Alkylsulfonyl-2,3-dihydrospiro[indene-1,4'-piperidine] analogs as glyt1 inhibitors, methods for making same, and use of same in treating psychiatric disorders

A method for preparing a compound comprising the steps of:

• a. providing an amino compound having a structure represented by a formula:
• wherein each ---- is an optional covalent bond;
• wherein R2 comprises eight substituents independently selected from hydrogen, halogen, OR, cyano, nitro SR, N(R)2, and optionally substituted organic residue comprising from 1 to 6 carbons;
• wherein each R is independently hydrogen or optionally substituted C1-6 aliphatic, or two R groups on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• wherein R3 is hydrogen or optionally substituted organic residue comprising 1 to 6 carbons;
• wherein R4 is hydrogen, optionally substituted organic residue comprising 1 to 6 carbons, or a hydrolysable residue;
• wherein R5 comprises two substituents independently selected from hydrogen, halogen, OR, cyano, nitro SR, N(R)2, and optionally substituted organic residue comprising 1 to 6 carbons;
• wherein each Y is independently selected from N or C—R6, with the proviso that no more than two of Y are N;
• wherein each R6 is independently selected from hydrogen, halogen, OR, cyano, nitro SR, N(R)2, and optionally substituted organic residue comprising from 1 to 6 carbon atoms;
• and
• wherein Z is hydrogen, a hydrolysable residue, or R1-substituted sulfonyl, wherein R1 is optionally substituted organic residue comprising 1 to 12 carbon atoms, and
• b. reacting the amino compound with a carboxyl compound having a structure represented by a formula:
• wherein Ar comprises an optionally substituted aromatic cyclic moiety having from 4 to 16 carbons;
• and
• wherein X is a leaving group.

A method for the treatment of a disorder associated with glycinergic or glutamatergic neurotransmission dysfunction in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:

• wherein each ---- is an optional covalent bond;
• wherein R1 is optionally substituted organic residue comprising 1 to 12 carbon atoms;
• wherein R2 comprises eight substituents independently selected from hydrogen, halogen, OR, nitrile, nitro, SR, N(R)2, and optionally substituted organic residue comprising from 1 to 6 carbons;
• wherein each R is independently hydrogen or optionally substituted C1-6 aliphatic, or two R groups on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• wherein R3 is hydrogen or optionally substituted organic residue comprising 1 to 6 carbons;
• wherein R4 is hydrogen, optionally substituted organic residue comprising 1 to 6 carbons, or a hydrolysable residue;
• wherein R5 comprises two substituents independently selected from hydrogen, halogen, OR, nitrile, nitro, SR, N(R)2, and optionally substituted organic residue comprising 1 to 6 carbons;
• wherein each Y is independently selected from N or C—R6, with the proviso that no more than two of Y are N;
• wherein each R6 is independently selected from hydrogen, halogen, OR, nitrile, nitro, SR, N(R)2, and optionally substituted organic residue comprising from 1 to 6 carbon atoms;
• wherein Ar comprises an optionally substituted aromatic cyclic moiety having from 4 to 16 carbons;
• or a pharmaceutically acceptable derivative thereof, in a dosage and amount effective to treat the disorder in the mammal.