11-OXO-10,11-DIHYDRODIBENZO[B,F][1,4]THIAZEPINE S-OXIDE DERIVATIVES AND THEIR USE AS DOPAMINE D2 RECEPTOR ANTAGONISTS

摘要

The disclosure includes compounds and pharmaceutically acceptable salts of Formula (I). Certain compounds and salts of Formula (I) are selective inhibitors of the Dopamine D2 receptor. The variables R1-R4, n, and L are defined herein. The disclosure also provides methods of synthesizing compounds of Formula (I) and pharmaceutical compositions containing compounds of Formula (I). Additionally the disclosure provides methods or treating patients suffering from central nervous system disorders, including Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, or schizophrenia.;

主权项

1. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein L is NHC(O)—, C(O)NH—, —OC(O)— or C(O)O—; n is and integer from 1 to 4 andis unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, or C1-C2haloalkoxy;
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, (C3-C7cycloalkyl)C0-C2alkyl, (mono- or di-C1-C4alkylamino)C1-C4alkyl, or (mono- or di-C1-C4alkylamino)C1-C4 alkoxy; R2 is mono-, bi-, or tricyclic carbocyclic or heterocylic group, a (mono- or di-C1-C4alkylamino)C2-C4alkyl group, or C4-C8alkyl, each of which R2 is unsubstituted or substituted with one more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, —OR11, —(CH2)0-4C(O)R11, —(CH2)0-4NR11R12, —(CH2)0-4C(O)NR11R12, —(CH2)0-4N(R11)C(O)(R12), —(CH2)0-4C(O)OR11, —(CH2)0-4OC(O)R11, —(CH2)0-4C(S)R11, —(CH2)0-4 S(O)aR11, —(CH2)0-4 S(O)bNR11R12, —(CH2)0-4N(R11)S(O)bR12, and (phenyl)C0-C2alkyl, where a is 0, 1, or 2, and b is 1 or 2, R11, R12, and R13 are independently chosen at each occurrence from hydrogen and a C1-C6aliphatic group; each of R11, R12, and R13 is unsubstituted or substituted with one or more substituents independently chosen from: halogen, hydroxyl, vinyl, allenyl, oxo, cyano, amino, —COOH, C1-C6alkyl, C1-C6alkoxy, (mono- and di-C1-C6alkylamino)C0-C2alkyl, C1-C6alkylester, C1-C6alkylthio, C1-C2haloalkyl, and C1-C2haloalkoxy; R3 and R4 are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4alkyl, C1-C4alkoxy, C2-C4alkanoyl, (mono- and di-C1-C4alkylamino)C0-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; with the proviso that when R1 is ethyl, the group is not 4-methoxybenzyl-NHC(O)—, pyridin-2-ylmethyl-NHC(O)—, 3-(morpholin-1-yl)propyl-NHC(O)—, 3-(azepan-1-yl)propyl-NHC(O)—, 3-(azepan-1-yl)ethyl-NHC(O)—, 3-(pyrrolidin-1-yl)propyl-NHC(O)—, 3-(4-methylpiperazin-1-yl)propyl-NHC(O)—, 3-(piperidin-1-yl)propyl-NHC(O)—, di-isopropylaminopropyl-NHC(O)—, di-propylaminopropyl-NHC(O)—, di-butylaminopropyl-NHC(O)—, or 3-(butyl(ethyl)amino)propyl-NHC(O)—.