132741-81-2

The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.

The photocyclization of N-(2-arylethyl)phthalimides to 4-aryl-2-benzazepine-1,5-diones is described.We found that the presence of electron donating substituents on the aryl ring (as in 10a and b) is necessary for the cyclization process to occur.The procedure also allowed synthesis of 2-benzazepinediones with a carboxylate group at C3 (11c and d) which were obtained as 1:1 mixture of diastereoisomers.The results of irradiating phthalimides 12, which bear an oxygenated substituent at the benzylic position, depended on the nature of the substituent.Attempts to photocyclize N-(indan-2-yl)phthalimides 16 and the electron-rich phthalimide 23 failed.

Four cyclic analgues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied.These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm.Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA*HCl (1.75 mg/kg) from saline.In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were also evaluated.None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats.Compounds 4a and 4b did not substitute in MDMA-trained rats.Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart.In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc.Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for paroxetine.By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity.These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.