Aminonapthoquinone compounds and pharmaceutical composition for blocking ubiquitination-proteasome system in diseases

1. A compound of Formula (I):

wherein

R 1 is halogen;

each R 2 is the same or different, representing H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, NH 2 , NO 2 , C 1-10 alkyloxy, C 1-10 alkylthio, C 1-10 alkylamino, C 1-10 alkyloxyC 1-10 alkyl, OH or CN, C 6-10 aryl or C 5-7 heterocyclic having 1 to 3 heteroatoms selected from the group consisting of N, O and S;

R 3 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, NH 2 , NO 2 , OH or CN;

R 4 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, NH 2 , NO 2 , OH and CN;

R 5 is OH, C 3-8 cycloalkyl, phenyl unsubstituted or substituted with one to three same or different substituents selected from OH, CN, halogen, NH 2 or C 1-4 alkylpiperazinyl, C 1-6 alkylpiperazinyl, C 1-6 alkylpyridinyl, C 1-6 alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazapurinyl, indanyl, morpholinoyl or C 1-4 alkylmorpholinoyl, each of which is unsubstituted or substituted with one, two or three groups selected from OH, CN, halogen NO 2 , C 1-4 alkyl, or NH 2 ;

and

X is —C(O)

Y is —N—;

m is an integer of 0-3; and

n is an integer of 1-7;

or a tautomer, enantiomer, stereoisomer thereof, or a solvate or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein m is 0; R 1 is halogen; n is any integer of 1-4; R 3 is H; X is C(O); R 4 is H; and R 5 is OH, C 3-8 cycloalkyl, phenyl unsubstituted or substituted with one to three same or different substituents selected from OH, CN, halogen, NH 2 or C 1-4 alkylpiperazinyl, C 1-6 alkylpiperazinyl, C 1-6 alkylpyridinyl, C 1-6 alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazapurinyl, indanyl, morpholinoyl or C 1-4 alkylmorpholinoyl, each of which is unsubstituted or substituted with one, two or three groups selected from OH, CN, halogen or NH 2 ; or a tautomer, enantiomer, stereoisomer thereof, or a solvate or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein m is 0; R 1 is halogen; n is any integer of 1-2; R 3 is H; X is C(O); R 4 is H; and R 5 is OH, C 3-8 cycloalkyl, pyridinyl, phenyl substituted by one to three of NH 2 , halogen, OH, CN or C 1-4 alkylpiperazinyl; pyrimidinyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; pyrazinyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; thiazolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; benzimidazolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; pyrazolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; indazolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; quinolinyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; indolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; -azaindazolyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; deazapurinyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; indanyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; or morpholinoyl unsubstituted or substituted with NO 2 , NH 2 or C 1-4 alkyl; or a tautomer, enantiomer, stereoisomer thereof, or a solvate or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , which is selected from:

4-(((3-bromo-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-2-yl)benzamide;

4-(((3-chloro-14-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyrimidin-4-yl)benzamide;

4-(((3-chloro-1.4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyrazin-2-yl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-hydroxybenzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-2-yl)benzamide;

N-(2-aminophenyl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-3-yl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-4-yl) benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(3-fluorophenyl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(4-fluorophenyl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-phenylbenzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(2-fluorophenyl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(thiazol-2-yl)benzamide;

N-(1H-benzo[d]imidazol-2-yl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(4-hydroxyphenyl) benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(3-ethynylphenyl) benzamide;

4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(2-fluoro-4-iodophenyl)benzamide;

N-(1H-benzo[d]imidazol-5-yl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino) methyl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-cyclopropylbenzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-cyclopentylbenzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indazol-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(5-methylthiazol-2-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(5-methyl-3H-pyrazol-3-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(3-nitropyridin-4-yl) benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-6-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-8-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-3-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(2-methylquinolin-4-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indol-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(2-methyl-1H-indol-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indol-7-yl) benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indol-4-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-indazol-6-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide;

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide; and

4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(2,3-dihydro-1H-inden-4-yl)benzamide;

or a tautomer or stereoisomer thereof, or a solvate or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , which is 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-4-yl)benzamide, having the following formula:

or a tautomer, enantiomer, stereoisomer thereof, or a solvate or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 , further comprising a second therapeutic agent.

8. The pharmaceutical composition of claim 7 , wherein the second therapeutic agent is selected from a mitotic inhibitor, vinca alkaloids and vepesid; an anthracycline antibiotic; a nucleoside analog; an EGFR inhibitor; a folate antimetabolite; cisplatin, carboplatin or an HDAC inhibitor.

9. The pharmaceutical composition of claim 7 , wherein the second therapeutic agent is selected from a corticosteroid, a keratolytic agent, a vitamin D 3 derivative, PUVA and anthralin, β 2 -agonist, immunosuppressant, NSAID, COX-2 inhibitor, non-steroidal calcineurin inhibitor, steroidal anti-inflammatory agent, 5-amino salicylic acid, DMARD, hydroxychloroquine sulfate, inflammatory modulator, agent that interferes with B cell action or penicillamine.

10. A method for therapeutically treating multiple myeloma or colorectal adenocarcinoma, comprising administrating an effective amount of the compound of claim 1 to a cell or a subject.

11. A method for reducing tumor volume growth relative to vehicle control in a cancer selected from breast cancer or ovarian cancer in a subject in need thereof, the method comprising administering to the subject a compound of claim 1 .