90525-99-8

Upstream product

• 21900-46-9 2,3-dimethylbenzoyl chloride 
• 124-40-3 dimethyl amine 
• 603-79-2 2,3-dimethylbenzoic acid 
• 13360-57-1 dimethylamino sulfonyl chloride 
• 78162-58-0 N,N-dimethyl-1H-imidazole-1-sulfonamide 

Downstream Products

• 1613436-03-5 4,5-dimethyl-3-phenylisoquinolin-1(2H)-one 
• 1260150-57-9 5-methyl-3-phenylisoquinolin-1(2H)-one 
• 1560949-11-2 5-methyl-3-(4-methylphenyl)isoquinolin-1-one 
• 1613435-52-1 3-(4-chlorophenyl)-5-methylisoquinolin-1(2H)-one 
• 1613435-53-2 5-methyl-3-(4-trifluoromethylphenyl)isoquinolin-1(2H)-one 
• 1613435-54-3 3-(2-chlorophenyl)-5-methylisoquinolin-1(2H)-one 
• 1613435-55-4 3-(3-chlorophenyl)-5-methylisoquinolin-1(2H)-one 
• 1613435-56-5 3-(2,6-dichlorophenyl)-5-methylisoquinolin-1(2H)-one 
• 1454901-02-0 3-(4-bromophenyl)-5-methyl-2H-isoquinolin-1-one 
• 1613435-58-7 5-methyl-3-(4-phenylethynylphenyl)isoquinolin-1(2H)-one 
• 1369949-88-1 2-ethyl-N,N,3-trimethylbenzamide 
• 1454898-07-7 5-methyl-3-(4-(pyrrolidin-1-ylmethyl)phenyl)isoquinolin-1(2H)-one 
• 1454898-09-9 5-methyl-3-(4-(piperidin-1-ylmethyl)phenyl)isoquinolin-1-one 
• 1613436-05-7 3-(4-(1,1-dimethylethyl)phenyl)-5-methylisoquinolin-1(2H)-one 

Relevant academic research and scientific papers

A novel method for the one-pot conversion of carboxylic acids to N,N-dimethylamides

A simple, efficient, and new method has been developed for the preparation of N,N-dimethylamides from carboxylic acids. As described below, treatment of a variety of aromatic carboxylic acids with N,N-dimethylsulfamoyl imidazole or N,N-dimethylsulfamoyl chloride in the presence of a mixture of methanesulfonic acid/phosphorus pentoxide (2:1, v/w) proceeded effectively to afford the corresponding N,N-dimethylamides inmoderate to good yields. Thismethod is easy, rapid, and good yielding for the synthesis of N,N-dimethylamides from carboxylic acids. Iranian Chemical Society 2012.

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.

TANKYRASE INHIBITORS

The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.