Methods for treating neuroblastoma

Abstract

Substituted indazole derivatives of formula (I) or formula 2.(I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with a deregulated protein kinase activity, like cancer.

1 - 21 . (cancelled) 
     
     
         22 . A method of treating neuroblastoma cancer in a patient, wherein said neuroblastoma is associated with deregulated protein kinase activity, the method comprising administering to said patient a therapeutically effective amount of a compound selected from the group consisting of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, and N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 22 , wherein the compound is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 22 , wherein the compound is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 22 , wherein the compound is N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 22 , wherein said neuroblastoma is associated with deregulated protein kinase activity of ROS1. 
     
     
         27 . The method of  claim 22 , wherein said neuroblastoma is associated with deregulated protein kinase activity of TrkA. 
     
     
         28 . The method of  claim 22 , wherein said neuroblastoma is associated with deregulated protein kinase activity of TrkB. 
     
     
         29 . The method of  claim 22 , wherein said neuroblastoma is associated with deregulated protein kinase activity of TrkC. 
     
     
         30 . A method of inhibiting deregulated protein kinase activity in a neuroblastoma cell, wherein said deregulated protein kinase activity isone or more of tyrosine kinase ROS1, high affinity receptor tyrosine kinase TrkA, TrkB or TrkC activity, comprising administering to said cell an effective amount of a compound selected from the group consisting of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, and N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 30 , wherein the compound is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 30 , wherein the compound is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 30 , wherein the compound is N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl) benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of  claim 30 , wherein said deregulated protein kinase activity is activity of ROS1. 
     
     
         35 . The method of  claim 30 , wherein said deregulated protein kinase activity is activity of TrkA. 
     
     
         36 . The method of  claim 30 , wherein said deregulated protein kinase activity is activity of TrkB. 
     
     
         37 . The method of  claim 30 , wherein said deregulated protein kinase activity is activity of TrkC.