1,2-naphthoquinone based derivative and method of preparing the same

1. A compound represented by Formula (1) below or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof:

wherein R 1 and R 2 are each independently hydrogen, a halogen, hydroxyl, substituted or unsubstituted C1-C20 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C2-C10 heteroaryl, —NO 2 , —NR′ 1 R′ 2 , —NR′ 1 (CO(O)R′ 2 ), —NR′ 1 (C(O)NR′ 1 R′ 2 ), —CO(O)R′ 1 , —C(O)NR′ 1 R′ 2 , —CN, —SO(O)R′ 1 , —SO(O)NR′ 1 R′ 2 , —NR′ 1 (SO(O)R′ 2 ), —CSNR′ 1 R′ 2 , or R 1 and R 2 form a ring structure of substituted or unsubstituted C4-C10 aryl through coupling or a ring structure of substituted or unsubstituted C2-C10 heteroaryl,

where R′ 1 and R′ 2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted —(CR″ 1 R″ 2 )m′-C4-C10 aryl, substituted or unsubstituted —(CR″ 1 R″ 2 )m′-C4-C10 heteroaryl or substituted or unsubstituted NR″ 1 R″ 2 ; where R″ 1 and R″ 2 are each independently hydrogen, or C1-C3 alkyl, or R″ 1 and R″ 2 form a ring structure of substituted or unsubstituted C4-C10 aryl through coupling;

R 3 is hydrogen, oxygen, a halogen, unsubstituted branched C3-C10 alkyl, substituted or unsubstituted C2-C20 alkene, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C4-C10 aryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C4-C10 aryloxy, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C1-C10 heteroaryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —NR′ 3 R′ 4 , substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C2-C10 heterocycloalkyl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —OR′ 3 , substituted or unsubstituted —(CR′ 5 R′ 6 ) m (O)COR′ 3 , —CO(O)R′ 3 , —CONR′ 3 R′ 4 , —NR′ 3 R′ 4 , —NR′ 3 (C(O)R′ 4 );

where R′ 3 and R′ 4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C4-C10 aryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C4-C10 aryloxy, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —C1-C10 heteroaryl, —CO(O)R′″ 3 , or R′ 3 and R′ 4 form a ring structure of substituted or unsubstituted C2-C10 heterocycloalkyl or substituted or unsubstituted C1-C10 heteroaryl through coupling;

R′ 5 and R′ 6 are each independently hydrogen or C1-C3 alkyl; and R′″ 3 is C1-C6 alkyl;

wherein a substituted group is at least one selected from the group consisting of hydroxy, a nitro group, a halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2-C10 heteroaryl;

X 1 , X 2 , X 3 and X 4 are each independently C(H), CO, or N (R″ 3 );

X 6 is O when X 5 is N (R″ 4 ) and X 6 is N (R″ 4 ) when X 5 is O;

where R″ 3 and R″ 4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, or substituted or unsubstituted —(CH 2 ) n —C4-C6 aryl, and the substituted group is at least one selected from the group consisting of hydroxy, a halogen, and C1-C5 alkyl;

m, m′, and n are each independently a natural number of 1 to 4;

a heteroatom is at least one selected from N, O, and S; and

“ ” means a single bond or a double bond.

2. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 1 ,

wherein X 1 , and X 2 are each independently C(H), CO, or N(R 3 ″), where R 3 ″ is hydrogen or C1-C3 alkyl; and

X 3 and X 4 are each independently C(H) or N.

3. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 2 , wherein X 1 is C(H), N, NH, or NCH 3 ;

X 2 is C(H) or CO; and

X 3 and X 4 are each independently C(H) or N.

4. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 1 , wherein R 1 and R 2 are each independently hydrogen, F, Cl, —OCH 3 , —OCH 2 CH 3 , —O(CH 2 ) 2 CH 3 , —CH 3 , —NO 2 , —NH 2 —, —N(CH 3 ) 2 , —NHCOCH 3 , —NHCOC 3 H 5 , —NHCOC 3 H 7 , or —CN or —OH.

5. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 1 , wherein R 3 is hydrogen, isopropyl, isobutyl, t-butyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —OR′ 3 , substituted or unsubstituted —(CR′ 5 R′ 6 ) m —OCOR′ 3 , or substituted or unsubstituted —(CR′ 5 R′ 6 ) m —NR′ 3 R′ 4 ; where R′ 3 and R′ 4 are each independently hydrogen, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted C4-C10 aryl, or R′ 3 and R′ 4 forms a ring structure of substituted or unsubstituted C4-C10 heterocycloalkyl or substituted or unsubstituted C1-C6 heteroaryl through coupling;

R′ 5 and R′ 6 are each independently hydrogen or C1-C3 alkyl;

a substituted group is at least one selected from the group consisting of hydroxy, a halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;

a heteroatom is at least one selected from N, O, and S; and

m is a natural number of 1 to 4.

6. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 5 , wherein R 3 is isopropyl, isobutyl, t-butyl, neopentyl, substituted or unsubstituted phenyl, substituted or unsubstituted —(CR′ 5 R′ 6 ) m —OR′ 3 , or substituted or unsubstituted —(CHR′ 5 ) m —NF 3 F 4 ,

where R′ 3 and R′ 4 are each independently hydrogen, methyl, ethyl, propyl, or substituted or unsubstituted C4-C10 aryl, or R′ 3 and R′ 4 form a ring structure of substituted or unsubstituted C4-C6 heterocycloalkyl through coupling;

R′ 5 is hydrogen or methyl;

a substituted group is at least one selected from the group consisting of a halogen, C1-C3 alkyl, and C1-C3 alkoxy;

a heteroatom is at least one selected from N, O, and S; and

m is a natural number of 1 to 2.

7. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 5 , wherein R 3 is isopropyl, t-butyl, phenyl, phenyl substituted with fluorine, —CH 2 OCOCH 3 —CH 2 N (CH 3 ) 2 , substituted or unsubstituted —CH 2 NCH 3 C 6 H 5 , substituted or unsubstituted —CH 2 NHC 6 H 5

and

the substituted group is at least one selected from the group consisting of a halogen, methyl and methoxy.

8. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 1 , wherein R″ 4 is hydrogen, C1-C3 alkyl, substituted or unsubstituted —CH 2 —C4-C6 aryl, wherein a substituted group is a halogen.

9. The compound or the pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof according to claim 1 , wherein the compound of Formula (1) is one of compounds below:

10. A method of preparing the compound of Formula (1) according to claim 1 , the method comprising:

A) introducing —NH 2 to a compound of Formula (2) below;

B) reacting the compound generated in the introducing (A) with R 3 COH, R 3 X or 4-nitrophenyl chloroformate under acidic conditions or reacting with R 3 COH or R 3 X under acidic conditions after reacting MX; and

C) oxidizing the compound generated in the reacting (B) or oxidizing the compound generated in the reacting (B) after reacting under acidic conditions:

wherein X 1 to X 4 and R 1 to R 3 are the same as defined in Formula (1), M is Cu, Al, or B, and X is a halogen.

11. The method according to claim 10 , wherein, in the introducing (A), the compound of Formula (2) and O-benzylhydroxylamine hydrochloride or NaN 3 are reacted to introduce —NH 2 .

12. The method according to claim 10 , further comprising reacting the compound generated in the oxidizing (C) and MX′ or R″ 4 X′,

wherein M is Cu, Al, or B; X′ is a halogen; and R″ 4 is the same as defined in Formula (1).

13. The method according to claim 10 , further comprising (D) reacting the compound generated in the oxidizing (C) with HNO 3 to introduce —NO 2 .

14. A method of preparing the compound of Formula (1) according to claim 1 , the method comprising:

a) introducing —NH 2 to the compound of Formula (2);

b) reacting the compound generated in the introducing (a) with (R 8 O) 2 CH (CH 2 ) n′ X under acidic conditions; and

c) oxidizing the compound generated in the reacting (b) and then reacting with R 9 R 10 NH or R′ 3 COOK, or reacting the compound generated in the reacting (b) with R 9 R 10 NH and then oxidizing,

wherein R 8 is C1-C3 alkyl;

R 9 and R 10 are each independently hydrogen, C1-C3 alkyl, substituted or unsubstituted phenyl, or R 9 and R 10 forms a ring structure of C4-C6 heterocycloalkyl through coupling, wherein a heteroatom is at least one selected from the group consisting of N, O, and S and a substituted group is at least one selected from a halogen, C1-C3 alkyl and C1-C3 alkoxy;

R′ 3 is the same as defined Formula (1);

X is a halogen; and

n′ is an integer of 0 to 4.

15. A method of preparing the compound of Formula (1) according to claim 1 , the method further comprising:

A′) introducing —NO 2 to the compound of Formula (4) below through HNO 3 reaction;

B′) reducing the compound generated in the introducing (A′) or reducing after reacting with R 6 X″; and

C′) reacting the compound generated in the reducing (B′) and the compound generated in the introducing (A) with R 3 COH under acidic conditions and then oxidizing,

wherein X 1 to X 4 and R 1 to R 3 are the same as defined in Formula (1); R 5 and R 6 each are C1-C5 alkyl; and X″ is a halogen.

16. A method of preparing the compound of Formula (1) according to claim 1 , the method comprising:

1) reacting the compound of Formula (5) below with R 7 NH 2 ; and

2) oxidizing the compound generated in the reacting (1),

wherein X 1 to X 4 and R 1 to R 3 are the same as defined in Formula (1); and R 7 is C1-C5 alkyl or benzyl.

17. The method according to claim 16 , further comprising (3) introducing NO 2 to the compound generated in the oxidizing (2).

18. The method according to claim 17 , further comprising (4) hydrogenating the compound generated in the introducing (3).

19. The method according to claim 18 , further comprising (5) reacting the compound generated in the hydrogenating (4) with CuX′″, where X′″ is a halogen or CN.

20. The method according to claim 18 , further comprising (4-1) reacting the compound generated in the hydrogenating (4) with R 3 COCl, where R 3 is the same as defined in claim 1 .

21. A method of preparing the compound of Formula (1) according to claim 1 , the method comprising:

(1′) alkylating the compound of Formula (6) below, and then reducing NO 2 to NH 2 through reduction and introducing a halogenation group; and

(2′) reacting the compound generated in the alkylating (1′) with R 3 COCl;

(3′) cyclizing the compound generated in reacting (2′) and then hydrogenating; and

(4′) oxidizing the compound generated in the cyclizing (3′),

wherein X 1 to X 4 and R 1 to R 3 are the same as defined in Formula (1).

22. The method according to claim 21 , further comprising (2′-1) reacting the compound generated in the reacting (2′) with a metal halide and alkylating between the reacting (2′) and cyclizing (3′).

23. A pharmaceutical composition comprising (a) a therapeutically effective amount of the compound of Formula (1) according to claim 1 and/or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, and/or pharmaceutically acceptable diastereomer thereof; and (b) a pharmaceutically acceptable carrier, diluent, or vehicle, or a combination thereof.

24. A method of treating metabolic syndromes using a therapeutically effective amount of the compound of Formula (1) according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, or pharmaceutically acceptable diastereomer thereof.