Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists

A method of making a compound of formula I

• a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein
• X is N(CH3) or O;
• R1 is OH or C1-6 alkoxy;
• R2 is H or C1-6 alkyl;
• R3 is (CH2)n Q, CH2CH(OH)Q, CH(CH3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
• Q is thienyl or furanyl, and
• Q is optionally substituted with one or two moieties independently selected from halo, C1-6 alkyl, C1-6 alkoxy, hydroxy, S(O)2NH2, trifluoromethyl, or cyano, and
• n is 1 or 2;
• and
• R4 is H or C1-6 alkyl;
• comprising the step of coupling a reagent of formula II
• wherein X and R2 are as defined in formula I;
• with a reagent of formula III
• wherein R3 and R4 are as defined in formula I;
• to provide the compound of formula I.

A method of making a compound of formula I

• a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein
• X is N(CH3) or O;
• R1 is OH or C1-6 alkoxy;
• R2 is H or C1-6 alkyl;
• R3 is (CH2)n Q, CH2CH(OH)Q, CH(CH3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
• Q is thienyl or furanyl, and
• Q is optionally substituted with one or two moieties independently selected from halo, C1-6 alkyl, C1-6 alkoxy, hydroxy, S(O)2NH2, trifluoromethyl, or cyano, and
• n is 1 or 2;
• and
• R4 is H or C1-6 alkyl;
• comprising the step of coupling a compound of formula II
• wherein X and R2 are as defined in formula I;
• and
• R5 is CH3, CF3, F, p-bromobenzene, p-nitrobenzene, or p-methylbenzene;
• with a reagent of formula m
• wherein R3 and R4 are as defined in formula I;
• to provide the compound of formula I.

A method of making a compound of formula I

• a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein
• X is N(CH3) or O;
• R1 is OH or C1-6 alkoxy;
• R2 is H or C1-6 alkyl;
• R3 is (CH2)n Q, CH2CH(OH)Q, CH(CH3)Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
• Q is thienyl or furanyl, and
• Q is optionally substituted with one or two moieties independently selected from halo, C1-6 alkyl, C1-6 alkoxy, hydroxy, S(O)2NH2, trifluoromethyl, or cyano, and
• n is 1 or 2;
• and
• R4 is H or C1-6 alkyl;
• comprising the step of coupling a reagent of formula II
• wherein X is as defined in formula I;
• with a reagent of formula III
• wherein R2, R3, and R4 are as defined in formula I;
• to provide the compound of formula I.