PLP1-A242V) The expression level decreased and the localization of the fusion protein in the cell membrane was low (B). In addition, as shown in FIG. 2, the fluorescence intensity of the fusion protein in the mutant type (PLP1-A242V) cells is generally lower than that in the normal type (PLP1-WT) cells, In particular, the fluorescence intensity of the fusion protein localized in the cell membrane was reduced.

^{PLP1 A242V} GFP fusion protein was transfected into HEK293 cells and MO3.13 cells (derived from oligodendrocytes) by the lipofectamine method. Next, each stable cell line was prepared by adding G418 (Geneticin (registered trademark)), which is an aminoglycoside used for selection of eukaryotic cells. It was confirmed by live cell imaging and anti-GFP staining with a fluorescence microscope that GFP was contained in the obtained cell colony. For staining, anti-tGFP (TA150041, OriGene Technologies, × 200) was used as the primary antibody, and Goat Anti-Mouse IgG H & L (Alexa Fluor (registered trademark) 568, Abcam, × 250) was used as the secondary antibody. .

<III. Method>
[III-1. GFP fluorescence intensity analysis in whole cells]
In the intracellular localization analysis of proteins, it was judged that MO3.13 cells were more suitable than HEK293 cells, considering the cytoplasmic morphology and the origin of oligodendrocytes of the central nervous system. 275 drugs included in the drug library were added to the ^{PLP1 A242V} stable expression strain of MO3.13 cells, and changes in GFP fluorescence intensity and subcellular localization before and after the addition of the drug were determined by ICA (GE Healthcare). ). As a primary screening, an agent that increases the fluorescence intensity of the whole cell was selected by the following procedure. The PLP1 ^A242V stably expressing cell line of MO3.13 cells was seeded in a 96-well plate at a cell density of 1 × 10 ⁴ cells / well. Twenty-four hours after seeding, 275 drugs contained in the drug library were added to each well so that the final concentration was 10 μM. Twenty-four hours after the addition of the drug, the fluorescence intensity of the whole cell was measured using ICA, and the relative value of the fluorescence intensity of the test group with the drug added to the fluorescence intensity of the control without the drug was calculated. The same measurement was repeated 3 times to select drugs that significantly increased the fluorescence intensity of the whole cell.

[III-2. Analysis of GFP fluorescence intensity in cell membrane by image using confocal laser microscope]
In the analysis by ICA using the 96-well plate described in III-1, the intracellular localization of GFP could not be stably analyzed. Therefore, as a secondary screening, the following procedure is used to examine the fluorescence intensity of the cell membrane by taking images of MO3.13 cells before and after compound addition using the confocal laser microscope. Analysis was performed with ICA using the following protocol. The MO3.13 cell ^{PLP1 A242V} stably expressing cell line was seeded in an 8-well plate at a cell density of 2 × 10 ⁴ cells / well. Twenty-four hours after seeding, the drug selected in the analysis of III-1 was added to each well so that the final concentration was 10 μM. Twenty-four hours after the addition of the drug, 10 images of each image were taken using a confocal laser microscope (× 600). Using ICA, the fluorescence intensity of the fusion protein localized in the cell membrane and the fluorescence intensity of the fusion protein in the whole cell in the photographed image were measured, and a drug that significantly increased the fluorescence intensity of the cell membrane was selected.

[III-3. Analysis of endoplasmic reticulum stress response by drug addition]
It was verified that the addition of a drug selected by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein described in III-1 and III-2 reduced the endoplasmic reticulum stress. The PLP1 ^A242V stably expressing cell line of MO3.13 cells was seeded in a 96-well plate at a cell density of 1 × 10 ⁴ cells / well. Immediately after seeding, the selected drugs were added to each well to a final concentration of 10 μM. 24 hours after the addition of the drug, an endoplasmic reticulum stress detection vector (ERAI ER Stress Detector (registered trademark), Cosmo Bio) was transfected by the lipofectamine method. After 18 hours, the medium in each well was placed in a medium containing tunicamycin (5 μg / ml) that induces endoplasmic reticulum stress by XBP1 via an inositol-requiring enzyme 1α (hereinafter also referred to as “IRE1α”) protein sensor. Exchanged. Six hours after the medium exchange, luciferase activity reflecting endoplasmic reticulum stress was analyzed using Nano-Glo Dual-Luciferase Reporter Assay System (registered trademark) (Promega).

[III-4. Gene expression analysis by drug addition using microarray]
In order to analyze the gene expression change of ^{PLP1 A242V} by candidate drugs, microarray analysis was performed. Drug No. 537 (Piracetam) was used as a candidate drug. HEK293 cell ^{PLP1 A242V} stable expression cell line candidate drug addition group ( ^{PLP1 A242V} + Piracetam), stable expression cell line candidate drug addition group ( Three groups of RNA, ^{PLP1 A242V} ) and normal ^PLP1- expressing cell line (PLP1 ^Wt ) of HEK293 cells, were extracted using RNeasy (registered trademark) Mini kit (QIAGEN). This RNA was sent to Takara Bio Inc. to request microarray analysis. From the analysis results, gene expression ratios using Log2 values were compared.

<IV. Results>
[IV-1. GFP fluorescence intensity analysis]
FIG. 3 shows a part of the results of primary screening of each drug in the drug library by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein described in III-1. In the figure, the vertical axis indicates the relative value of the fluorescence intensity of the test group to which the drug was added relative to the fluorescence intensity of the control. The dotted line in the horizontal axis direction indicates the value of the fluorescence intensity that is determined to be effective.

As shown in FIG. 3, in some drugs, an increase in fluorescence intensity due to the addition of the drug was observed. In particular, when Drug Nos. 537 and 938 (indicated by a box in FIG. 3) were added, a stable increase in fluorescence intensity was observed. Therefore, secondary screening was performed for drugs No. 537 and 938 by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein described in III-2 above. In the GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein in the cell membrane described in III-2 above, the drug library drug Nos. 537 and 938 are added to the ^{PLP1 A242V} stable expression strain of MO3.13 cells. FIG. 4 shows a confocal laser microscope image (600 ×) of the cells. In the figure, (A) and (B) show cells to which drug No. 537 has been added, and (C) show cells to which drug No. 537 has been added. Further, FIG. 5 shows the results of secondary screening of drug Nos. 537 and 938 in the drug library by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein in the cell membrane described in III-2 above. In the figure, (A) shows the fluorescence intensity of the fusion protein localized in the cell membrane, and (B) shows the fluorescence intensity of the fusion protein present in the whole cell. In addition, the parentheses in the figure indicate that the P value relative to the control calculated by the student t-test is less than 0.01.

  As shown in FIGS. 4 and 5, the addition of drugs No. 537 and 938 increased the fluorescence intensity of the fusion protein present in the whole cell in addition to the fusion protein localized in the cell membrane. Based on these results, two types of drugs No. 537 and 938 were determined to be effective. Although the results are not shown, in the primary screening by GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein described in III-1 above, Drug Nos. 93 and 101 in which an increase in fluorescence intensity due to drug addition was observed 271, 297, 317, 329, 341 and 1104 were also subjected to GFP fluorescence intensity analysis of the mutant PLP1-GFP fusion protein in the cell membrane described in III-2 above.

  The compound names and chemical structures of the two candidate drugs are shown below.

[IV-2. Analysis of endoplasmic reticulum stress response by drug addition]
FIG. 6 shows the analysis results of the endoplasmic reticulum stress response after the addition of the drug No. 537 or 938 in the drug library described in III-3 above. In the figure, the vertical axis indicates the fluorescence intensity due to luciferase activity. In addition, the parentheses in the figure indicate that the P value relative to the control calculated by Student's t-test is less than 0.04 or 0.22.

  As shown in FIG. 6, a decrease in fluorescence intensity due to luciferase activity reflecting the endoplasmic reticulum stress response was observed by the addition of drug No. 537 or 938. From this result, it is presumed that the endoplasmic reticulum stress induced by tunicamycin was significantly reduced by the addition of the drug No. 537 or 938.

[IV-3. Gene expression analysis by drug addition using microarray]
The gene whose expression was decreased in the ^{PLP1 A242V} group was increased in the ^{PLP1 A242V} + Piracetam group. In contrast, genes whose expression was increased in the ^{PLP1 A242V} group decreased in the ^{PLP1 A242V} + Piracetam group. PLP1 ^A242V + piracetam genes whose expression was increased in groups, 42 different, genes whose expression was decreased in PLP1 ^A242V + piracetam group was 83 types identified. The gene expression is decreased in Table 2 in PLP1 ^A242V group, a gene whose expression is increased in PLP1 ^A242V group in Table 3, respectively. In Table 2, underlined genes indicate genes whose expression was increased in the ^{PLP1 A242V} + Piracetam group. In Table 3, the underlined genes are genes whose expression is reduced in the ^{PLP1 A242V} + Piracetam group.

  As shown in Tables 2 and 3, since the gene whose expression level is changed by the addition of piracetam was a gene mainly involved in cell adhesion or signal transduction, it is assumed that piracetam is mainly involved in cell adhesion or signal transduction. Is done.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Moreover, it is possible to add, delete, and / or replace another configuration with respect to a part of the configuration of each embodiment.

Claims (12)

Formula (I-1) below:
[Where:
n is an integer from 1 to 6,
R ¹¹ is independently from each other when a plurality of R ¹¹ are present, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or Unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Replacement Chloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Substituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, Substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, Or unsubstituted heteroaryl alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ¹² is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Telocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted Or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxy Carbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N11 and R ^N12 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarboni , Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxy Carbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. ]
Or formula (I-2):
[Where:
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or non-substituted Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl Alkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted Chloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Substituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, Substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, Substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ²⁶ is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Telocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted Or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxy Carbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N21 and R ^N22 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarboni , Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxy Carbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl Aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl, or substituted or unsubstituted amino;
R ^N24 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl Aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl or substituted or unsubstituted amino. ]
Or a stereoisomer or a salt thereof, or a solvate thereof as an active ingredient. n is 6,
R ¹¹ is both hydrogen,
R ¹² is hydrogen;
R ^N11 and R ^N12 are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered structure heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino, proteolipid protein 1 according to claim 1 of (PLP1) Remedy for dysfunction. R ²¹ , R ²² and R ²³ are all hydroxyl,
R ²⁴ and R ²⁵ are both hydrogen,
R ²⁶ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member a heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N23 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N24 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino, improvement of structural failure of proteolipid protein 1 according to claim 1 (PLP1) Agent. The following formula:
The structure failure of proteolipid protein 1 (PLP1) as described in any one of Claims 1-3 containing the compound represented by these, its stereoisomer, those salts, or those solvates as an active ingredient Improver.   The agent for improving structural failure of proteolipid protein 1 (PLP1) according to any one of claims 1 to 4, for improving endoplasmic reticulum stress caused by structural failure of proteolipid protein 1 (PLP1). Formula (I-1) below:
[Where:
n is an integer from 1 to 6,
R ¹¹ is independently from each other when a plurality of R ¹¹ are present, hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or Unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Replacement Chloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Substituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, Substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, Or unsubstituted heteroaryl alkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ¹² is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Telocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted Or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxy Carbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N11 and R ^N12 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarboni , Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxy Carbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino. ]
Or formula (I-2):
[Where:
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or non-substituted Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl Alkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted Chloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Substituted heteroarylalkyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, Substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, Substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ²⁶ is hydrogen, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted Telocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted Or unsubstituted acyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxy Carbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyl Oxycarbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N21 and R ^N22 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarboni , Substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxy Carbonyl, substituted or unsubstituted acyl, or substituted or unsubstituted amino,
R ^N23 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl Aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl, or substituted or unsubstituted amino;
R ^N24 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl Substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl Aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted heterocycloalkoxycarbonyl, substituted or unsubstituted Aryloxycarbonyl, substituted or unsubstituted arylalkyloxycarbonyl, substituted or unsubstituted arylalkenyloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted Acyl or substituted or unsubstituted amino. ]
Or a stereoisomer or salt thereof, or a solvate thereof as an active ingredient is used for the prevention or treatment of a disease or symptom caused by structural failure of proteolipid protein 1 (PLP1) For medicine. n is 6,
R ¹¹ is both hydrogen,
R ¹² is hydrogen;
R ^N11 and R ^N12 are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino, medicament according to claim 6. R ²¹ , R ²² and R ²³ are all hydroxyl,
R ²⁴ and R ²⁵ are both hydrogen,
R ²⁶ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ^N21 and R ^N22 are independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ ~C ₅ Arco Alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted Of C ₇ -C ₂₀ arylalkyloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryloxycarbonyl, substituted or unsubstituted 5-15 member a heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N23 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino,
R ^N24 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ ~ C ₆ cycloalkyl alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxycarbonyl Replacement Ku is unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxycarbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy carbonyl, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl aryloxycarbonyl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, or substituted or unsubstituted amino, medicament according to claim 6. The following formula:
The pharmaceutical as described in any one of Claims 6-8 which contains the compound represented by these, its stereoisomer, those salts, or those solvates as an active ingredient.   The medicament according to any one of claims 6 to 9, for improving endoplasmic reticulum stress caused by structural failure of proteolipid protein 1 (PLP1).   The disease or symptom caused by structural failure of proteolipid protein 1 (PLP1) is one or more diseases or symptoms selected from the group consisting of hereditary neuroleukoplasia, cerebral ischemia and manic depression, The medicine according to any one of claims 6 to 10.   12. The medicament according to claim 11, wherein the inherited neuroleukoplasia is Pelizaeus-Merzbacher disease.