Dihydropyrazolopyrimidinone derivatives

Abstract

The invention relates to compounds of a general formula (I): wherein Ar 1 is an optionally-substituted aryl or heteroaromatic group; R 1 is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R 2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R 3 is a hydrogen atom or a lower alkyl group; R 4 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of —N(R 1k )R 1m ; T and U are a nitrogen atom or a methine group, etc. The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.

1 - 28 . (canceled) 
     
     
         29 . A method for treating a Weel kinase mediated cancer selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphatic leukemia, chronic myelocytic leukemia, and Hodgkin's lymphoma, which comprises administering to a subject in need thereof a therapeutically-effective amount of a compound, or a salt thereof; wherein the compound is selected from the group consisting of:
 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide;   2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one;   2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one; and   2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.   
     
     
         30 . The method of  claim 29 , wherein the compound is 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide. 
     
     
         31 . The method of  claim 29 , wherein the compound is 2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         32 . The method of  claim 29 , wherein the compound is 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         33 . The method of  claim 29 , wherein the compound is 2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         34 . A method for treating ovarian cancer which comprises administering to a subject in need thereof a therapeutically-effective amount of a compound, or a salt thereof; wherein the compound is selected from the group consisting of:
 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide;   2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one   2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one; and   3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide.   
     
     
         35 . The method of  claim 34 , wherein the compound is 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide. 
     
     
         36 . The method of  claim 34 , wherein the compound is 2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         37 . The method of  claim 34 , wherein the compound is 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         38 . The method of  claim 34 , wherein the compound is 2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         39 . A method for treating lung cancer which comprises administering to a subject in need thereof a therapeutically-effective amount of a compound, or a salt thereof; wherein the compound is selected from the group consisting of:
 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide;   2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one;   2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one; and   2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.   
     
     
         40 . The method of  claim 39 , wherein the compound is 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide. 
     
     
         41 . The method of  claim 39 , wherein the compound is 2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         42 . The method of  claim 39 , wherein the compound is 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 
     
     
         43 . The method of  claim 39 , wherein the compound is 2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.