1. Patent Search
  2. Details

COMPOSITION FOR PREVENTING OR INHIBITING AXONAL DEGENERATION

20230010258 · 2023-01-12

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a composition capable of preventing or inhibiting axonal degeneration and effectively preventing, improving, or treating various neurological diseases caused by the axonal degeneration.

    Claims

    1. A pharmaceutical composition for preventing or inhibiting axonal degeneration containing, as an active ingredient, a compound selected from among a compound represented by the following Formula (1), and a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: ##STR00093## wherein X.sub.1 to X.sub.5 are each independently N or C(R.sub.3), provided that at least one of X.sub.1 to X.sub.5 is N; L.sub.1 is a direct bond or a C.sub.1-C.sub.6 alkylene group; L.sub.2 and L.sub.3 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, a divalent C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a divalent non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms; R.sub.1 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.2 is a group represented by the following Formula 2; R.sub.3 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.3 is present in a plural number, the plurality of R.sub.3 are the same as or different from each other, or the plurality of R.sub.3 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkylene group in L.sub.1 to L.sub.3, the cycloalkylene group, heterocycloalkylene group, arylene group, heteroarylene group, divalent non-aromatic fused polycyclic group and divalent non-aromatic fused heteropolycyclic group in L.sub.2 and L.sub.3, and the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.1 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.3, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.3 adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; ##STR00094## wherein * denotes a bonding position; L.sub.4 and L.sub.5 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, *—(CH.sub.2)a-O—(CH.sub.2)b-*, a carbonyl group (*—C(═O)—*), *—N(R.sub.5)—*, and an amide group (*—C(═O)—N(H)—* or *—N(H)—C(═O)—*); a and b are each independently an integer ranging from 0 to 6; R.sub.4 is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and *—N(R.sub.6)(R.sub.7); R.sub.5 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.6 and R.sub.7 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, or they bond to each other to form a heterocycloalkyl ring having 5 to 7 nuclear atoms, a heteroaryl ring having 5 to 14 nuclear atoms, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.5 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and the alkylene group, arylene group and heteroarylene group in L.sub.4 and L.sub.5, the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.4, R.sub.6 and R.sub.7, the alkyl group in R.sub.6 and R.sub.7, and the heterocycloalkyl ring, heteroaryl ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between R.sub.6 and R.sub.7, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other, or the plurality of substituents present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms.

    2. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 3: ##STR00095## wherein X.sub.1, X.sub.3 to X.sub.5, L.sub.1 to L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 1.

    3. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 6: ##STR00096## wherein m is an integer ranging from 0 to 6; R.sub.9 and R.sub.10 are each independently selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when m is an integer ranging from 2 to 6, the plurality of R.sub.9 are the same as or different from each other and the plurality of R.sub.10 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.9 and R.sub.10 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.2, L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 1.

    4. The pharmaceutical composition of claim 1, wherein L.sub.2 is a direct bond or a C.sub.1-C.sub.6 alkylene group unsubstituted or substituted with a C.sub.1-C.sub.6 alkyl group; L.sub.3 is a direct bond or is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, and a heteroarylene group having 5 to 14 nuclear atoms, and the cycloalkylene group, heterocycloalkylene group, arylene group and heteroarylene group in L.sub.3 are each independently substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms.

    5. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 7: ##STR00097## wherein n is an integer ranging from 0 to 6; R.sub.11 and R.sub.12 are each independently selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when n is an integer ranging from 2 to 6, the plurality of Ru are the same as or different from each other and the plurality of R.sub.12 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.11 and R.sub.12 are each independently unsubstituted or substituted with at least one substituent from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.1, L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 1.

    6. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 8 or 9: ##STR00098## wherein and p are each independently an integer ranging from 0 to 4; q is an integer ranging from 0 to 5; R.sub.13 is selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when R.sub.13 is present in a plural number, the plurality of R.sub.13 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.13 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.1, L.sub.2, R.sub.1 and R.sub.2 are as defined in claim 1.

    7. The pharmaceutical composition of claim 1, wherein R.sub.4 is a group represented by the following Formula 12: ##STR00099## wherein * denotes a bonding position; Y.sub.1 is O or S; Z.sub.1 to Z.sub.4 are each independently N or C(R.sub.14); R.sub.14 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.14 is present in a plural number, the plurality of R.sub.14 are the same as or different from each other, or the plurality of R.sub.14 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.14, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.14 present adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other.

    8. The pharmaceutical composition of claim 7, wherein R.sub.4 is represented by any one of the following Formulas a1 to a7: ##STR00100## wherein r is an integer ranging from 0 to 4; s is an integer ranging from 0 to 6; t is an integer ranging from 0 to 10; u is an integer ranging from 0 to 3; R.sub.15 is selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.15 is present in a plural number, the plurality of R.sub.15 are the same as or different from each other, or the plurality of R.sub.15 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.15, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.15 present adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1 to C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and Y.sub.1 is as defined in claim 7.

    9. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is a compound selected from the group consisting of the following compounds: N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(naphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(oxazolo[4,5-c]pyridin-2-yl)benzyl)nicotinamide; N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-ethylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)-6-(trifluoromethyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)benzamide; N-(4-(5,6,7,8-tetrahydronaphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(4-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-bromobenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-(pyridin-3-yl)benzo[d]oxazol-2-yl)benzyl)nicotinamide; methyl 2-(4-(nicotinamidomethyl)phenyl)benzo[d]oxazole-7-carboxylate; N-(4-(6-methoxybenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(((1r,4r)-4-(6-methylbenzo[d]oxazol-2-yl)cyclohexyl)methyl)nicotinamide; N-(((1r,4r)-4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)cyclohexyl)methyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)-3-(pyridin-3-yl)propanamide; N-(4-(benzo[d]thiazol-2-yl)benzyl)nicotinamide; N-(4-(benzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-((4-chloro-1H-pyrazol-1-yl)methyl)benzyl)nicotinamide; N-(4-(5-methoxybenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)phenyl)nicotinamide; N-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide; N-(2-(nicotinamido)ethyl)-3-(p-tolyl)-1,2,4-oxadiazole-5-carboxamide; N-(4-(2-methyl-1H-imidazol-1-yl)benzyl)nicotinamide; N-(4-(piperidin-1-yl)benzyl)nicotinamide; and N-(4-(pyridin-2-ylmethoxy)benzyl)nicotinamide.

    10. A pharmaceutical composition for preventing or inhibiting neurological diseases caused by axonal degeneration containing, as an active ingredient, a compound selected from among a compound represented by the following Formula (1), and a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: ##STR00101## wherein X.sub.1 to X.sub.5 are each independently N or C(R.sub.3), provided that at least one of X.sub.1 to X.sub.5 is N; L.sub.1 is a direct bond or a C.sub.1-C.sub.6 alkylene group; L.sub.2 and L.sub.3 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, a divalent C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a divalent non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms; R.sub.1 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.2 is a group represented by the following Formula 2; R.sub.3 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.3 is present in a plural number, the plurality of R.sub.3 are the same as or different from each other, or the plurality of R.sub.3 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkylene group in L.sub.1 to L.sub.3, the cycloalkylene group, heterocycloalkylene group, arylene group, heteroarylene group, divalent non-aromatic fused polycyclic group and divalent non-aromatic fused heteropolycyclic group in L.sub.2 and L.sub.3, and the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.1 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.3, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.3 adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; ##STR00102## wherein * denotes a bonding position; L.sub.4 and L.sub.5 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, *—(CH.sub.2)a-O—(CH.sub.2)b-*, a carbonyl group (*—C(═O)—*), *—N(R.sub.5)—*, and an amide group (*—C(═O)—N(H)—* or *—N(H)—C(═O)—*); a and b are each independently an integer ranging from 0 to 6; R.sub.4 is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and *—N(R.sub.6)(R.sub.7); R.sub.5 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.6 and R.sub.7 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, or they bond to each other to form a heterocycloalkyl ring having 5 to 7 nuclear atoms, a heteroaryl ring having 5 to 14 nuclear atoms, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.5 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and the alkylene group, arylene group and heteroarylene group in L.sub.4 and L.sub.5, the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.4, R.sub.6 and R.sub.7, the alkyl group in R.sub.6 and R.sub.7, and the heterocycloalkyl ring, heteroaryl ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between R.sub.6 and R.sub.7, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other, or the plurality of substituents present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms.

    11. The pharmaceutical composition of claim 10, wherein the compound represented by Formula 1 is a compound represented by the following Formula 3: ##STR00103## wherein X.sub.1, X.sub.3 to X.sub.5, L.sub.1 to L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 10.

    12. The pharmaceutical composition of claim 10, wherein the compound represented by Formula 1 is a compound represented by the following Formula 6: ##STR00104## wherein m is an integer ranging from 0 to 6; R.sub.9 and R.sub.10 are each independently selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when m is an integer ranging from 2 to 6, the plurality of R.sub.9 are the same as or different from each other and the plurality of R.sub.10 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.9 and R.sub.10 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.2, L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 10.

    13. The pharmaceutical composition of claim 10, wherein L.sub.2 is a direct bond or a C.sub.1-C.sub.6 alkylene group unsubstituted or substituted with a C.sub.1-C.sub.6 alkyl group; L.sub.3 is a direct bond or is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, and a heteroarylene group having 5 to 14 nuclear atoms, and the cycloalkylene group, heterocycloalkylene group, arylene group and heteroarylene group in L.sub.3 are each independently substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms.

    14. The pharmaceutical composition of claim 10, wherein the compound represented by Formula 1 is a compound represented by the following Formula 7: ##STR00105## wherein n is an integer ranging from 0 to 6; R.sub.11 and R.sub.12 are each independently selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when n is an integer ranging from 2 to 6, the plurality of Ru are the same as or different from each other and the plurality of R.sub.12 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.11 and R.sub.12 are each independently unsubstituted or substituted with at least one substituent from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.1, L.sub.3, R.sub.1 and R.sub.2 are as defined in claim 10.

    15. The pharmaceutical composition of claim 10, wherein the compound represented by Formula 1 is a compound represented by the following Formula 8 or 9: ##STR00106## wherein and p are each independently an integer ranging from 0 to 4; q is an integer ranging from 0 to 5; R.sub.13 is selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when R.sub.13 is present in a plural number, the plurality of R.sub.13 are the same as or different from each other; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.13 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and X.sub.1 to X.sub.5, L.sub.1, L.sub.2, R.sub.1 and R.sub.2 are as defined in claim 10.

    16. The pharmaceutical composition of claim 10, wherein R.sub.4 is a group represented by the following Formula 12: ##STR00107## wherein * denotes a bonding position; Y.sub.1 is O or S; Z.sub.1 to Z.sub.4 are each independently N or C(R.sub.14); R.sub.10 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.14 is present in a plural number, the plurality of R.sub.14 are the same as or different from each other, or the plurality of R.sub.14 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.14, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.14 present adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other.

    17. The pharmaceutical composition of claim 16, wherein R.sub.4 is represented by any one of the following Formulas a1 to a7: ##STR00108## wherein r is an integer ranging from 0 to 4; s is an integer ranging from 0 to 6; t is an integer ranging from 0 to 10; u is an integer ranging from 0 to 3; R.sub.15 is selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.15 is present in a plural number, the plurality of R.sub.15 are the same as or different from each other, or the plurality of R.sub.15 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.15, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.15 present adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1 to C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and Y.sub.1 is as defined in claim 16.

    18. The pharmaceutical composition of claim 10, wherein the compound represented by Formula 1 is a compound selected from the group consisting of the following compounds: N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(naphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(oxazolo[4,5-c]pyridin-2-yl)benzyl)nicotinamide; N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-ethylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)-6-(trifluoromethyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)benzamide; N-(4-(5,6,7,8-tetrahydronaphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(4-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-bromobenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(5-(pyridin-3-yl)benzo[d]oxazol-2-yl)benzyl)nicotinamide; methyl 2-(4-(nicotinamidomethyl)phenyl)benzo[d]oxazole-7-carboxylate; N-(4-(6-methoxybenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(((1r,4r)-4-(6-methylbenzo[d]oxazol-2-yl)cyclohexyl)methyl)nicotinamide; N-(((1r,4r)-4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)cyclohexyl)methyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)-3-(pyridin-3-yl)propanamide; N-(4-(benzo[d]thiazol-2-yl)benzyl)nicotinamide; N-(4-(benzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-((4-chloro-1H-pyrazol-1-yl)methyl)benzyl)nicotinamide; N-(4-(5-methoxybenzo[d]oxazol-2-yl)benzyl)nicotinamide; N-(4-(6-methylbenzo[d]oxazol-2-yl)phenyl)nicotinamide; N-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide; N-(2-(nicotinamido)ethyl)-3-(p-tolyl)-1,2,4-oxadiazole-5-carboxamide; N-(4-(2-methyl-1H-imidazol-1-yl)benzyl)nicotinamide; N-(4-(piperidin-1-yl)benzyl)nicotinamide; and N-(4-(pyridin-2-ylmethoxy)benzyl)nicotinamide.

    19. A method for preventing or inhibiting axonal degeneration comprising a step of administering, to a subject in need of administration, a pharmaceutically effective amount of a compound selected from among a compound represented by the following Formula (1), and a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: ##STR00109## wherein X.sub.1 to X.sub.5 are each independently N or C(R.sub.3), provided that at least one of X.sub.1 to X.sub.5 is N; L.sub.1 is a direct bond or a C.sub.1-C.sub.6 alkylene group; L.sub.2 and L.sub.3 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, a divalent C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a divalent non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms; R.sub.1 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.2 is a group represented by the following Formula 2; R.sub.3 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.3 is present in a plural number, the plurality of R.sub.3 are the same as or different from each other, or the plurality of R.sub.3 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkylene group in L.sub.1 to L.sub.3, the cycloalkylene group, heterocycloalkylene group, arylene group, heteroarylene group, divalent non-aromatic fused polycyclic group and divalent non-aromatic fused heteropolycyclic group in L.sub.2 and L.sub.3, and the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.1 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.3, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.3 adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; ##STR00110## wherein * denotes a bonding position; L.sub.4 and L.sub.5 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, *—(CH.sub.2)a-O—(CH.sub.2)b-*, a carbonyl group (*—C(═O)—*), *—N(R.sub.5)—*, and an amide group (*—C(═O)—N(H)—* or *—N(H)—C(═O)—*); a and b are each independently an integer ranging from 0 to 6; R.sub.4 is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and *—N(R.sub.6)(R.sub.7); R.sub.5 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.6 and R.sub.7 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, or they bond to each other to form a heterocycloalkyl ring having 5 to 7 nuclear atoms, a heteroaryl ring having 5 to 14 nuclear atoms, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.5 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and the alkylene group, arylene group and heteroarylene group in L.sub.4 and L.sub.5, the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.4, R.sub.6 and R.sub.7, the alkyl group in R.sub.6 and R.sub.7, and the heterocycloalkyl ring, heteroaryl ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between R.sub.6 and R.sub.7, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other, or the plurality of substituents present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms.

    20. A method for preventing or treating neurological diseases caused by axonal degeneration comprising a step of administering, to a subject in need of administration, a pharmaceutically effective amount of a compound selected from among a compound represented by the following Formula (1), and a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: ##STR00111## wherein X.sub.1 to X.sub.5 are each independently N or C(R.sub.3), provided that at least one of X.sub.1 to X.sub.5 is N; L.sub.1 is a direct bond or a C.sub.1-C.sub.6 alkylene group; L.sub.2 and L.sub.3 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, a divalent C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a divalent non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms; R.sub.1 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.2 is a group represented by the following Formula 2; R.sub.3 is selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.3 is present in a plural number, the plurality of R.sub.3 are the same as or different from each other, or the plurality of R.sub.3 present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkylene group in L.sub.1 to L.sub.3, the cycloalkylene group, heterocycloalkylene group, arylene group, heteroarylene group, divalent non-aromatic fused polycyclic group and divalent non-aromatic fused heteropolycyclic group in L.sub.2 and L.sub.3, and the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.1 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.3, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.3 adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; ##STR00112## wherein * denotes a bonding position; L.sub.4 and L.sub.5 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, *—(CH.sub.2)a-O—(CH.sub.2)b-*, a carbonyl group (*—C(═O)—*), *—N(R.sub.5)—*, and an amide group (*—C(═O)—N(H)—* or *—N(H)—C(═O)—*); a and b are each independently an integer ranging from 0 to 6; R.sub.4 is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and *—N(R.sub.6)(R.sub.7); R.sub.5 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms; R.sub.6 and R.sub.7 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, or they bond to each other to form a heterocycloalkyl ring having 5 to 7 nuclear atoms, a heteroaryl ring having 5 to 14 nuclear atoms, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms; the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.5 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and the alkylene group, arylene group and heteroarylene group in L.sub.4 and L.sub.5, the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.4, R.sub.6 and R.sub.7, the alkyl group in R.sub.6 and R.sub.7, and the heterocycloalkyl ring, heteroaryl ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between R.sub.6 and R.sub.7, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other, or the plurality of substituents present adjacent to each other bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms.

    Description

    BRIEF DESCRIPTION OF DRAWINGS

    [0174] FIG. 1 shows the results of examining changes in the expression levels of JNK and phosphorylated JNK by Western blot assay after treating the gastric cancer cell line MKN1 with the compound according to the present invention in Experimental Example 1.

    [0175] FIGS. 2 to 12 show the results of examining changes in the expression level of phosphorylated JNK by Western blot analysis after treating the F11 cell line with the compound according to the present invention and the SARM1 activator AP20187 in Experimental Example 2.

    [0176] FIG. 13 schematically shows an experimental design of Experimental Example 3 of the present invention.

    [0177] FIG. 14 shows the results of imaging the green fluorescent protein signal of the optic nerve in the cerebral hemisphere by a confocal microscope after treating a tadpole optic nerve axotomy model with the compound according to the present invention and LSN 3154567 and KPT9274 as controls in Experimental Example 3 of the present invention.

    [0178] FIG. 15 shows the results of measuring the degree of delay in Wallerian degeneration after treating a tadpole optic nerve axotomy model with the compound according to the present invention and LSN 3154567 and KPT9274 as controls in Experimental Example 3 of the present invention.

    [0179] FIG. 16 shows the results of measuring the axon survival score after treating a tadpole optic nerve axotomy model with the compound according to the present invention in Experimental Example 4 of the present invention.

    BEST MODE

    [0180] One embodiment of the present invention is directed to a pharmaceutical composition for prevention or inhibition of axonal degeneration or for prevention or treatment of neurological diseases caused by axonal degeneration, the pharmaceutical composition containing, as an active ingredient, a compound selected from among a compound represented by the following Formula (1), and a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:

    ##STR00015##

    [0181] Wherein

    [0182] X.sub.1 to X.sub.5 are each independently N or C(R.sub.3), provided that at least one of X.sub.1 to X.sub.5 is N;

    [0183] L.sub.1 is a direct bond or a C.sub.1-C.sub.6 alkylene group;

    [0184] L.sub.2 and L.sub.3 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.3-C.sub.7 cycloalkylene group, a heterocycloalkylene group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, a divalent C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a divalent non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms;

    [0185] R.sub.1 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms;

    [0186] R.sub.2 is a group represented by the following Formula 2;

    [0187] R.sub.3 may be selected from the group consisting of hydrogen, a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when R.sub.3 is present in a plural number, the plurality of R.sub.3 may be the same as or different from each other, or the plurality of R.sub.3 present adjacent to each other may bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms;

    [0188] the alkylene group in L.sub.1 to L.sub.3, the cycloalkylene group, heterocycloalkylene group, arylene group, heteroarylene group, divalent non-aromatic fused polycyclic group and divalent non-aromatic fused heteropolycyclic group in L.sub.2 and L.sub.3, and the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.1 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other;

    [0189] the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group, non-aromatic fused heteropolycyclic group, alkoxycarbonyl group and alkylsulfonyl group in R.sub.3, and the cycloalkyl ring, heterocycloalkyl ring, aryl ring, heteroaryl ring, non-aromatic fused polycyclic ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between the plurality of R.sub.3 adjacent to each other, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other;

    ##STR00016##

    [0190] wherein

    [0191] * denotes a bonding position;

    [0192] L.sub.4 and L.sub.5 are each independently selected from the group consisting of a direct bond, a C.sub.1-C.sub.6 alkylene group, a C.sub.6-C.sub.14 arylene group, a heteroarylene group having 5 to 14 nuclear atoms, *—(CH.sub.2)a-O—(CH.sub.2)b-*, a carbonyl group (*—C(═O)—*), *—N(R.sub.5)—*, and an amide group (*—C(═O)—N(H)—* or *—N(H)—C(═O)—*);

    [0193] a and b are each independently an integer ranging from 0 to 6;

    [0194] R.sub.4 is selected from the group consisting of a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and *—N(R.sub.6)(R.sub.7);

    [0195] R.sub.5 is selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, and a heterocycloalkyl group having 5 to 7 nuclear atoms;

    [0196] R.sub.6 and R.sub.7 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, or they bond to each other to form a heterocycloalkyl ring having 5 to 7 nuclear atoms, a heteroaryl ring having 5 to 14 nuclear atoms, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms;

    [0197] the alkyl group, cycloalkyl group and heterocycloalkyl group in R.sub.5 are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6 to C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, and a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other; and

    [0198] the alkylene group, arylene group and heteroarylene group in L.sub.4 and L.sub.5, the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, non-aromatic fused polycyclic group and non-aromatic fused heteropolycyclic group in R.sub.4, R.sub.6 and R.sub.7, the alkyl group in R.sub.6 and R.sub.7, and the heterocycloalkyl ring, heteroaryl ring and non-aromatic fused heteropolycyclic ring, which are formed by bonding between R.sub.6 and R.sub.7, are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, a C.sub.3-C.sub.7 cycloalkoxy group, a C.sub.3-C.sub.7 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl group, a heteroaryl group having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic group, a non-aromatic fused heteropolycyclic group having 5 to 14 nuclear atoms, a carboxy group (*—C(═O)—OH), a C.sub.1-C.sub.6 alkoxycarbonyl group, and a C.sub.1-C.sub.6 alkylsulfonyl group, and when they are substituted with a plurality of substituents, these substituents are the same as or different from each other, or the plurality of substituents present adjacent to each other may bond to each other to form a C.sub.3-C.sub.7 cycloalkyl ring, a heterocycloalkyl ring having 5 to 7 nuclear atoms, a C.sub.6-C.sub.14 aryl ring, a heteroaryl ring having 5 to 14 nuclear atoms, a C.sub.5-C.sub.14 non-aromatic fused polycyclic ring, or a non-aromatic fused heteropolycyclic ring having 5 to 14 nuclear atoms.

    MODE FOR INVENTION

    [0199] Hereinafter, the present invention will be described in more detail with reference to examples. These examples are only for illustrating the present invention in more detail, and it will be obvious to those of ordinary skill in the art that the scope of the present invention according to the subject matter of the present invention is not limited by these examples.

    EXAMPLES

    [Preparation Example 1] Preparation of intermediate 1 ((4-(6-methylbenzo[d]oxazol-2-yl)phenyl)methanamine)

    [0200] ##STR00017##

    [0201] 4-(aminomethyl)benzoic acid (1.99 mmol) and 6-amino-m-cresol (1.99 mmol) were dissolved in polyphosphoric acid (PPA, excess) and then refluxed at 200° C. for 12 hours. The reaction mixture was dissolved in an excess of distilled water, and the precipitated salt was filtered, dried under vacuum, and used in the next step without further purification.

    [Preparation Example 2] Preparation of intermediate 2 ((4-(6-chlorobenzo[d]oxazol-2-yl)phenyl)methanamine)

    [0202] ##STR00018##

    [0203] 4-(aminomethyl)benzoic acid (1.32 mmol) and 2-amino-5-chlorophenol (1.32 mmol) were dissolved in polyphosphoric acid (PPA, excess) and then refluxed at 200° C. for 12 hours. The reaction mixture was dissolved in an excess of distilled water, and the precipitated salt was filtered, dried under vacuum, and used in the next step without further purification.

    [Preparation Example 3] Preparation of intermediate 3 (4-(naphtho[2,3-d]oxazol-2-yl)phenyl)methanamine)

    [0204] ##STR00019##

    [0205] 4-(aminomethyl)benzoic acid (1.32 mmol) and 3-amino-2-naphthol (1.32 mmol) were dissolved in polyphosphoric acid (PPA, excess) and then refluxed at 200° C. for 12 hours. The reaction mixture was dissolved in an excess of distilled water, and the precipitated salt was filtered, dried under vacuum, and used in the next step without further purification.

    [Preparation Example 4] Preparation of (4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)phenyl)methanamine

    [0206] ##STR00020##

    [0207] 4-(aminomethyl)benzoic acid (1 eq.) and 2-amino-4-(methylsulfonyl)phenol (1 eq.) were placed in a 20-ml vial, and 4 g of polyphosphoric acid (PPA) was added thereto, followed by stirring at 120° C. for 12 hours. The reaction mixture was adjusted to pH 7 using a 10% K.sub.2CO.sub.3 aqueous solution and then transferred to a separatory funnel and extracted three times with dichloromethane (MC). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was used in the next reaction without a separate purification process.

    [Synthesis Example 1] Preparation of N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4276)

    [0208] ##STR00021##

    [0209] Nicotinic acid (1.06 mmol), the (4-(6-methylbenzo[d]oxazol-2-yl)phenyl)methanamine (1.06 mmol) prepared in Preparation Example 1, (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.11 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 2.11 mmol), and N,N-diisopropylethylamine (DIPEA, 3.17 mmol) were dissolved in dimethylformamide (DMF, 4 ml) and then refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified using dichloromethane (MC) and hexane (HX) to obtain N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide (hereinafter referred to as “A4276”) as a white solid compound.

    [0210] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (t, J=5.6 Hz, 1H), 9.09 (d, J=1.2 Hz, 1H), 8.74 (dd, J=4.6, 1.3 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.1 Hz, 1H), 7.62-7.51 (m, 4H), 7.23 (d, J=8.0 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 2.47 (s, 3H).

    [Synthesis Example 2] Preparation of N-(4-(6-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide hydrochloride (A4276H)

    [0211] ##STR00022##

    [0212] A4276 (1 eq., 4.45 mmol) obtained in Synthesis Example 1 was placed in a 20-ml vial, and 5 ml of a solution 4 M hydrochloric acid (HCl) in 1,4-dioxane was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with ether and stirred at room temperature for 30 minutes. Next, the product was filtered and dried in a vacuum pump to obtain A4276 hydrochloride (A4276H) as a white solid.

    [0213] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.96-9.92 (t, 1H), 9.39-9.38 (d, 1H), 9.03-8.90 (m, 2H), 8.17-8.14 (m, 2H), 7.68-7.60 (m, 4H), 7.25 (d, 2H), 4.65-4.63 (d, 2H), 2.47 (s, 3H).

    [Synthesis Example 3] Preparation of N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4266)

    [0214] ##STR00023##

    [0215] Nicotinic acid (0.77 mmol), the (4-(6-chlorobenzo[d]oxazol-2-yl)phenyl)methanamine (0.77 mmol) prepared in Preparation Example 2, (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.54 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 1.54 mmol), and N,N-diisopropylethylamine (DIPEA, 2.31 mmol) were dissolved in dimethylformamide (DMF, 4 ml) and refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified using dichloromethane (MC) and hexane (HX) to obtain N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)nicotinamide (hereinafter referred to as “A4266”) as a white solid compound.

    [0216] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (t, J=5.6 Hz, 1H), 9.09 (s, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.17 (d, J=8.1 Hz, 2H), 8.00 (d, J=1.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.62-7.51 (m, 3H), 7.47 (d, J=8.5 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H).

    [Synthesis Example 4] Preparation of N-(4-(naphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide (A4265)

    [0217] ##STR00024##

    [0218] Nicotinic acid (0.73 mmol), the (4-(naphtho[2,3-d]oxazol-2-yl)phenyl)methanamine (0.73 mmol) prepared in Preparation Example 3, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.46 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 1.46 mmol), and N,N-diisopropylethylamine (DIPEA, 2.19 mmol) were dissolved in dimethylformamide (DMF, 4 ml) and then refluxed overnight at room temperature. Next, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified using dichloromethane (MC) and hexane (HX) to obtain N-(4-(naphtho[2,3-d]oxazol-2-yl)benzyl)nicotinamide (hereinafter referred to as “A4265”) as a white solid compound.

    [0219] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (t, J=5.5 Hz, 1H), 9.10 (s, 1H), 8.75 (d, J=3.4 Hz, 1H), 8.34 (s, 1H), 8.31-8.24 (m, 4H), 8.09 (t, J=8.6 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.58-7.49 (m, 3H), 4.65 (d, J=5.5 Hz, 2H).

    [Synthesis Example 5] Preparation of N-(4-(oxazolo[4,5-c]pyridin-2-yl)benzyl)nicotinamide (B1471)

    [0220] ##STR00025##

    [0221] Nicotinic acid (2.44 mmol), 4-(naphtho[2,3-d]oxazol-2-yl)phenyl)methanamine (2.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.87 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 4.87 mmol), and N,N-diisopropylethylamine (DIPEA, 7.31 mmol) were dissolved in dimethylformamide (DMF, 10 ml) and then refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified using dichloromethane (MC) and hexane (HX) to obtain N-(4-(oxazolo[4,5-c]pyridin-2-yl)benzyl)nicotinamide (hereinafter referred to as “B1471”) as a white solid compound.

    [0222] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (t, 1H, J=5.8 Hz), 9.14-9.08 (m, 2H), 8.74 (dd, 1H, J=4.8, 1.5 Hz), 8.60 (d, 1H, J=5.5 Hz), 8.29-8.25 (m, 1H), 8.22 (d, 2H, J=8.3 Hz), 7.91 (dd, 1H, J=5.5, 0.7 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.55 (dd, 1H, J=7.9, 4.9 Hz), 4.63 (d, 2H, J=5.8 Hz).

    [Synthesis Example 6] Preparation of N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide (A4510)

    [0223] ##STR00026##

    [0224] Nicotinic acid (1 eq., 1.41 mmol), the (4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)phenyl)methanamine (1 eq., 1.41 mmol) prepared in Preparation Example 1, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.1 eq., 1.55 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 1.1 eq., 1.55 mmol), and N,N-diisopropylethylamine (DIPEA, 3 eq., 4.22 mmol) were dissolved in MC (0.1 M, 14.1 ml) and then refluxed at room temperature overnight. Thereafter, the reaction mixture was transferred to a separatory funnel and distilled water was added thereto, followed by extraction three times with MC. The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% MeOH in dichloromethane), and then dried in a vacuum pump to obtain N-(4-(5-(methylsulfonyl)benzo[d]oxazole-2-yl)benzyl)nicotinamide (A4510) as a white solid (yield: 66.9%).

    [0225] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (t, J=5.8 Hz, 1H), 9.05 (s, 1H), 8.73-8.67 (m, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.26-8.16 (m, 3H), 8.03 (d, J=8.5 Hz, 1H), 7.96 (dd, J=8.6, 1.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.51 (dd, J=7.9, 4.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.27 (s, 3H).

    [Synthesis Example 7] Preparation of N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide hydrochloride (A4510H)

    [0226] ##STR00027##

    [0227] A4510 (1 eq., 4.45 mmol) obtained in Synthesis Example 5 was placed in a 20-ml vial, and 5 ml of a solution of 4M HCl in 1,4-dioxane was added thereto, followed by stirring at room temperature for 4 hours. The reaction product was diluted with ether and then stirred at room temperature for 30 minutes. Thereafter, the product was filtered and dried in a vacuum pump to obtain A4510 hydrochloride (A4510H) as a white solid (yield: 90%).

    [0228] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.69 (s, 1H), 9.23 (s, 1H), 8.88 (d, J=4.1 Hz, 1H), 8.67-8.60 (m, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.19 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.6 Hz, 1H), 7.96 (dd, J=8.6, 1.7 Hz, 1H), 7.87-7.79 (m, 1H), 7.60 (d, J=8.2 Hz, 2H), 4.61 (d, J=5.8 Hz, 2H), 3.27 (s, 3H).

    [Synthesis Example 8] Preparation of N-(4-(5-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4275)

    [0229] ##STR00028##

    [0230] Nicotinic acid (2.44 mmol), (4-(5-methylbenzo[d]oxazol-2-yl)phenyl)methanamine (2.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.87 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 4.87 mmol) and N,N-diisopropylethylamine (DIPEA, 7.31 mmol) were dissolved in dimethylformamide (DMF, 10 ml) and then refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% methanol in dichloromethane) and then dried in a vacuum pump to obtain N-(4-(5-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4275).

    [0231] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.36 (t, J=5.5 Hz, 1H), 9.09 (s, 1H), 8.76-8.73 (m, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.17 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.61-7.51 (m, 4H), 7.24 (d, J=8.2 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H), 2.45 (s, 3H)

    [Synthesis Example 9] Preparation of N-(4-(5-ethylbenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4508)

    [0232] ##STR00029##

    [0233] Nicotinic acid (2.44 mmol), (4-(5-ethylbenzo[d]oxazol-2-yl)phenyl)methanamine (2.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.87 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 4.87 mmol), and N,N-diisopropylethylamine (DIPEA, 7.31 mmol) were dissolved in dimethylformamide (DMF, 10 ml) and then refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% methanol in dichloromethane) and then dried in a vacuum pump to obtain a final compound (hereinafter referred to as “A4508”).

    Synthesis Examples 10 to 30

    [0234] The acid (2.44 mmol) and amine (2.44 mmol) shown in Table 1 below, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.87 mmol), 1-hydroxybenzotriazole monohydrate (HOBt, 4.87 mmol), and N,N-diisopropylethylamine (DIPEA, 7.31 mmol) were dissolved in dimethylformamide (DMF, 10 ml) and then refluxed overnight at room temperature. Then, the reaction mixture was transferred to a separate funnel, and then an aqueous NH.sub.4Cl solution was added thereto, followed by extraction three times with ethyl acetate (EA). The extract was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% methanol in dichloromethane) and then dried in a vacuum pump, thereby preparing the final compounds shown in Table 2 below.

    TABLE-US-00001 TABLE 1 Synthesis Example Acid Amine Synthesis Example 10 [00030]embedded image [00031]embedded image Synthesis Example 11 [00032]embedded image [00033]embedded image Synthesis Example 12 [00034]embedded image [00035]embedded image Synthesis Example 13 [00036]embedded image [00037]embedded image Synthesis Example 14 [00038]embedded image [00039]embedded image Synthesis Example 15 [00040]embedded image [00041]embedded image Synthesis Example 16 [00042]embedded image [00043]embedded image Synthesis Example 17 [00044]embedded image [00045]embedded image Synthesis Example 18 [00046]embedded image [00047]embedded image Synthesis Example 19 [00048]embedded image [00049]embedded image Synthesis Example 20 [00050]embedded image [00051]embedded image Synthesis Example 21 [00052]embedded image [00053]embedded image Synthesis Example 22 [00054]embedded image [00055]embedded image Synthesis Example 23 [00056]embedded image [00057]embedded image Synthesis Example 24 [00058]embedded image [00059]embedded image Synthesis Example 25 [00060]embedded image [00061]embedded image Synthesis Example 26 [00062]embedded image [00063]embedded image Synthesis Example 27 [00064]embedded image [00065]embedded image Synthesis Example 28 [00066]embedded image [00067]embedded image Synthesis Example 29 [00068]embedded image [00069]embedded image Synthesis Example 30 [00070]embedded image [00071]embedded image

    TABLE-US-00002 TABLE 2 Synthesis Compound Final Example Name Compound Synthesis Example 10 A4307 [00072]embedded image   N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)-6- (trifluoromethyl)nicotinamide Synthesis Example 11 A4306 [00073]embedded image   N-(4-(6-methylbenzo[d]oxazol-2-yl) benzyl)benzamide Synthesis Example 12 A4366 [00074]embedded image   N-(4-(5,6,7,8-tetrahydronaphtho[2,3-d]oxazol- 2-yl)benzyl)nicotinamide Synthesis Example 13 A4367 [00075]embedded image   N-(4-(4-methylbenzo[d]oxazol-2-yl)benzyl)nicotinamide Synthesis Example 14 A4375 [00076]embedded image   N-(4-(5-bromobenzo[d]oxazol-2-yl)benzyl)nicotinamide Synthesis Example 15 A4376 [00077]embedded image   N-(4-(5(pyridin-3-yl)benzo[d]oxazol-2-yl)benzyl)nicotinamide Synthesis Example 16 A4511 [00078]embedded image   methy 2-(4-nicotinamidomethyl)phenylbenzo[d]oxazol- 7-carboxylate Synthesis Example 17 A4512 [00079]embedded image   N-(4-(6-methoxybenzo[d]oxazol-2-yl)benzyl)nicotinamide Synthesis Example 18 A4560 [00080]embedded image   N-(((1r,4r)-4-(6-methylbenzo[d]oxazol-2- yl)cyclohexyl)methyl)nicotinamide Synthesis Example 19 A4562 [00081]embedded image   N-(((1r,4r)-4-(5- (methylsulfonyl)benzo[d]oxazol-2- yl)cyclohexyl)methyl)nicotinamide Synthesis Example 20 A4635 [00082]embedded image   N-(4-(6-methylbenzo[d]oxazol-2- yl)benzyl)-3-(pyridin-3-yl)propanamide Synthesis Example 21 B1469 [00083]embedded image   N-(4-benzo[d]thiazol-2- yl)benzyl)nicotimamide Synthesis Example 22 B1470 [00084]embedded image   N-(4-benzo[d]oxazol-2- yl)benzyl)nicotimamide Synthesis Example 23 B1473 [00085]embedded image   N-(4-((4-chloro-1H-pyrazol-1- yl)methyl)benzyl)nicotinamide Synthesis Example 24 B1474 [00086]embedded image   N--(4-(5-methoxybenzo[d]oxazol-2- yl)benzyl)nicotimamide Synthesis Example 25 B1481 [00087]embedded image   N-(4-(6-methylbenzo[d]oxazol-2-yl)phenyl)nicotimamide Synthesis Example 26 B1482 [00088]embedded image   N-(4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3- yl)phenyl)nicotimamide Synthesis Example 27 B1857 [00089]embedded image   N-(2-nicotimamide)ethyl-3-(p-tolyl)- 1,2,4-oxadiazole-5-carboxamide Synthesis Example 28 B1967 [00090]embedded image   N-(4-(2-methyl-1H-imidazol-1-yl) benzyl)nicotimamide Synthesis Example 29 B1978 [00091]embedded image   N-(4-(piperidin-1-yl)benzyl)nicotinamide Synthesis Example 30 B1979 [00092]embedded image   N-(4-(pyridin-2-ylmethoxy)benzyl)nicotinamide

    [Experimental Example 1] Evaluation of the Ability to Inhibit SARM1 Enzyme that Triggers Axonal Degeneration (1)

    [0235] As described above, it has been reported that SARM1 promotes axonal degeneration through MKK4-JNK as a downstream signaling in a traumatic axonal injury model (Yang et al., Cell 2015, PMID 25594179), and that SARM1 promotes JNK phosphorylation, and as a result, promotes immune responses around injured neurons (Wang et al., Cell Reports 2018, PMID 29669278). In addition, it has been reported that the JNK pathway is required for axonal degeneration, and that this axonal degeneration is delayed upon JNK inhibition (Miller et al., Nature Neuroscience volume 12, pages 387-389(2009); PNAS Dec. 26, 2012, 109 (52) 21199-21200).

    [0236] Accordingly, in order to evaluate the axonal degeneration inhibitory effects of the compounds according to the present invention, the abilities of these compounds to inhibit SARM1 enzyme were analyzed. Specifically, whether phosphorylation of JNK protein, a representative sub-regulatory marker of SARM1, decreased, was evaluated by Western blot assay. A method for preparing the protein used in the Western blot assay is as follows. The gastric cancer cell line MKN1 was treated with PBS, harvested, washed with PBS, and then lysed using RIPA buffer as a cell lysis buffer containing each of A4276H, A4510H, A4265, A4275, A4367, A4375, A4376 and A4512 prepared in the Synthesis Examples. The entire cell lysate was fractionated using a centrifuge, and then only the solution containing the protein was extracted. The extracted protein was quantified by the Bradford method. The protein of the same concentration obtained through quantification was separated by SDS-polyacrylamide gel electrophoresis, and then transferred to a PVDF membrane. The membrane to which the protein has been transferred was blocked with a TBS-T (Tris-buffered saline/0.1% Tween-20) solution containing 5% non-fat milk at room temperature for 1 hour in order to reduce non-specific binding, and incubated with a primary antibody (diluted in 5% BSA solution) at 4° C. for 12 hours or more, and then incubated with a secondary antibody (1:5000 dilution) at room temperature for 1 hour. For visualization, an enhanced chemiluminescence system was used. Western blot assay was performed using JNK protein, a representative marker whose phosphorylation is regulated by SARM1, and the housekeeping protein Hsp90 was used for quantitative comparison of expression. The results are shown in FIG. 1.

    [0237] As shown in FIG. 1, it could be confirmed that all of the compounds according to the present invention inhibited JNK phosphorylation. On the other hand, although not shown in the figure, it could be seen that N-(4-(6-chlorobenzo[d]oxazol-2-yl)benzyl)nicotinamide (A4266) also had the effect of inhibiting JNK phosphorylation. These compounds are characterized by commonly having a nicotinamide group and a benzoxazole group at both ends.

    [Experimental Example 2] Evaluation of the Ability to Inhibit SARM1 Enzyme that Triggers Axonal Degeneration (2)

    [0238] 24 hours before the experiment, the F11 cell line (a fusion of the mouse neuroblastoma cell line N18TG-2 with embryonic rat dorsal-root ganglion (DRG) neurons) was seeded into 6-well plates at a density of 3×10.sup.5 cell/well. Using Lipofectamine 2000 reagent, each well was transfected with 1 μg of a pCMV-FKBPF36V-TIR vector. The reason for attaching the FKBP domain (FKBPF36V) to the TIR is that the dimerization of the FKBP domain can be artificially induced upon administration of the AP20187 substance, which in turn induces dimerization of and activates the SARM1 TIR domain attached thereto. After 24 hours, each well was pre-treated with each of the compounds according to the present invention at a concentration of 10 μM for 1 hour, and then treated with 500 nM AP20187 for activation of the TIR domain. After 24 hours, each well was washed with cold PBS and then lysed using RIPA buffer. Next, the protein was quantified by the Bradford assay and then sampled using SDS buffer. 10 μg of the sample was loaded on 12% SDS-PAGE gel. The protein-loaded gel was transferred to a PVDF membrane, incubated in a blocking solution (5% skim milk) for 1 hour, and then subjected to an antigen-antibody reaction with a primary antibody (diluted 1:1,000) at 4° C. for 12 hours or more. After unbound antibody was removed by washing three times with 1× TBST for 10 minutes, the gel was subjected to an antigen-antibody reaction with a secondary antibody (diluted 1:3,000) at room temperature for 1 hour. In addition, after unbound antibody was removed by washing three times with 1× TBST for 10 minutes, a color reaction was developed using the ECL solution to visualize the band. The results are shown in FIGS. 2 to 12.

    [0239] As shown in FIGS. 2 to 12, it could be seen that all of the compounds according to the present invention had the effect of inhibiting JNK phosphorylation, and the inhibited phosphorylation of the JNK protein was not restored by AP20187, suggesting that the effect of the compounds on the inhibition of JNK phosphorylation was the effect obtained by the inhibition of SARM1 or the inhibition of a downstream pathway thereof. For reference, AP20187 is known as a substance that activates the FKBP domain by promoting the dimerization thereof (Yang et al., Cell 2015, PMID 25594179; Wang et al., Cell Reports 2018, PMID 29669278).

    [Experimental Example 3] Preparation of Tadpole Optic Nerve Axotomy Model and Drug Efficacy Experiment (1)

    [0240] In order to verify the axon protective effect of the compound according to the present invention in the tadpole optic nerve axotomy model, an experiment was conducted according to the design shown in FIG. 13. Specifically, an in vitro fertilized Xenopus tropicalis (African frog) embryo (Nasco, Fort Atkinson, Wis. 53538, USA) is cultured to stage 27, and then a plasmid DNA expressing Enhanced Green Fluorescence Protein (EGFP) is delivered into the retinal progenitor cells of one eye by an electroporation technique. After culturing to stage 41, the axons of the retinal ganglion cells expressing the green fluorescent protein reach the optic tectum of the contralateral brain hemisphere, and this axon bundle is referred to as the optic nerve. When the optic nerve is axotomized at stage 41, Wallerian degeneration occurs in which axons distal from the cell body degenerate by fragmentation over about 72 hours. While the optic nerve was axotomized, the embryo was treated with various drugs, including N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide (A4510), and LSN 3154567 and KPT9274 as controls. 48 hours after treatment, the embryo was fixed in a solution of 4% paraformaldehyde in phosphate buffered saline. After extraction of the brain of the fixed embryo, the green fluorescent protein signal of the optic nerve in the brain hemisphere was imaged using a confocal microscope (model LSM700, Carl Zeiss, Oberkochen, Germany), and the results are shown in FIG. 14. Wallerian degeneration of the Xenopus optic nerve occur in a stereotypical pattern at 24 hours, 48 hours and 72 hours after axotomy, and the degree of delay in Wallerian degeneration was quantified as percentage by comparing the degree of Wallerian degeneration in the drug-treated group with this pattern. The results of the quantification are shown in FIG. 15.

    [0241] As shown in FIGS. 14 and 15, it could be seen that LSN 3154567 and KPT9274 used as controls did not exhibit a significant axon protective effect, but the compound according to the present invention exhibited an excellent axon protective effect.

    [Experimental Example 4] Preparation of Tadpole Optic Nerve Axotomy Model and Drug Efficacy Experiment (2)

    [0242] In order to verify the axon protective effect of the compound according to the present invention in the tadpole optic nerve axotomy model, an experiment was conducted in the same manner as in Experimental Example 3. Specifically, GFP-expressing DNA was delivered into one retina of a Xenopus tropicalis tadpole at stage 27 (before retinal development) by electroporation. At stage 43 (the time when the connection between the retina and the visual center of the brain is finished), axons of the epectroporated retina were axotomized, and the tissue was fixed at 24-hour intervals, followed by extraction of the brain. Next, the ventral midline of the brain was excised and unfolded, and then the GFP signal in the contra-lateral brain hemisphere was imaged with a confocal microscope (LSM700, Carl Zeiss, 20×, z-step 3 μm). Thereby, it was possible to observe retinal ganglion cell axons located along the optic tract extending from the optic chiasm to the optic tectum. A non-axotomized uninterrupted GFP signal could be observed, which was defined as a healthy axon. Axonal degeneration could be quantified because the continuous GFP signal disappeared along the optic tract over time after axotomy. In most cases, compared to normal tissue, about 50% healthy axons, about 10% healthy axons and 0% healthy axons appeared after 24 hours, 48 hours and 72 hours, respectively. The degree of inhibition of axonal degeneration by the drug was evaluated 48 hours after axotomy. As the drug, N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl) benzyl)nicotinamide hydrochloride (A4510H) was used, and as a control, DMSO was used. Treatment with the drug or the control was performed simultaneously with axotomy, and the non-axotomized group was included in each experiment. The percentage of healthy axons in the drug group relative to the control group taken as 100% was calculated and used as the axon survival score (0 to 100%). The results are shown in FIG. 16.

    [0243] As shown in FIG. 16, it could be seen that N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide hydrochloride (A4510H) according to the present invention exhibited an excellent axon protective effect.

    [Experimental Example 5] Evaluation of Inhibitory Effect Against Axonal Degeneration Caused by Anticancer Drugs

    [0244] The dorsal root ganglias (DRGs) of mouse embryos (1 to 5 days old) were separated into cell units, and then each cell was fluidically divided into the cell body and the axon by culture in a microfluidic device. At this time, only the axon region was treated with each of the compounds (drugs) of Synthesis Examples 1 to 30 according to the present invention, and movement of the treated drug from the axon region to the cell body region was prevented by increasing the amount of the cell body region medium compared to the amount of the axon region medium through application of pressure due to the difference in height between the media. Treatment with the drug was performed 24 hours before treatment with the anticancer drug vincristine or paclitaxel. The experiment was conducted using a total of three experimental groups: a control group (Untreated), a vincristine/paclitaxel-treated group, and a drug-treated group (40 nM vincristine/100 nM paclitaxel+2 μM test drug). 24 hours after drug treatment, fixing with 4% paraformaldehyde (PFA) was performed. Immunocytochemistry (ICC) was performed with acetylation-alpha-tubulin, and axonal degeneration was quantitatively analyzed by imaging the degree of axonal degeneration with a fluorescence microscope.

    [0245] As a result, although not shown in the drawings, it could be confirmed that, when treatment with the compound according to the present invention was performed, axonal degeneration was inhibited even when subsequent treatment with an anticancer agent such as vincristine or paclitaxel was performed.

    [0246] Thereby, it could be seen that that the compound of the present invention could exhibit the effect of inhibiting axonal degeneration, and could also effectively prevent or treat chemotherapy-induced peripheral neuropathy (CIPN) by protecting axons from injury caused by anticancer drugs.

    [0247] Although the present invention has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this description is only of a preferred embodiment thereof, and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereto.

    INDUSTRIAL APPLICABILITY

    [0248] The present invention is directed to a composition capable of preventing or inhibiting axonal degeneration and effectively preventing, ameliorating or treating various neurological diseases caused by axonal degeneration.