2,3-dihydro-isoindole-1-on derivative as btk kinase suppressant, and pharmaceutical composition including same

Abstract

The present invention provides a compound selected from the group consisting of a compound of formula (I), pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates and isomers thereof; a use of the compound for the treatment, relief or prevention of diseases caused by abnormal or uncontrolled activation of protein kinase, and a use of the compound for the manufacture of a medicament for the treatment, relief or prevention of the diseases; a pharmaceutical composition comprising the compound as an active ingredient; and a method for the treatment, relief or prevention of the diseases using the compound. The inventive compound is useful for the treatment, relief or prevention of diseases caused by abnormal or uncontrolled activation of protein kinase.

What is claimed is: 
     
         1 . A compound selected from the group consisting of a compound of formula (I), pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates and isomers thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         A is 
       
       
         
           
           
               
               
           
         
          and R 8  is hydrogen, halogen, or C 1-3  alkyl; 
         R 1  and R 2  are each independently hydrogen or C 1-3  alkyl; and 
         R 3  to R 7  are each independently hydrogen, halogen, cyano, nitro or C 1-3  haloalkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein R 3  to R 7  are each independently hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, difluoromethyl or trifluoromethyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  and R 2  are each independently hydrogen or methyl; R 3  to R 7  are each independently hydrogen, fluoro, chloro, cyano or trifluoromethyl; and R 8  is hydrogen or fluoro. 
     
     
         4 . The compound of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
 1) 1-(2,6-dichloro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   2) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-trifluoromethyl-phenyl)-urea;   3) 1-(2,6-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   4) 1-(2-chloro-6-fluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   5) 1-(2,6-bis-trifluoromethyl-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   6) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2-fluoro-6-trifluoromethyl-phenyl)-urea;   7) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2,4,6-trifluoro-phenyl)-urea;   8) 1-(2,6-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-1-methyl-urea;   9) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-pentafluorophenyl-urea;   10) 1-(2,5-difluorophenyl)-3-(3-fluoro-4-(7-(5-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-4-yl)phenyl)urea;   11) 1-(2,4-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   12) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2,3,6-trifluoro-phenyl)-urea;   13) 1-(3,5-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   14) 1-(3,4-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea;   15) 1-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-(7-(5-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-4-yl)phenyl)urea;   16) 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(7-(5-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-4-yl)phenyl)urea;   17) 1-(3-chloro-2,6-difluorophenyl)-3-(3-fluoro-4-(7-(5-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-4-yl)phenyl)urea;   18) 1-(2-chloro-3,6-difluorophenyl)-3-(3-fluoro-4-(7-(5-methyl-1H-imidazol-2-yl)-1-oxoisoindolin-4-yl)phenyl)urea;   19) 1-(4-chloro-2,6-difluoro-phenyl)-3-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-urea; and   20) 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-3-(2,3,5,6-tetrafluoro-phenyl)-urea.   
     
     
         5 . The compound of  claim 1 , wherein the isomers are enantiomer, diastereomer or racemic mixture. 
     
     
         6 . A pharmaceutical composition comprising the compound of any one of  claims 1  to  5  as an active ingredient for the treatment, relief or prevention of diseases caused by abnormal or uncontrolled activation of protein kinase. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said protein kinase is ABL, ACK, AXL, Aurora, BLK, BMX, BTK, CDK, CSK, DDR, EPHA, FER, FES, FGFR, FGR, FLT, FRK, FYN, HCK, IRR, ITK, JAK, KDR, KIT, LCK, LYN, MAPK, MER, MET, MINK, MNK, MST, MUSK, PDGFR, PLK, RET, RON, SRC, SRM, TIE, SYK, TNK1, TRK or TNIK. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the diseases caused by abnormal or uncontrolled activation of protein kinase are cancer, inflammation associated with rheumatoid arthritis and osteoarthritis, asthma, allergy, atopic dermatitis, or psoriasis. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the cancer is lymphoma, leukemia, blood cancer, stomach cancer, non-small cell lung cancer, liver cancer, colorectal cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, ovarian cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, fibroadenoma, or glioblastoma. 
     
     
         10 . The pharmaceutical composition of  claim 6 , which further comprises at least one additive selected from the group consisting of antibiotic, alkylating agent, antimetabolite, hormonal agent, immunological agent, interferon-type agent and anticancer agent. 
     
     
         11 . A method for the treatment, relief or prevention of diseases caused by abnormal or uncontrolled activation of protein kinase in a mammal, comprising administering to the mammal the compound of any one of  claims 1  to  5 . 
     
     
         12 . A use of the compound of any one of  claims 1  to  5  for the manufacture of a medicament for the treatment, relief or prevention of diseases caused by abnormal or uncontrolled of protein kinase.