Compounds and pharmaceutical composition associated with ubiquitination-proteasome system

1. A compound having the following Formula (I):

wherein

R 1 is halogen, alkyl, alkenyl, alkynyl, NH 2 , NO 2 , OH or CN;

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

R 3 is H, alkyl, alkenyl, alkynyl, NH 2 , NO 2 , OH or CN;

R 4 is H, alkyl, alkenyl, alkynyl, NH 2 , NO 2 , OH or CN, or R 4 together with nitrogen atom attached therefrom and R 5 form a fused bicyclic ring having 0 to 3 heteroatoms selected from O; N and S;

R 5 is alkylene-R 6 wherein R 6 is OH, NO 2 , CN, alkyl, alkenyl, alkynyl, NR a R b , cycloalkyl, aryl, heterocyclic ring having 0 to 3 heteroatoms selected from O; N and S or fused heterocyclic ring having 0 to 3 heteroatoms selected from O, N and S, each of cycloalkyl, aryl, heterocyclic ring and fused heterocyclic ring is unsubstituted or substituted with one to three of OH; halogen; NH 2 ; NO 2 , CN, alkyl; alkenyl; alkynyl; alkyloxy; heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted with alkyl, alkenyl, alkynyl, OH, halogen, CN, NH 2 or NO 2 ; and

R a and R b are the same or different, independently representing H; OH; alkyl; alkenyl; alkynyl; alkyloxy; cycloalkyl; heterocyclyl; alkyleneamino; alkylene-N-(alkyl) 2 ; aryl unsubstituted or substituted with OH, halogen, CN, NH 2 , NO 2 , alkyl, alkenyl, alkynyl, alkyloxy or heteroaryl, heteroaryl unsubstituted or substituted with OH, halogen, CN, NH 2 , NO 2 , alkyl, alkenyl, alkynyl or alkyloxy; alkylene-heteroaryl; or alkylene-heterocyclyl unsubstituted or substituted with alkyl;

X is —C(O), —S(O) 2 — or —NH—C(O)—;

m is an integer of 0-3; and

n is an integer of 1-7;

or a tautomer or stereoisomer thereof, or a solvate, prodrug 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; R 5 is alkylene-R 6 wherein R 6 is NR a R b , C 5-7 heterocyclic ring having 0 to 3 hetero atoms selected from O, N and S; or C 10-12 fused heterocyclic ring having 0 to 3 hetero selected from O, N and S; and R a and R b are alkyl.

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; R 5 is (CH 2 ) 1-4 R 6 wherein R 6 is unsubstituted or substituted pyrrolidinyl, oxolanyl, thiolanyl, pyrrolyl, furanyl, thiophenyl, piperidinyl, oxanyl, thianyl, morpholinyl, pyridinyl, piperidinyl, piperazinyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl; benzimidazolyl; pyrazolyl; indazolyl; pyrazolyl; quinolinyl; indolyl; indazolyl; azaindolyl; azaindazolyl; deazapurinyl; or indanyl.

4. 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; R 5 is (CH 2 ) 1-4 R 6 wherein R 6 is unsubstituted or substituted pyrrolidinyl, morpholinyl, pyridinyl, piperidinyl, piperazinyl, or indolyl.

5. The compound of claim 1 , wherein m is 0; R 1 is Cl; n is 1; R 3 is H, x is C(O); R 4 is H; R 5 is CH 2 CH 2 N(CH 3 ) 2 , pyrrolidinyl substituted by ethyl, or CH 2 CH 2 N(CH 2 CH 3 ) 2 .

6. The compound of claim 1 , wherein the compound is selected from the group consisting of:

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

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

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

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

10. The pharmaceutical composition of claim 8 , wherein the second therapeutic agent is a corticosteroid, a lubricant, a keratolytic agent, a vitamin D 3 derivative, PUVA and anthralin, β 2 -agonist, a corticosteroid, immunosuppressant, NSAID, COX-2 inhibitor, biologic, non-steroidal calcineurin inhibitor, steroidal anti-inflammatory agent, 5-amino salicylic acid, DMARDs, hydroxychloroquine sulfate, inflammatory modulator, agents that interferes with B cell action or penicillamine.

11. The pharmaceutical composition of claim 9 , wherein the mitotic inhibitor is a taxane.

12. The pharmaceutical composition of claim 11 , wherein the taxane is selected from paclitaxel or docetaxel.

13. The pharmaceutical composition of claim 9 , wherein the vinca alkaloid is selected from vinblastine, vincristine, vindesine or vinorelbine.

14. The pharmaceutical composition of claim 9 , wherein the antracycline antibiotic is selected from doxorubicin, daunorubicin, daunorubicin, epirubicin, idarubicin, valrubicin or mitoxantrone.

15. The pharmaceutical composition of claim 9 , wherein the nucleoside analog is gemcitabine.

16. The pharmaceutical composition of claim 9 , wherein the EGFR inhibitor is selected from gefitinib or erlotinib.

17. The pharmaceutical composition of claim 9 , wherein the folate antimetabolite is selected from trimethoprim, pyrimethamine or pemetrexed.