Substituted urea derivatives and pharmaceutical uses thereof

1. A compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

wherein

each of ring A and ring E is independently C 6-10 aryl or C 1-12 heteroaryl;

each J is -G-(CH 2 ) n —R 2 ;

each G is independently —O—, —S(═O) t —, —S—, —C(═O)—, —OC(═O)—, —C(═S)—, —C(═S)—N(R 4 )— or —(CH 2 ) n —C(═O)—;

each R 1 and R 1a is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 alkylamino, C 1-4 alkyl-C(═O)—NH—, C 1-4 alkylthio, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

each R 2 is independently —NR 3 R 3a , cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl, alkyl-S(═O) t —, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkoxyalkyl, alkyl, alkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, heterocyclylalkylaryl, heterocylylalkylheteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, aryl, arylalkyl, heteroarylalkyl, heteroaryl, bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl;

each R 3 and R 3a is independently C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

each R 4 is independently H, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

ring K is 5- to 6-membered heteroaryl;

each L is independently amino, nitro, C 1-4 alkylthio, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-4 haloalkyl, C 1-4 alkylamino, hydroxy, F, Cl, Br, I, C 1-4 alkyl-C(═O)—NH—, C 1-4 alkoxy, C 1-4 hydroxyalkyl or cyano;

each a and e is independently 0, 1, 2, 3 or 4;

each n, d and b is independently 1, 2, 3 or 4; and

each t is independently 0, 1 or 2;

wherein optionally each aryl, —(CH 2 ) n —C(═O)—, alkyl-S(═O) t —, hydroxyalkyl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclyl, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, alkoxy, alkoxyalkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, cycloalkylalkyl, heterocyclylalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, heterocyclylalkylaryl, heterocyclylalkylheteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C(═O)—NH—, alkylthio and cycloalkyl described in R 1 , R 1a , R 2 , R 3 , R 3a , A, E, J, G, L and/or K is independently substituted with one or more R 2a which are the same or different, and wherein

each R 2a is independently H, F, Cl, Br, I, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkylamino, di-C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, cyano, nitro, —C(═O)—NH 2 , carboxy, —S(═O) t O—H, —OS(═O) t —H, —S(═O) t NH 2 , triazolyl, tetrazolyl, —(CR 3b R 3c ) n —NH 2 , amino, oxo (═O), C 1-4 alkyl-C(═O)—, benzyl, phenyl, C 1-6 alkyl-S(═O) t —, C 1-6 alkoxy-C 1-6 -alkyl, C 1-4 alkyl-C(═O)—NH—, C 1-4 alkoxy, C 1-4 hydroxyalkyl or C 1-4 alkylthio; and

each R 3b and R 3c is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl.

2. The compound according to claim 1 having Formula (II) or Formula (IIa), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R 0 is C 2-3 alkyl, trifluoromethyl, fluoromethyl, difluoromethyl or hydroxymethyl.

3. The compound according to claim 1 , wherein each ring A and ring E is independently one of the following sub-formulae:

wherein

each X, Y, Z, Z 1 , Z 2 , Z 3 and Z 4 is independently N or CH;

each T, T 1 and T 2 is independently —O—, —S—, —N(R 4 )— or —CH 2 —; and

each R 1 and R 1a is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 1-4 alkylamino, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl; or

each ring A and ring E is independently one of the following sub-formulae:

each R 1 and R 1a is independently H, F, Cl, Br, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, C 2-10 heterocyclyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl.

4. The compound according to claim 1 , wherein,

each R 2 is independently —NR 3 R 3a , C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 -alkyl, C 2-10 heterocyclyl-C 1-4 -alkyl, C 1-6 alkyl-S(═O) t —, C 1-4 hydroxyalkyl, C 1-4 hydroxyalkoxy, C 1-4 aminoalkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino-C 1-4 -haloalkoxy, C 1-4 alkylamino-C 1-4 -alkoxy, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl-C 1-4 -alkoxy, C 6-10 aryl-C 1-4 -alkylamino, C 1-9 heteroaryl-C 1-4 -alkoxy, C 1-9 heteroaryl-C 1-4 -alkylamino, C 2-10 heterocyclyl-C 1-4 -alkylamino, C 2-10 heterocyclyl-C 1-4 -alkyl-C 6-10 -aryl, C 2-10 heterocyclyl-C 1-4 -alkyl-C 1-9 -heteroaryl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylamino, C 2-10 heterocyclyl-C 1-4 -alkoxy, C 3-10 carbocyclyl-C 1-4 -alkoxy, C 3-10 carbocyclyl-C 1-4 -alkylamino, C 6-10 aryloxy-C 1-4 -alkoxy, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-9 heteroaryloxy-C 1-4 -alkoxy, C 2-10 heterocyclyloxy-C 1-4 -alkoxy, C 3-10 carbocyclyloxy-C 1-4 -alkoxy, C 2-10 heterocyclyloxy, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 1-9 heteroaryl, C 2-10 heterocyclyl, C 6-12 fused bicyclyloxy, C 6-12 fused bicyclyl-C 1-6 -alkyl, C 5-12 fused heterobicyclyl-C 1-6 -alkyl, C 5-12 fused heterobicyclyloxy, C 5-12 fused heterobicyclylamino, C 5-12 fused heterobicyclyl-C 1-6 -alkoxy, C 5-12 fused heterobicyclyl-C 1-6 -alkylamino, C 5-12 fused heterobicyclyloxy-C 1-6 -alkoxy, C 5-12 fused heterobicyclyloxy-C 1-6 -alkylamino, C 5-12 spiro heterobicyclyl-C 1-6 -alkyl, C 5-12 spiro heterobicyclyl-C 1-6 -alkoxy, C 5-12 bridged heterobicyclyl-C 1-6 -alkyl, C 5-12 bridged heterobicyclyloxy, C 5-12 bridged heterobicyclyl-C 1-6 -alkoxy, C 5-12 bridgedheterobicyclyl-C 1-6 -alkylamino, C 5-12 bridged heterobicyclyl, C 5-12 spiro heterobicyclyl or C 5-12 fused heterobicyclyl; and wherein each R 2 is independently substituted with one or more R 2a which are the same or different; and

each R 3 and R 3a is independently C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl; or

each R 2 is independently —NR 3 R 3a , C 1-4 alkoxy-C 1-4 -alkyl, C 1-4 alkyl or C 1-4 hydroxyalkyl, or each R 2 is independently one of the following sub-formulae:

wherein each X 6 , X 7 , X 8 and X 9 is independently N or CH;

each X 1 , X 2 , X 3 , X 4 and X 5 is independently —(C(R 4b ) 2 ) m —, —C(═O)—, —O—, —N(R 4a )— or —S(═O) t —;

each q, m, p and r is independently 0, 1, 2, 3 or 4;

each t is independently 0, 1 or 2;

wherein each R 2 is independently substituted with one or more R 2a which are the same or different;

each R 4a is independently H, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl, or C 1-4 hydroxyalkyl; and

each R 4b is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C 1-4 alkyl, C 3-10 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, —(CR 3b R 3c ) n —NH 2 , —C(═O)—NH 2 , C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl.

5. The compound according to claim 1 , wherein,

each R 2 is independently one of the following sub-formulae:

each R 3 and R 3a is independently methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

each R 4 and R 4a is independently H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

each R 4b is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethyl, methoxy, C 1-4 alkylamino, —(CR 3b R 3c ) n —NH 2 , —C(═O)—NH 2 , C 2-10 heterocycloalkyl, C 1-6 alkoxy-C 1-6 -alkyl or C 1-4 hydroxyalkyl;

wherein each sub-formula represented by R 2 is independently substituted with one or more R 2a which are the same or different; and

each R 2a is independently H, F, Cl, Br, I, trifluoromethyl, chloroethyl, trifluoroethyl, methyl, ethyl, propyl, isopropyl, dimethylamino, methylamino, diethylamino, ethylamino, hydroxy, cyano, nitro, —C(═O)—NH 2 , carboxy, —S(═O) t O—H, —OS(═O) t —H, —S(═O) t NH 2 , triazolyl, tetrazolyl, —(CH 2 )—NH 2 , —(CH 2 ) 3 —NH 2 , —(CH(CF 3 ))—NH 2 , —(CH 2 ) 2 —NH 2 , oxo (═O), methyl-C(═O)—, ethyl-C(═O)—, propyl-C(═O)—, benzyl or phenyl.

6. The compound according to claim 1 , wherein,

ring K is

and

each L is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 heterocycloalkyl, amino, cyano, nitro, F, Cl, Br, I, trifluoromethyl, 1,1,1-trifluoro-2-methylprop-2-yl, methyl, ethyl, butyl, propyl, isopropyl, tert-butyl, C 1-4 alkylamino, hydroxy, cyano, nitro, C 1-4 alkyl-C(═O)—NH—, C 1-4 alkoxy, hydroxymethyl, hydroxyethyl, 1-hydroxy-n-butyl, 2-hydroxy-n-propyl, hydroxy-tert-butyl or C 1-4 alkylthio.

7. The compound according to claim 1 having Formula (III) or (IIIa), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R 0 is C 2-3 alkyl, trifluoromethyl, fluoromethyl, difluoromethyl or hydroxymethyl.

8. The compound according to claim 1 having Formula (VIIa), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R 00 is C 1-3 alkyl, trifluoromethyl, fluoromethyl, difluoromethyl or hydroxymethyl.

9. The compound according to claim 1 having Formula (IV) or (V), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrumg thereof,

wherein each of X, Y, Z, Z 1 , Z 3 and Z 4 is independently N or CH.

10. The compound according to claim 1 having Formula (IIIb), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R 00 is C 1-3 alkyl, trifluoromethyl, fluoromethyl, difluoromethyl or hydroxymethyl.

11. A compound having one of the following structures, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

12. A pharmaceutical composition comprising the compound according to claim 1 ; and at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants or vehicles.

13. The pharmaceutical composition according to claim 12 further comprising other active agent used for treating a proliferative disease, an autoimmune disease or an inflammatory disease, wherein the other active agent is a chemotherapeutic agent, antiproliferative agent, immunosuppressive agent, immunostimulatory agent, antiinflammatory agent, an agent for treating atherosclerosis, an agent for treating pulmonary fibrosis, CDK4/6-kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP-competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.

14. The pharmaceutical composition according to claim 13 , wherein the other active agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogue, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon-α, leucovorin calcium, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, cabozantinib, ponatinib, midostaurin, pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, crenolanib, ENMD-2076, famitinib, dovitinib, PLX-3397, palbociclib, abemaciclib, ribociclib, rigosertib sodium, selinexor, roniciclib, AT-7519, seliciclib, alvocidib or a combination thereof.

15. A method of managing, treating or lessening a proliferative disease in a patient comprising administering to the patient a therapeutically effective amount of the compound according to claim 1 , wherein the proliferative disease is chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelogenous leukemia (AML), mutant chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), leukemia, colorectal cancer, stomach cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thyroid cancer, ovarian cancer, lymphoma, multiple myeloma, or non-small cell lung cancer.

16. A drug combination comprising the compound according to claim 1 and one or more other active agents used for the treatment of a proliferative disease, an autoimmune disease or an inflammatory disease; wherein the other active agent is chemotherapeutic agent, antiproliferative agent, immunosuppressive agent, immunostimulatory agent, antiinflammatory agent, CDK4/6-kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP-competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.

17. A method of managing, treating or lessening a proliferative disease in a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to claim 12 , wherein the proliferative disease is chronic myelogenous leukemia, gastrointestinal stromal tumor, acute myelogenous leukemia (AML), mutant chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), leukemia, colorectal cancer, stomach cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thyroid cancer, ovarian cancer, lymphoma, multiple myeloma, or non-small cell lung cancer.

18. A drug combination comprising the pharmaceutical composition according to claim 12 one or more other active agents used for the treatment of a proliferative disease, an autoimmune disease or an inflammatory disease; wherein the other active agent is chemotherapeutic agent, antiproliferative agent, immunosuppressive agent, immunostimulatory agent, antiinflammatory agent, CDK4/6-kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, aurora kinase inhibitor, non-ATP-competitive inhibitor of BCR-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.