Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function

Abstract

The present invention relates to a use of imidazopyrimidine or imidazotriazine compounds of chemical formula 1, or pharmaceutically acceptable salts, solvates, or hydrates thereof, for preventing, alleviating, or treating cognitive disorders or for improving cognitive function.

Description

Use of imidazopyrimidine or imidazotriazine compounds for preventing, alleviating or treating cognitive impairment or improving cognitive function

[0001] The present invention relates to the use of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the prevention, alleviation or treatment of cognitive disorder or for improving cognitive function:

[0002]

[0003] In the above chemical formula 1, X, Z, R1 and R2 are as defined herein.

[0004] The human brain possesses the ability to acquire, store, and retrieve information over decades. This information acquisition, or learning, alters the physiological state of specific neurons during the process of memory encoding. These physiological changes are learning-induced changes in cellular activity that become part of the neural code for that memory. These changes can manifest through the expression or function of ion channels that increase or decrease neuronal excitability, leading to increased or decreased action potentials, or more indirectly through changes in other electrical signals. Learning can drive neuronal growth through new connections, or conversely, through neuronal withdrawal through the elimination of existing connections. Learning can also lead to cell signal adaptation through changes in the overall ability of neurons to integrate different types of signals, or it can lead to morphological and functional changes in synapses that increase or decrease neuronal capacity. The molecular and cellular memory engrams formed by all neurons involved in learning serve as guides for later memory retrieval. After encoding, “index” memory trace cells strengthen the interconnections between concepts through a simplification process based on perceptual concepts, and are logically and efficiently managed. However, the number of memory traces continuously accumulates over time. Therefore, the efficiency of brain capacity is further increased through the process of forgetting, which deletes unused or infrequently used memory traces. The entire process of creating and managing memory traces so that information about previously experienced events or contents can be recalled and recognized later is a cognitive process (Davis & Zhong, 2017, “The Biology of Forgetting-A Perspective” Neuron. Aug 2;95(3):490-503).

[0005] Enhancing cognitive function involves stimulating the formation of new connections during neural growth, strengthening the adaptive process of cellular signaling, or aligning cellular activity toward more logical connections between concepts. Alternatively, it involves preventing cognitive impairment, such as the natural decay of memory traces, the creation of similar memory traces that impede the proper retrieval of desired information, or the structural alteration of memory traces that hinders memory retrieval.

[0006] Cognitive impairment (Cognitive Impairment) is a neurological disorder characterized by a decline in cognitive functions such as memory, attention, language, and judgment. Its severity ranges from mild to severe. Mild cognitive impairment (MCI) refers to a condition in which cognitive function is impaired while the ability to perform daily activities is preserved and instrumental activities are possible. Dementia is a condition in which cognitive function declines to the point of interfering with daily life. Mild cognitive impairment can occur as a transitional disorder during the development of dementia. Furthermore, aging, genetics, and cardiovascular disease are considered risk factors for cognitive impairment.

[0007] The present invention seeks to provide a method for preventing, alleviating or treating cognitive impairment or improving cognitive function.

[0008] In addition, the present invention provides a use of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing, alleviating or treating cognitive impairment, or for improving cognitive function:

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1, X, Z, R1 and R2 are as defined herein.

[0012] The present invention provides a drug for preventing, alleviating or treating cognitive impairment, or for improving cognitive function, comprising a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0013] [Chemical Formula 1]

[0014]

[0015] In the above chemical formula 1,

[0016] X is CH or N;

[0017] Z is O or S;

[0018] R1 is C6-C which is unsubstituted or substituted with one or more substituents selected from halo, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, C1-C5 alkyl-C(O)O-C1-C5 alkyl, 5 or 6 membered heterocycloalkyl-C1-C5 alkyl having 1 to 3 heteroatoms selected from N, O and S and di(C1-C5 alkyl)amino-C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl;

[0019] R2 is C6-C, which is unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl. 12Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C1-C5 alkyl.

[0020] In addition, the present invention provides a pharmaceutical composition for preventing, alleviating or treating cognitive impairment or for improving cognitive function, comprising a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further comprising at least one pharmaceutically acceptable carrier.

[0021] In addition, the present invention provides a method for preventing, alleviating or treating cognitive impairment, or improving cognitive function, comprising administering to a subject of treatment a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0022] In addition, the present invention provides a use of the imidazopyrimidine or imidazotriazine compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the prevention, alleviation or treatment of cognitive impairment, or in treatment for improving cognitive function.

[0023] According to one specific example of the present invention, in the above formula 1, R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, and C1-C5 alkyl-C(O)O-C1-C5 alkyl; Or a 5 to 10 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl.

[0024] According to another specific embodiment of the present invention, in the above formula 1, R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy, and C1-C5 alkyl; or 5 or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, and substituted or unsubstituted with 1 to 3 substituents selected from halo and C1-C5 alkyl.

[0025] According to another specific example of the present invention, in the chemical formula 1,

[0026] X is CH or N;

[0027] Z is O;

[0028] R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, and C1-C5 alkyl-C(O)O-C1-C5 alkyl; or a 5 to 9 membered unsaturated heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, and halo-C1-C5 alkyl;

[0029] R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl; or 6-membered heteroaryl having 1 or 2 nitrogen atoms, unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

[0030] According to another specific example of the present invention, in the chemical formula 1,

[0031] R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl and C1-C5 alkyl-C(O)O-C1-C5 alkyl; 1,3-benzodioxolyl unsubstituted or substituted with 1 or 2 halo; or pyridyl or pyrimidinyl unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl,

[0032] R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl; or pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

[0033] According to another specific example of the present invention, in the chemical formula 1,

[0034] X is CH;

[0035] Z is O;

[0036] R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl and C1-C5 alkoxy-C1-C5 alkyl;

[0037] R2 is pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

[0038] Representative examples of the compounds of chemical formula 1 according to the present invention include the following:

[0039] 6-(2-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0040] 2-phenoxymethyl-6-phenylimidazo[1,2-a]pyrimidine;

[0041] 6-(2,4-difluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0042] 6-(2-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0043] 6-(2-methylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0044] 6-(4-fluoro-2-methylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0045] 6-(2,3-difluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0046] 6-(4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0047] 6-(3-aminophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0048] 6-(2-aminophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0049] 6-(3-amino-6-methylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0050] 6-(3-amino-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0051] 6-(3-chloro-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0052] 6-(2-dimethylaminophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0053] 6-(2-chloro-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0054] 6-(2-hydroxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0055] 6-(3-hydroxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0056] 6-(4-fluoro-2-trifluoromethylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0057] 6-(3,4-difluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0058] 6-(2-methoxy-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0059] 6-(4-fluoro-3-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0060] 6-(4-chloro-2-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0061] 6-(4-cyano-2-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0062] 6-(7-Fluorobenzo[1,3]dioxol-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0063] 6-(4-fluoro-2-hydroxymethylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0064] 6-(4-fluoro-2-methylthiophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0065] 6-(2-amino-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0066] 6-(2,4-difluoro-5-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0067] 6-(2-fluoropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0068] 6-(6-methoxypyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0069] 6-(6-fluoropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0070] 6-(4-methylpyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0071] 6-(2,6-difluoropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0072] 6-(6-chloropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0073] 6-(2-fluoropyridin-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0074] 6-(3-chloropyridin-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0075] 6-(4-chlorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0076] 6-(6-fluoro-4-methyl-3-pyridyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0077] 6-(6-fluoro-5-methyl-3-pyridyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0078] 6-(5-fluoro-2-pyridyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

[0079] 6-(2,4-difluorophenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0080] 6-(4-fluoro-2-methoxyphenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0081] 6-(4-fluoro-3-hydroxyphenyl)-2-(3-fluorophenoxymethyl)-imidazo[1,2-a]pyrimidine;

[0082] 6-(2-aminophenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0083] 6-(3-chloropyridin-4-yl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0084] 6-(4-methylpyridin-3-yl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0085] 6-(2,4-difluorophenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0086] 6-(4-fluoro-2-methylphenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0087] 6-(3-chloropyridin-4-yl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0088] 6-(2,6-dimethylphenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

[0089] 2-[(4-fluorophenoxy)methyl]-6-(6-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0090] 4-[[6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-2-yl]methoxy]phenol;

[0091] 2-[(4-fluorophenoxy)methyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

[0092] 2-[(3-fluorophenoxy)methyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

[0093] 2-Fluoro-5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

[0094] 2-[(4-fluorophenoxy)methyl]-6-phenyl-imidazo[1,2-a]pyrimidine;

[0095] 5-Fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

[0096] 5-Fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

[0097] 6-(4-fluorophenyl)-2-[(2,3,4,5,6-pentadeuteriophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0098] 2-[(4-fluorophenoxy)methyl]6-(o-tolyl)imidazo[1,2-a]pyrimidine;

[0099] 6-(5-Fluoro-2-methyl-phenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0100] 2-[(4-fluorophenoxy)methyl]-6-(2-fluoro-4-pyridyl)imidazo[1,2-a]pyrimidine;

[0101] 2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

[0102] 6-(2-Fluoro-4-methyl-phenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0103] 2-[(4-fluorophenoxy)methyl]-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

[0104] 2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0105] 6-(2-chloro-4-fluoro-phenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0106] 4-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxy-benzonitrile;

[0107] 6-(4-chloro-2-methoxy-phenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0108] 2-Fluoro-5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0109] 6-(2,6-difluoro-3-pyridyl)-2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0110] 5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-2-methyl-aniline;

[0111] 4,5-Difluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0112] 2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-5-methyl-aniline;

[0113] 5-chloro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0114] 2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-4-methyl-aniline;

[0115] 5-Fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0116] 2-[(4-fluorophenoxy)methyl]-6-(4-methyl-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0117] 2-[(3-fluorophenoxy)methyl]-6-(2-fluoro-4-pyridyl)imidazo[1,2-a]pyrimidine;

[0118] 2-[(3-fluorophenoxy)methyl]-6-[6-(trifluoromethyl)-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0119] 2-[(3-fluorophenoxy)methyl]-6-(6-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0120] 2-[(3-fluorophenoxy)methyl]-6-(2-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0121] 6-(5,6-difluoro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0122] 5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-2-methoxy-aniline;

[0123] 2-[(4-fluorophenoxy)methyl]-6-(5-fluoro-2-pyridyl)imidazo[1,2-a]pyrimidine;

[0124] 2-[(4-fluorophenoxy)methyl]-6-(5-methoxy-2-pyridyl)imidazo[1,2-a]pyrimidine;

[0125] 6-(4-chloro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0126] 6-(5-chloro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0127] 2-[(4-fluorophenoxy)methyl]-6-(5-methoxy-3-pyridyl) imidazo[1,2-a]pyrimidine;

[0128] 5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ol;

[0129] 6-(6-fluoro-5-methyl-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0130] 2-[(4-fluorophenoxy)methyl]-6-(6-methyl-3-pyridyl)imidazo[1,2-a]pyrimidine;

[0131] 2-[(3-fluorophenoxy)methyl]-6-(5-fluoro-2-pyridyl)imidazo[1,2-a]pyrimidine;

[0132] 2-[(3-fluorophenoxy)methyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

[0133] 4-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxy-benzonitrile;

[0134] [5-fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[0135] [5-fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[0136] 6-(4-Fluoro-2-methylsulfanyl-phenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

[0137] 2-[(4-fluorophenoxy)methyl]-6-(2-methoxy-4-pyridyl)imidazo[1,2-a]pyrimidine;

[0138] 2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-4-methyl-aniline;

[0139] 5-Fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0140] 6-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0141] 6-(2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0142] 6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0143] 6-(2,4-difluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0144] 6-(4-fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0145] 6-(2,3-difluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0146] 6-(5-Fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0147] 6-(3-fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0148] 6-(7-Fluoro-2H-benzo[1,3]dioxol-4-yl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0149] 6-(4-chloro-2-methoxyphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0150] 6-(3-Fluoro-2-methoxy-phenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0151] 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0152] 6-(4-fluoro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0153] 6-(2-ethylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0154] 6-(4-fluoro-2-methyl-phenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0155] 6-(2-Fluoro-4-methyl-phenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0156] 6-(4-fluoro-2-methoxy-phenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0157] 2-[(5-fluoro-2-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

[0158] 6-(2,4-difluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0159] 6-(3-Fluoro-2-methoxy-phenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0160] 6-(2,3-difluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0161] 6-(4-fluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0162] 6-(3-fluoro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0163] 2-[(4-fluoro-2-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

[0164] 2-[(5-fluoro-2-pyridyl)oxymethyl]-6-(o-tolyl)imidazo[1,2-a]pyrimidine;

[0165] 6-(4-chloro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0166] 6-(2,4-dimethylphenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0167] 6-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0168] 2-(2-pyridyloxymethyl)-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

[0169] 2-[(5-fluoro-2-pyridyl)oxymethyl]-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

[0170] 6-(5-fluoro-2-pyridyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0171] 2-Fluoro-5-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0172] 2-Fluoro-5-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0173] [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[0174] 3-methoxy-4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]benzonitrile;

[0175] 4-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxy-benzonitrile;

[0176] 6-(4-Fluoro-2-methylsulfanyl-phenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0177] [5-fluoro-2-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[0178] 4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]benzonitrile;

[0179] 6-[4-fluoro-2-(methoxymethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0180] [2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]-5-(trifluoromethyl)phenyl]methanol;

[0181] 6-(2-isopropylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0182] 4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]-3-(trifluoromethyl)benzaldehyde;

[0183] 6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0184] 6-(4-fluorophenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0185] 6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0186] 6-(2,4-difluorophenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0187] 6-(4-fluoro-2-methylphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0188] 6-(4-fluoro-2-hydroxyphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0189] 6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0190] 6-(2,4-difluorophenyl)-2-(pyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0191] 6-(2-methylphenyl)-2-(5-fluoro-pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0192] 6-(4-fluoro-2-methylphenyl)-2-(5-fluoro-pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0193] 6-(4-fluoro-2-methoxyphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0194] 6-(4-fluoro-2-hydroxyphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0195] 6-(2,4-difluorophenyl)-2-(6-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0196] 6-(4-fluoro-2-methylphenyl)-2-(6-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0197] 6-(4-Fluoro-2-methylphenyl)-2-(2-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0198] 6-(4-fluoro-2-methylphenyl)-2-(5-chloropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0199] 6-(2,4-difluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0200] 6-(4-fluoro-2-methylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0201] 6-(4-Fluoro-2-methoxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0202] 6-(4-fluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0203] 6-(2,3-difluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0204] 6-(2-fluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0205] 6-(4-fluoro-2-hydroxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0206] 6-(2-methylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0207] 6-(2-hydroxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0208] 6-(4-Fluoro-2-hydroxymethylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0209] 6-(4-fluorophenyl)-2-[(5-fluoro-3-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0210] 2-[(2-chloro-4-pyridyl)oxymethyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

[0211] 2-[(5-fluoro-3-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

[0212] 2-[(2-fluoro-4-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

[0213] 5-Fluoro-2-[2-[(5-fluoro-3-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0214] 5-Fluoro-2-[2-[(2-fluoro-4-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[0215] [5-fluoro-2-[2-[(5-fluoro-3-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[0216] 2-(2,4-difluorophenyl)-6-(phenoxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0217] 2-(2,4-difluorophenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0218] 2-(2,4-difluorophenyl)-6-((pyridin-2-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0219] 2-(4-fluorophenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0220] 2-(2-methylphenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0221] 2-(2,4-difluorophenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0222] 2-(4-fluoro-2-methylphenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0223] 2-(2-methylphenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

[0224] 2-[4-fluoro-2-(trifluoromethyl)phenyl]-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0225] 2-(3-Fluoro-2-methyl-phenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0226] 2-(4-fluoro-2-methyl-phenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0227] 2-[4-chloro-2-(trifluoromethyl)phenyl]-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0228] 2-(4-chloro-2-methyl-phenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0229] 2-(4-fluoro-2-methyl-phenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

[0230] 2-(4-fluoro-2-methyl-phenyl)-6-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-b][1,2,4]triazine;

[0231] [5-Fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methyl carbamate;

[0232] [5-fluoro-2-[2-(phenoxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methyl carbamate;

[0233] [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methyl carbamate;

[0234] [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methyl acetate;

[0235] 6-[2-(chloromethyl)-4-fluoro-phenyl]-2-[(4-fluorophenoxy)methyl)imidazo[1,2-a]pyrimidine;

[0236] 6-[4-fluoro-2-(fluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine; and

[0237] 6-[4-Fluoro-2-(fluoromethyl)phenyl]-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine.

[0238] More specifically, representative examples of the compound of formula 1 according to the present invention include the following:

[0239] 6-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

[0240] 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[0241] 6-(4-fluoro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0242] 6-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

[0243] [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol; and

[0244] 6-[4-Fluoro-2-(fluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine.

[0245] The imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 can be prepared by a person having ordinary knowledge of compound synthesis in the art using known compounds or compounds that can be easily prepared therefrom. In particular, a method for preparing the compound of the above chemical formula 1 is described in detail in International Patent Publication No. WO 2016 / 137260 A1, which is incorporated herein by reference. The compound of the above chemical formula 1 can be chemically synthesized by the method described in the above document, but this is only to suggest one exemplary method, and the order of unit operations, etc. can be selectively changed as needed, and is not intended to limit the scope of the invention.

[0246] The imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 can be used for preventing, alleviating or treating cognitive impairment, or improving cognitive function.

[0247] The imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 can also be applied to the prevention, alleviation or treatment of cognitive impairment symptoms.

[0248] Symptoms of cognitive impairment can manifest in a variety of ways, including memory loss, attention deficits, language impairments, visuospatial impairments, reasoning impairments, impaired judgment, disorganized thinking, slow thinking, difficulty comprehending, poor concentration, impaired problem-solving skills, fragmented memory, difficulty expressing thoughts, difficulty integrating thoughts, sensations, and actions, or difficulty eliminating inappropriate thoughts. These symptoms can manifest as repetition of the same words or questions, difficulty conveying information due to loss, getting lost, inaccurate names, and memory for time or place.

[0249] In one specific example, the imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 can be used to alleviate or treat a disease associated with cognitive impairment.

[0250] Diseases related to the above cognitive impairment include mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age-associated memory impairment, drug-associated cognitive disorder, immunodeficiency syndrome-associated cognitive disorder, Vascular disease-associated cognitive impairment, Cognitive Impairment Associated With Schizophrenia, Parkinson's disease-associated cognitive impairment,One or more selected from cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.

[0251] In one specific embodiment, the disease associated with cognitive impairment is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, dementia of the Alzheimer type, presenile dementia, early-onset Alzheimer's disease, senile dementia, early-onset amnestic disorder, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and cognitive impairment associated with schizophrenia.

[0252] Therefore, the pharmaceutical or pharmaceutical composition of the present invention can be used to prevent, alleviate or treat the above cognitive impairment disease, but the scope of the present invention is not limited to the above disease.

[0253] In addition, the pharmaceutical or pharmaceutical composition of the present invention can be used to prevent, alleviate or treat symptoms of cognitive impairment, which symptoms include, but are not limited to, decreased attention, decreased language ability, decreased visuospatial ability, decreased reasoning ability and decreased judgment.

[0254] The efficacy of the compound of the above chemical formula 1 on cognitive impairment can be confirmed using known models. Animal models related to the prevention and treatment of cognitive impairment can be used, such as animal models in which cognitive ability is impaired by administering a cognitive inhibitor, and animal models for cognitive function improvement can be used, such as a natural forgetting model in which natural forgetting occurs over time. Among these, an animal model in which cognitive ability is impaired by dizocilpine (MK-801) treatment is widely used as a means of verifying drug efficacy for the development of treatments for cognitive impairment (NMWJ de Bruin et al., Neurobiology of learning and memory, 2016, Vol. 133, p. 100-117). In addition, the natural forgetting rat model is also used as a means of verifying drug efficacy for the development of cognitive function improvement agents (MV King et al., Neuropharmacology 47 (2004) 195-204).

[0255] The dosage of the imidazopyrimidine or imidazotriazine compound of formula 1 for the prevention, alleviation or treatment of the above disease will usually vary depending on the severity of the disease, the body weight and metabolic state of the subject to be treated. A “therapeutically effective amount” for an individual patient means an amount sufficient to achieve the above-mentioned pharmacological effect, i.e., a therapeutic effect. A therapeutically effective amount of the compound of formula 1 may be included in the pharmaceutical composition at 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight), per day when administered to a mammal including a human, and such pharmaceutical composition may be administered once a day or in two or more divided doses.

[0256] The compound of the present invention can be administered by conventional methods used for administering therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous, or rectal administration.

[0257] A pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may comprise a therapeutically effective amount of a compound selected from the group consisting of an imidazopyrimidine or imidazotriazine compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate thereof, and a combination thereof.

[0258] The pharmaceutically acceptable salts described above include acid or base addition salts and their stereochemically isomeric forms. The salts include, but are not limited to, any salt that maintains the activity of the parent compound in the subject being administered and does not cause undesirable effects. Such salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idetic acid, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, edicilinic acid, esylinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolylarsanilic acid, methylnitric acid, polygalacturic acid, hexylisorcinonic acid, malonic acid, It can be hydramic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, methanesulfonic acid, or teoclic acid. In addition, the basic salt form includes, for example, alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, salts with organic bases such as benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine. In addition, the salt form can be converted into the free form by treatment with a suitable base or acid. The term "additional salt" includes compounds of formula 1 and solvates with which salts thereof can form. Such solvates are, for example, hydrates and alcoholates.

[0259] A medicament or pharmaceutical composition according to one embodiment of the present invention may be for oral or parenteral administration, and is preferably for oral administration. In the case of parenteral administration, it may be for parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, or rectal administration. In the case of oral administration, the medicament or pharmaceutical composition of the present invention may be formulated in the form of powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc. according to methods known in the art. A pharmaceutical composition according to one embodiment may be formulated as a tablet, or the active agent may be coated or formulated to protect it from degradation in the stomach. In addition, the composition may be administered by any device that allows the active agent to travel to the target cells. The route of administration may vary depending on the general condition and age of the subject to be treated, the nature of the treatment condition, and the active ingredient selected.

[0260] The appropriate dosage of the drug or pharmaceutical composition according to one embodiment of the present invention varies depending on factors such as the formulation method, administration method, patient's age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity, and a generally skilled physician can easily determine and prescribe a dosage effective for the desired treatment or prevention. The pharmaceutical composition according to one embodiment may be administered in one or multiple doses, for example, may be administered once to four times a day. The pharmaceutical composition according to one embodiment may contain the compound of formula 1 in an amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight).

[0261] A pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be manufactured in a unit dosage form or may be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and thereby. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablet or capsule, and may additionally include a dispersing agent or stabilizer. In addition, the pharmaceutical composition may be administered in the form of a suppository, spray, ointment, cream, gel, inhalant or skin patch. In addition, the pharmaceutical composition may be manufactured for administration to mammals, more preferably for administration to humans.

[0262] The pharmaceutically acceptable carrier may be solid or liquid and may be one or more selected from excipients, antioxidants, buffers, bacteriostatic agents, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release-controlling agents, wetting agents, stabilizers, suspending agents, and lubricants. In addition, the pharmaceutically acceptable carrier may be selected from saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0263] In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrin and maltodextrin), cellulose or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.

[0264] In one embodiment, suitable binders include, but are not limited to, magnesium aluminum silicate, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch paste, or mixtures thereof.

[0265] In one specific example, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA or mixtures thereof.

[0266] In one specific example, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or mixtures thereof.

[0267] In one embodiment, suitable sweeteners include, but are not limited to, sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose or mixtures thereof.

[0268] In one specific example, suitable glidants include, but are not limited to, silica, colloidal silicon dioxide, talc, and the like.

[0269] In one specific embodiment, suitable lubricants include, but are not limited to, long-chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glyceride waxes, or mixtures thereof.

[0270] The imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 can be used together with an additional drug for preventing, alleviating or treating cognitive impairment or improving cognitive function.

[0271] Therefore, the pharmaceutical or pharmaceutical composition of the present invention may be a combination preparation comprising, as a therapeutically effective amount of an active ingredient, an imidazopyrimidine or imidazotriazine compound of the above chemical formula 1 and such an additional drug.

[0272] Such additional drugs may include, for example, one or more selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.

[0273] Accordingly, a pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may further include one or more drugs selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine.

[0274] In one specific example, when the pharmaceutical or pharmaceutical composition of the present invention is the above-mentioned combination preparation, the weight ratio (a:b) of the imidazopyrimidine or imidazotriazine compound of the above-mentioned chemical formula 1 [component (a)] and the additional drug [component (b)] in the combination preparation may be, for example, within the range of 1,000:1 to 1:1,000, or 500:1 to 1:500, or 100:1 to 1:100, or 50:1 to 1:50, or 10:1 to 1:10, but is not limited thereto.

[0275] The terms “prevent,” “preventing,” and “prevention” as used herein mean reducing the likelihood of or eliminating the possibility of contracting a disease.

[0276] The terms "alleviate", "alleviating" and "alleviation" as used herein mean alleviating all or part of a disease and / or its accompanying symptoms.

[0277] The terms “treat,” “treating,” and “treatment” as used herein mean eliminating all or part of a disease and / or its accompanying symptoms.

[0278] The term "subject" as used herein means an animal, preferably a mammal (e.g., primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), and most preferably humans, that is the object of treatment, observation or experiment.

[0279] The term "therapeutically effective amount" as used herein means that amount of an active compound or pharmaceutical preparation that is sought by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in a tissue system, animal, or human, including alleviating the symptoms of the disease or disorder being treated.

[0280] The term "composition" as used herein includes a product comprising a specified ingredient in a specified amount and any product resulting directly or indirectly from a combination of specified ingredients in specified amounts.

[0281] The term "cognitive disorder" as used herein refers to a disorder that exhibits impairment in cognitive functions or cognitive domains of an animal, such as working memory, attention and arousal, verbal learning and memory, visual learning and memory, reasoning and problem solving, such as executive function, task processing speed, and / or social cognition. In particular, cognitive disorder is known to exhibit attention deficits, disorganized thinking, slow thinking, difficulty comprehending, low concentration, loss of problem solving skills, sloppy memory, difficulty expressing thoughts, and / or difficulty integrating thoughts, sensations, and actions, or difficulty eliminating inappropriate thoughts, and may be used interchangeably with the term "cognitive deficit."

[0282] The pharmaceutical and pharmaceutical composition according to the present invention can effectively prevent, alleviate or treat cognitive impairment or improve cognitive function.

[0283] Figure 1 shows the results showing the effects of test compounds (0.03, 0.1, 0.3 mg / kg) on ​​the object recognition test in a rat model with impaired cognitive ability due to dizocilpine treatment.

[0284] Figure 2 shows the results showing the effects of test compounds (0.1, 0.3, 1 mg / kg) on ​​the Y-maze test in a rat model with impaired cognitive ability due to dizocilpine treatment.

[0285] Figure 3 shows the results showing the effects of test compounds (0.1, 0.3 mg / kg) on ​​object recognition tests in a natural amnesia rat model.

[0286] Figure 4 shows the results showing the effect of the test compound (1, 3 mg / kg) on ​​the object recognition test in a natural amnesia rat model.

[0287] The present invention is described in more detail below through examples. However, these examples are only intended to illustrate one or more specific examples and are not intended to limit the scope of the invention.

[0288] Manufacturing Example: Preparation of Test Compound

[0289] 6-[4-Fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine (test compound) was prepared according to the method described in Example 113 of International Publication No. WO 2016 / 137260.

[0290] Example 1: Effects on object recognition tests in rat models with impaired cognitive ability due to dizocilpine treatment

[0291] An animal model of cognitive impairment was used in which cognitive ability was impaired by administering dizocilpine, a cognitive inhibitor.

[0292] laboratory animals

[0293] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimated to the animal room for more than 1 week. The animals were raised in a lighting-controlled environment (12 h on / 12 h off), maintained at 19–25°C and 30–70% relative humidity, and provided with free access to food and water. They were housed and cared for in accordance with the laboratory animal care standards of the Institutional Animal Care and Use Committee (IACUC). After stabilizing for more than a week, the rats were used in the object recognition test. The rats were randomly divided into each group, and the test was performed under lighting.

[0294] drugs

[0295] To create an animal model in which cognitive impairment symptoms are induced, experimental animals were treated with dizocilpine, an N-methyl-D-aspartate (NMDA) receptor inhibitor.

[0296] Dizocilpine (purchased from Sigma) was freshly prepared by dissolving it in saline used as a vehicle and administered subcutaneously at a dose of 0.1 mg / kg in a volume of 1 ml / kg of rat body weight 30 minutes before training. The control group was administered saline only.

[0297] Test compounds were dissolved in 5% dimethyl sulfoxide (DMSO) in 10% Cremophor and administered orally at doses of 0.03, 0.1, and 0.3 mg / kg 1 h before training in a volume of 1 ml / kg of rat body weight. As a control group, only vehicle (5% DMSO in 10% Cremophor) was administered.

[0298] Object Recognition Test

[0299] Rats were individually handled by the experimenter for at least 3 minutes and underwent two 3-minute box adaptation periods in an empty box before the experiment. The rats were administered vehicle or test compound intraperitoneally at a dose of 1 mg / kg 1 hour before training, and vehicle or dizocilpine subcutaneously 30 minutes before training. The rats were then placed in the boxes and trained. Training was conducted by exposing the rats to boxes containing two identical plastic cylinders or stainless steel cones. One hour after training, the rats were tested in boxes containing one plastic cylinder and one stainless steel cone. The time the rats spent exploring each object during the test was measured, and the results of the test were analyzed using the stainless steel cone as the novel object in rats trained in the box containing two plastic cylinders, and the results of the test were analyzed using the plastic cylinder as the novel object in rats trained in the box containing two stainless steel cones.

[0300] Statistical analysis of experimental results

[0301] A recognition index was calculated based on the time spent exploring the objects, and data on the recognition index between groups were analyzed using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test, and effects were considered significant when p<0.05. All results are expressed as mean ± SEM.

[0302] test

[0303] The cognitive index of the negative control group treated only with dizocilpine was 49.77±1.03 seconds, which was a significant decline in cognitive function compared to the cognitive index of 63.29±1.56 seconds in the vehicle group, which was the positive control group (P<0.001). When the test compound was administered together with dizocilpine, the 0.1 mg / kg and 0.3 mg / kg groups showed a significant recovery of cognitive function compared to the negative control group with impaired cognitive function, with the cognitive index at 57.95±1.8 seconds and 57.62±1.89 seconds, respectively (all P<0.01).

[0304] Table 1 summarizes the results of the cognitive index analysis of test compounds in the object recognition test in a rat model with impaired cognitive ability due to dizocilpine treatment.

[0305]

[0306] [Table 1]

[0307] Results of cognitive index analysis of test compounds on object recognition tests in a rat model with impaired cognitive ability due to dizocilpine treatment

[0308]

[0309]

[0310] From this, it was confirmed that the test compound administered resulted in a synergistic increase in the recovery effect on cognitive function impairment.

[0311] Example 2: Effects on the Y-maze test in a rat model with impaired cognitive ability due to dizocilpine treatment.

[0312] laboratory animals

[0313] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimated to the animal room for more than 1 week. The animals were raised in a lighting-controlled environment (12 h on / 12 h off), maintained at 19–25°C and 30–70% relative humidity, with free access to food and water. They were housed and cared for in accordance with the standards for laboratory animal care established by the Institutional Animal Care and Use Committee of the Korean Animal Research and Ethics Committee. After stabilizing for more than 1 week, the rats were used in the Y-maze experiment. The rats were randomly divided into each group, and the test was performed under lighting.

[0314] drugs

[0315] To create an animal model in which cognitive impairment symptoms are induced, experimental animals were treated with dizocilpine, an NMDA receptor antagonist.

[0316] Dizocilpine (purchased from Sigma) was freshly prepared by dissolving it in saline used as a vehicle and administered subcutaneously at a dose of 0.1 mg / kg in a volume of 1 ml / kg of rat body weight 30 minutes before training. The control group was administered saline only.

[0317] Test compounds were dissolved in 5% DMSO in 9.5% Cremophor and orally administered 1 h before training at doses of 0.1, 0.3, and 1 mg / kg in a volume of 5 ml / kg of rat body weight. The control group was administered only the vehicle (5% DMSO in 9.5% Cremophor).

[0318] Y-maze experiment

[0319] Rats were handled by the experimenter for 3 min each for two days, and then tested in the Y-maze the following day. For the Y-maze test, the rats were intraperitoneally administered vehicle or test compound 1 h before the test, and subcutaneously administered vehicle or dizocilpine 30 min before the test. The rats were placed at the end of one arm of the Y-maze and allowed to move freely for 5 min. The three arms, positioned at the same angle, were identical, measuring 45 cm in length, 10 cm in width, and 20 cm in height. Alternation behavior was defined as a case where a rat visited three different arms consecutively.

[0320] Statistical analysis of experimental results

[0321] In the Y-maze experiment, alternation behavior was determined based on the records of rats' visits to each arm, and the alternation rate was calculated. The data on alternation rates between groups were analyzed using one-way ANOVA and Dunnett's multiple comparison method, and effects were considered significant when p<0.05. All results are expressed as mean ± SEM.

[0322] test

[0323] The alternation ratio of the negative control group treated only with dizocilpine was 49.2±5.3 seconds, which was a significant decline in cognitive function compared to the alternation ratio of 70.1±2.8 seconds in the vehicle group, which was the positive control group (P<0.001). When the test compound was co-administered with dizocilpine, the alternation ratio of the 0.1 mg / kg group was 67.3±3.5 seconds, which showed a significant recovery in cognitive function compared to the negative control group with impaired cognitive function (P<0.001).

[0324] The alternation ratio of the group administered 0.3 mg / kg of the test compound was 57.3±5.7 seconds, showing a tendency toward recovery of cognitive function compared to the control group with impaired cognitive function.

[0325] Table 2 summarizes the results of the alternation ratio analysis of the test compounds in the Y-maze experiment in a rat model of cognitive impairment caused by dizocilpine treatment.

[0326]

[0327] [Table 2]

[0328] Results of alternation ratio analysis of test compounds in the Y-maze experiment in a rat model of cognitive impairment caused by dizocilpine treatment

[0329]

[0330]

[0331] From this, it was confirmed that the test compound administered resulted in a synergistic increase in the recovery effect on cognitive function impairment.

[0332] Example 3: Effects on object recognition tests in a rat model of spontaneous forgetting.

[0333] A natural forgetting model, in which natural forgetting occurs over time, was used as an animal model of cognitive impairment.

[0334] laboratory animals

[0335] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimated to the animal room for more than 1 week. The animals were raised in a lighting-controlled environment (12 h on / 12 h off), maintained at 19–25°C and 30–70% relative humidity, with free access to food and water. The animals were housed and cared for in accordance with the standards for laboratory animal care established by the Animal Care and Use Ethics Committee of the Republic of Korea. After stabilizing for more than a week, the rats were used in the object recognition test. The rats were randomly divided into groups, and the test was performed under lighting conditions.

[0336] drugs

[0337] Test compounds were dissolved in 5% DMSO in 10% Cremophor and administered orally 1 h before training at a dose of 1 mg / kg. The control group was administered only vehicle (5% DMSO in 10% Cremophor).

[0338] Object Recognition Test

[0339] Rats were individually handled by the experimenter for at least 3 min each, and two 3-min box adaptation periods were performed in an empty box before the experiment. The vehicle or test compound was administered intraperitoneally at a dose of 1 mg / kg 1 h before training, and the rats were then placed in the box for training. Training was conducted by exposing the rats to boxes containing two identical plastic cylinders or stainless steel cones. Twenty-four hours after training, the rats were tested in boxes containing one plastic cylinder and one stainless steel cone. The time the rats spent exploring each object during the test was measured, and the results of the test were analyzed using the stainless steel cone as a novel object in rats trained in boxes containing two plastic cylinders, and the results of the test using the plastic cylinder as a novel object in rats trained in boxes containing two stainless steel cones.

[0340] Statistical analysis of experimental results

[0341] Cognitive indices were calculated based on the time spent exploring objects, and data on cognitive indices between groups were analyzed using one-way ANOVA and Dunnett's multiple comparison method. Effects were considered significant when p<0.05. All results are expressed as mean ± SEM.

[0342] test

[0343] The experiment was conducted twice, varying the dose of the test compound. In the first experiment, the recognition index in the vehicle group, the control group, was 48.61±1.87 seconds. This was similar to the recognition index of 50, which indicates that subjects would not be able to distinguish between existing and novel objects and would explore them for exactly the same amount of time. Therefore, sufficient natural forgetting occurred over a 24-hour period.

[0344] When the test compound was administered at 0.1 mg / kg and 0.3 mg / kg, the recognition index was 56.57±2.37 seconds and 59.77±2.64 seconds, respectively, showing a significant difference compared to the control group in which natural forgetting occurred (P<0.05, P<0.01, respectively).

[0345] The results of the cognitive index analysis of the test compounds (0.1 mg / kg, 0.3 mg / kg) in the object recognition test in a rat model in which natural forgetting occurred are summarized in Table 3.

[0346]

[0347] [Table 3]

[0348] Results of cognitive index analysis of test compounds (0.1 mg / kg, 0.3 mg / kg) on ​​object recognition test in a rat model of natural forgetting

[0349]

[0350]

[0351] In the second experiment, the recognition index in the vehicle group, which was the control group, was 51.20±2.61 seconds, which was not different from the recognition index of 50 when searching for exactly the same amount of time without being able to distinguish between existing and new objects, thus confirming that sufficient natural forgetting occurred over a period of 24 hours.

[0352] When the test compound was administered at 1 mg / kg, the cognitive index was 60.91±2.72 seconds, showing a significant difference compared to the control group in which natural forgetting occurred (P<0.01), and in the group administered at 3 mg / kg of the test compound, the cognitive index was 56.20±2.27 seconds, showing that natural forgetting was alleviated compared to the control group in which natural forgetting occurred.

[0353] Table 4 summarizes the results of the cognitive index analysis of the test compounds (1 mg / kg, 3 mg / kg) in the object recognition test in a rat model in which natural forgetting occurred.

[0354]

[0355] [Table 4]

[0356] Results of cognitive index analysis of test compounds (1 mg / kg, 3 mg / kg) on ​​object recognition test in a rat model of natural forgetfulness

[0357]

[0358]

[0359] From the experimental results in this natural forgetting model, we confirmed the alleviating effect of the test compound on natural forgetting through improved cognitive function in a normal cognitive state.

Claims

1. A drug for preventing, alleviating or treating cognitive impairment, or for improving cognitive function, comprising a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, X is CH or N; Z is O or S; R1 is C6-C which is unsubstituted or substituted with one or more substituents selected from halo, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, C1-C5 alkyl-C(O)O-C1-C5 alkyl, 5 or 6 membered heterocycloalkyl-C1-C5 alkyl having 1 to 3 heteroatoms selected from N, O and S, and di(C1-C5 alkyl)amino-C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl; R2 is C6-C, which is unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C1-C5 alkyl.

2. In the first paragraph, R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl and C1-C5 alkyl-C(O)O-C1-C5 alkyl; Or a 5 to 10 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl.

3. A drug according to claim 1, characterized in that R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl; or 5 or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, and substituted or unsubstituted with 1 to 3 substituents selected from halo and C1-C5 alkyl.

4. In paragraph 1, wherein X is CH or N; The above Z is O; wherein R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl and C1-C5 alkyl-C(O)O-C1-C5 alkyl; or a 5 to 9 membered unsaturated heterocyclyl having 1 or 2 heteroatoms selected from N, O and S, which is unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl; A drug, characterized in that the above R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl; or a 6-membered heteroaryl having 1 or 2 nitrogen atoms, unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

5. In paragraph 1, wherein R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl and C1-C5 alkyl-C(O)O-C1-C5 alkyl; 1,3-benzodioxolyl unsubstituted or substituted with 1 or 2 halo; or pyridyl or pyrimidinyl unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl, A drug, characterized in that the above R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl; or pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

6. In paragraph 1, wherein X is CH; The above Z is O; wherein R1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl and C1-C5 alkoxy-C1-C5 alkyl; A drug, wherein the above R2 is pyridyl which is unsubstituted or substituted with 1 or 2 substituents selected from halo and C1-C5 alkyl.

7. A drug, characterized in that in the above-mentioned clause, the imidazopyrimidine or imidazotriazine compound of chemical formula 1 is selected from the following compounds: 6-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine; 6-[4-Fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine; 6-(4-Fluoro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine; 6-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine; [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol; and 6-[4-Fluoro-2-(fluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine.

8. A drug used for the prevention, alleviation or treatment of cognitive impairment symptoms in paragraph 1.

9. A drug in clause 8, wherein the cognitive impairment symptoms are decreased attention, decreased language ability, decreased spatiotemporal ability, decreased reasoning ability, or decreased judgment.

10. A drug used for alleviating or treating a disease related to cognitive impairment in paragraph 1.

11. In paragraph 10, the disease related to cognitive impairment is mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age associated memory impairment, drug-associated cognitive disorder, and cognitive impairment associated with immunodeficiency syndrome. Immunodeficiency syndrome-associated cognitive disorder, vascular disease-associated cognitive impairment, cognitive impairment associated with schizophrenia, Parkinson's disease-associated cognitive impairment,An agent selected from the group consisting of cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.

12. In paragraph 11, the disease related to cognitive impairment is a drug selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, senile dementia, early-onset amnestic disorder, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and cognitive impairment related to schizophrenia.

13. A drug according to paragraph 1, manufactured for administration to mammals.

14. A drug comprising an imidazopyrimidine or imidazotriazine compound of chemical formula 1 in an amount of 0.1 to 500 mg / kg (body weight) in accordance with paragraph 1.

15. A drug for parenteral administration in paragraph 1, selected from the group consisting of oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, and rectal administration.

16. A pharmaceutical composition according to claim 1, further comprising at least one drug selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine.

17. A pharmaceutical composition for preventing, alleviating or treating cognitive impairment, or for improving cognitive function, comprising a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further comprising at least one pharmaceutically acceptable carrier: [Chemical Formula 1] In the above chemical formula 1, X is CH or N; Z is O or S; R1 is C6-C which is unsubstituted or substituted with one or more substituents selected from halo, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, C1-C5 alkyl-C(O)O-C1-C5 alkyl, 5 or 6 membered heterocycloalkyl-C1-C5 alkyl having 1 to 3 heteroatoms selected from N, O and S, and di(C1-C5 alkyl)amino-C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl; R2 is C6-C, which is unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl. 12Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C1-C5 alkyl.

18. A pharmaceutical composition used for the prevention, alleviation or treatment of cognitive impairment symptoms in clause 17.

19. A pharmaceutical composition according to claim 18, wherein the cognitive impairment symptoms are decreased attention, decreased language ability, decreased spatiotemporal ability, decreased reasoning ability, or decreased judgment.

20. A pharmaceutical composition used for alleviating or treating a disease associated with cognitive impairment in accordance with claim 17.

21. In clause 20, the disease related to cognitive impairment is mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age associated memory impairment, drug-associated cognitive disorder, and cognitive impairment associated with immune deficiency syndrome. Immunodeficiency syndrome-associated cognitive disorder, vascular disease-associated cognitive impairment, cognitive impairment associated with schizophrenia, Parkinson's disease-associated cognitive impairment,A pharmaceutical composition selected from the group consisting of cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder and learning deficit disorder.

22. A pharmaceutical composition according to claim 21, wherein the disease associated with cognitive impairment is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, senile dementia, early-onset amnesia disorder, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and cognitive impairment associated with schizophrenia.

23. A pharmaceutical composition prepared for administration to mammals according to claim 17.

24. A pharmaceutical composition comprising an imidazopyrimidine or imidazotriazine compound of chemical formula 1 in an amount of 0.1 to 500 mg / kg (body weight) in accordance with claim 17.

25. A pharmaceutical composition for parenteral administration in claim 17, wherein the pharmaceutical composition is for oral administration or for parenteral administration selected from the group consisting of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, and rectal administration.

26. A pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable carrier is at least one selected from excipients, antioxidants, buffers, bacteriostatics, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, lubricants, release-controlling agents, wetting agents, stabilizers, suspending agents, and lubricants.

27. A pharmaceutical composition according to claim 17, further comprising at least one drug selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine.

28. A method for preventing, alleviating or treating cognitive impairment, or improving cognitive function in a subject, comprising administering to the subject a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, X is CH or N; Z is O or S; R1 is C6-C which is unsubstituted or substituted with one or more substituents selected from halo, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, C1-C5 alkyl-C(O)O-C1-C5 alkyl, 5 or 6 membered heterocycloalkyl-C1-C5 alkyl having 1 to 3 heteroatoms selected from N, O and S, and di(C1-C5 alkyl)amino-C1-C5 alkyl. 12Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl; R2 is C6-C, which is unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C1-C5 alkyl.

29. A method for preventing, alleviating or treating cognitive impairment symptoms in paragraph 28.

30. A method according to claim 29, wherein the cognitive impairment symptoms are decreased attention, decreased language ability, decreased spatiotemporal ability, decreased reasoning ability, or decreased judgment ability.

31. A method for alleviating or treating a disease associated with cognitive impairment in accordance with paragraph 28.

32. In claim 31, the disease associated with cognitive impairment is mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age associated memory impairment, drug-associated cognitive disorder, and cognitive impairment associated with immune deficiency syndrome. Immunodeficiency syndrome-associated cognitive disorder, vascular disease-associated cognitive impairment, cognitive impairment associated with schizophrenia, Parkinson's disease-associated cognitive impairment,A method selected from the group consisting of cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.

33. A method in claim 32, wherein the disease associated with cognitive impairment is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, senile dementia, early-onset amnestic disorder, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and cognitive impairment associated with schizophrenia.

34. A method according to claim 28, characterized in that the subject is a mammal.

35. A method according to claim 28, characterized in that 0.1 to 500 mg / kg (body weight) of an imidazopyrimidine or imidazotriazine compound of the chemical formula 1 is administered.

36. A method according to claim 28, characterized in that at least one drug selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine is additionally administered.

37. Use of an imidazopyrimidine or imidazotriazine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing, alleviating or treating cognitive impairment, or for improving cognitive function: [Chemical Formula 1] In the above chemical formula 1, X is CH or N; Z is O or S; R1 is C6-C which is unsubstituted or substituted with one or more substituents selected from halo, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, amino, di(C1-C5 alkyl)amino, cyano, formyl, halo-C1-C5 alkyl, hydroxy-C1-C5 alkyl, C1-C5 alkoxy-C1-C5 alkyl, carbamoyloxy-C1-C5 alkyl, C1-C5 alkyl-C(O)O-C1-C5 alkyl, 5 or 6 membered heterocycloalkyl-C1-C5 alkyl having 1 to 3 heteroatoms selected from N, O and S, and di(C1-C5 alkyl)amino-C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and halo-C1-C5 alkyl; R2 is C6-C, which is unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C1-C5 alkyl. 12 Aryl; or a 5 to 12 membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C1-C5 alkyl.

38. In clause 37, for use in preventing, alleviating or treating cognitive impairment symptoms.

39. In clause 38, the use in which the cognitive impairment symptoms are decreased attention, decreased language ability, decreased spatiotemporal ability, decreased reasoning ability, or decreased judgment ability.

40. In clause 37, for use in alleviating or treating diseases related to cognitive impairment.

41. In clause 40, the disease associated with cognitive impairment is mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age associated memory impairment, drug-associated cognitive disorder, and cognitive impairment associated with immunodeficiency syndrome. Immunodeficiency syndrome-associated cognitive disorder, vascular disease-associated cognitive impairment, cognitive impairment associated with schizophrenia, Parkinson's disease-associated cognitive impairment,Use selected from the group consisting of cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder and learning deficit disorder.

42. In claim 41, the disease related to cognitive impairment is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, senile dementia, early-onset amnestic disorder, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and cognitive impairment related to schizophrenia.

43. Use for administration to mammals in clause 37.

44. A use characterized in that in claim 37, an imidazopyrimidine or imidazotriazine compound of the chemical formula 1 is used in an amount of 0.1 to 500 mg / kg (body weight).

45. A use according to claim 37, characterized in that at least one drug selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine is additionally used.

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