Certain thienopyrimidine derivatives as phosphodiesterase 10 inhibitors

Abstract

Certain thienopyrimidine derivatives are useful for the inhibition of PDE10 enzymes, and thus are useful for treating psychiatric or neurological syndromes, e.g., psychoses, obsessive-compulsive disorder and/or Parkinson's disease, as well as, for example, treating a disease state modulated by PDE10 activity.

1 .- 62 . (canceled) 
   
   
       63 . A method of selectively inhibiting PDE10 enzyme in a patient in need thereof comprising administering to said patient an effective amount of at least one chemical entity chosen from compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein
 R 1  is chosen from: 
 (i) C 6-10  aryl; 
 (ii) substituted C 6-10  aryl chosen from mono-, di-, and tri-substituted aryl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, and thio; 
 (iii) heterocyclyl; 
 (iv) substituted heterocyclyl chosen from mono-, di-, and tri-substituted heterocyclyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4 alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio; 
 (v) heteroaryl; and 
 (vi) substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4 alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio; 
 R 2  is chosen from C 2-4  hydroxyalkyl, C 2-4  alkenyl, C 2-4  alkenylene-R 5 , C 2-4  alkynyl, C 2-4  alkynylene-R 5 , —O-arylene-Y—R 5 , —X(CR 3 R 4 ) n YR 5  and —(CR 6 R 7 ) m YR 5  where: 
 X is chosen from —O—, —S— and —NR 9 — where R 9  is chosen from H, C 1-8  alkyl; and C 3-8  cycloalkyl, substituted C 1-8  alkyl; and substituted C 3-8  cycloalkyl, wherein the substituents on the alkyl and cycloalkyl groups are independently chosen from halo, C 1-4 -alkyl, C 1-4 -alkoxy, and oxo; 
 Y is chosen from a covalent bond, —O—, —S— and —NR 9 —; 
 n is chosen from 2, 3, 4, and 5; 
 m is chosen from 2, 3, 4, and 5; 
 R 3  and R 4  are each independently chosen from:
 (i) H; 
 (ii) halo; 
 (iii) C 1-12  alkyl; 
 (iv) C 2-12  alkenyl; 
 (V) C 2-12  alkynyl; 
 (vi) C 3-12  cycloalkyl; 
 (vii) substituted C 1-12  alkyl chosen from mono-, di-, and tri-substituted C 1-12  alkyl and wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; 
 (viii) substituted C 2-12  alkenyl chosen from mono-, di-, and tri-substituted C 2-12  alkenyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; 
 (ix) substituted C 2-12  alkynyl chosen from mono-, di-, and tri-substituted C 2-12  alkynyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; and 
 (x) substituted C 3-12  cycloalkyl chosen from mono-, di-, and tri-substituted C 3-12  cycloalkyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkyl amino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; 
 
 R 6  and R 7  are independently chosen from
 (i) H; 
 (ii) halo; 
 (iii) C 1-12  alkyl; 
 (iv) C 2-12  alkenyl; 
 (V) C 2-12  alkynyl; 
 (vi) C 3-12  cycloalkyl; 
 (vii) substituted C 1-12  alkyl chosen from mono-, di-, and tri-substituted C 1-12  alkyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; 
 (viii) substituted C 2-12  alkenyl chosen from mono-, di-, and tri-substituted C 2-12  alkenyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkyl amino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; 
 (ix) substituted C 2-12  alkynyl chosen from mono-, di-, and tri-substituted C 2-12  alkynyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; and 
 (x) substituted C 3-12  cycloalkyl chosen from mono-, di-, and tri-substituted C 3-12  cycloalkyl wherein the substituents are independently chosen from halo, hydroxy, C 1-4 -alkoxy, halogenated C 1-4  alkoxy, nitro, cyano, carboxy, amino, C 1-4  alkylamino, di-C 1-4 -alkylamino, C 1-4 -hydroxyalkyl, C 2-4 -hydroxyalkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, and C 1-4 -alkylsulphonyl; and 
 
 R 5  is chosen from C 6-10  aryl, substituted C 6-10  aryl, Het, substituted Het, C 6-10  aryl-C 1-8  alkyl, substituted C 6-10  aryl-C 1-8  alkyl, Het-C 1-8  alkyl, and substituted Het-C 1-8  alkyl, wherein the alkyl portions of C 6-10  aryl-C 1-8  alkyl and Het-C 1-8  alkyl are optionally substituted by oxo and wherein:
 substituted C 6-10  aryl is chosen from mono-, di-, and tri-substituted C 6-10  aryl wherein the substituents are independently chosen from
 (1) C 1-8  alkyl, 
 (2) C 3-8  cycloalkyl, 
 (3) C 4-8  cycloalkylalkyl, 
 (4) C 1-8  alkoxy, 
 (5) C 3-8  cycloalkoxy, 
 (6) C 4-8  cycloalkylalkoxy, 
 (7) halo, 
 (8) amino, 
 (9) cyano, 
 (10) hydroxyl, 
 (11) nitro, 
 (12) C 1-8  halogenated alkyl, 
 (13) C 1-8  halogenated alkoxy, 
 (14) C 1-8  hydroxyalkyl, 
 (15) C 2-8  hydroxyalkoxy, 
 (16) C 3-8  alkenyloxy, 
 (17) C 1-8  alkylamino, 
 (18) di-C 1-8  alkylamino, 
 (19) carboxy, 
 (20) alkoxycarbonyl, 
 (21) carboxamido, 
 (22) aminocarbonyl, 
 (23) hydroxyaminocarbonyl, 
 (24) alkylaminocarbonyl, 
 (25) dialkylaminocarbonyl, 
 (26) urea, 
 (27) hydroxyurea, 
 (28) alkylurea, 
 (29) dialkylaminoalkylcarbonyl, 
 (30) aminocarbonylalkylaminocarbonyl, 
 (31) acylamido, 
 (32) HCO—NH—NH—CO—, 
 (33) NH 2 NHCO—, 
 (34) NH 2 NHCONH—, 
 (35) acyloxy, 
 (36) C 1-8  alkylthio, 
 (37) C 1-8  alkylsulphinyl, 
 (38) C 1-8  alkylsulphonyl, 
 (39) C 1-8  alkylsulphonamido, 
 (40) (alkylsuphonyl) 2 -amino-, 
 (41) thiol, 
 (42) aminosulfonyl, 
 (43) alkylaminosulfonyl, 
 44) C 6-10  aryl, 
 (45) substituted C 6-10  aryl chosen from mono-, di-, and trisubstituted C 6-10  aryl wherein the substituents are independently chosen from C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, C 1-8  hydroxyalkyl, C 2-8  hydroxyalkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, and thio; 
 (46) heterocyclyl; 
 (47) substituted heterocyclyl chosen from mono-, di-, and trisubstituted heterocyclyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio; 
 (48) heterocyclyl-carbonyl; and 
 (49) heterocyclyl-carbonyl chosen from mono-, di-, and trisubstituted heterocyclyl-carbonyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio; and 
 
 
 Het is chosen from heterocyclyl, substituted heterocyclyl chosen from mono-, di-, and tri-substituted heterocyclyl, heteroaryl, and substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl, wherein the substituents are independently chosen from
 (1) C 1-8  alkyl, 
 (2) C 3-8  cycloalkyl, 
 (3) C 4-8  cycloalkylalkyl, 
 (4) C 1-8  alkoxy, 
 (5) C 3-8  cycloalkoxy, 
 (6) C 4-8  cycloalkylalkoxy, 
 (7) halo, 
 (8) amino, 
 (9) cyano, 
 (10) hydroxyl, 
 (11) nitro, 
 (12) C 1-8  halogenated alkyl, 
 (13) C 1-8  halogenated alkoxy, 
 (14) C 1-8  hydroxyalkyl, 
 (15) C 2-8  hydroxyalkoxy, 
 (16) C 3-8  alkenyloxy, 
 (17) C 1-8  alkylamino, 
 (18) di-C 1-8  alkylamino, 
 (19) carboxy, 
 (20) alkoxycarbonyl, 
 (21) carboxamido, 
 (22) aminocarbonyl, 
 (23) hydroxyaminocarbonyl, 
 (24) alkylaminocarbonyl, 
 (25) dialkylaminocarbonyl, 
 (26) urea, 
 (27) hydroxyurea, 
 (28) alkylurea, 
 (29) dialkylaminoalkylcarbonyl, 
 (30) aminocarbonylalkylaminocarbonyl, 
 (31) acylamido, 
 (32) HCO—NH—NH—CO—, 
 (33) NH 2 NHCO—, 
 (34) NH 2 NHCONH—, 
 (35) acyloxy, 
 (36) C 1-8  alkylthio, 
 (37) C 1-8  alkylsulphinyl, 
 (38) C 1-8  alkylsulphonyl, 
 (39) C 1-8  alkylsulphonamido, 
 (40) (alkylsuphonyl) 2 -amino-, 
 (41) thiol, 
 (42) aminosulfonyl, 
 (43) alkylaminosulfonyl, 
 (44) oxo, 
 (45) C 6-20  aryl, 
 (46) substituted C 6-20  aryl chosen from mono-, di-, and tri-substituted C 6-20  aryl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, C 1-8  hydroxyalkyl, C 2-8  hydroxyalkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsuphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, and thio, 
 (47) heterocyclyl, 
 (48) substituted heterocyclyl chosen from mono-, di-, and trisubstituted heterocyclyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio, 
 (49) heteroaryl, 
 (50) substituted heteroaryl chosen from mono-, di-, and trisubstituted heteroaryl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 1-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio, 
 (51) heterocyclyl-carbonyl, 
 (52) substituted heterocyclyl-carbonyl chosen from mono-, di-, and trisubstituted heterocyclyl-carbonyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio, 
 (53) heteroaryl-carbonyl, and 
 (54) substituted heteroaryl-carbonyl chosen from mono-, di-, and trisubstituted heteroaryl-carbonyl wherein the substituents are independently chosen from halo, C 1-8  alkyl, halogenated C 1-8  alkyl, C 1-4  alkoxy, halogenated C 1-4  alkoxy, hydroxy C 1-8  alkyl, hydroxy C 2-8  alkoxy, amino, C 1-8  alkylamino, di-C 1-8  alkylamino, C 1-8  alkylsulphinyl, C 1-8  alkylsulphonyl, C 1-8  alkylsulphonamido, —COR 9 , —CSR 9 , —SR 9 , cyano, hydroxyl, nitro, oxo, and thio, and 
 
 R 9  is chosen from H, C 1-8  alkyl, C 3-8  cycloalkyl, substituted C 1-8  alkyl chosen from mono-, di-, and trisubstituted C 1-8  alkyl, and substituted C 3-8  cycloalkyl chosen from mono-, di-, and trisubstituted C 3-8  cycloalkyl wherein the substituents are independently chosen from halo, C 1-4 -alkyl, C 1-4 -alkoxy, and oxo; and 
 
     provided that the compound of Formula I is not chosen from:
 (i) when R 1  is 4-methylphenyl, then R 2  is not —O-p-phenylene-O—(CH 2 )phenyl, —O-p-phenylene-NH—C(O)-thiophen-2-yl, —O—(CH 2 ) 2 —O-(phenyl), —NH(CH 2 ) 2 -(4-hydroxyphenyl), —O—(CH 2 ) 2 -(1,3-dioxoisoindolin-1-yl), —NH(CH 2 ) 2 -(2-oxo-imidazolidin-1-yl), —NH(CH 2 ) 2 -(3,4,-dimethoxyphenyl), —S(CH 2 ) 2 -phenyl, —NH(CH 2 ) 2 -phenyl, —NH(CH 2 ) 2 -morpholin-4-yl, —NH(CH 2 ) 2 -thiophen-2-yl, —NH(CH 2 ) 2 -(3,4-methylenedioxyphenyl), —NH(CH 2 ) 3 -morpholinyl, or —S(CH 2 ) 3 -phenyl; 
 (ii) 2-methoxy-4-[[[2-[(5-phenylthieno[2,3-d]pyrimidin yl)amino]ethyl]imino]-methyl]-phenol; 
 (iii) 4,4′-[1,3-phenylenebis(oxy)bis[5-(4-chlorophenyl)-thieno[2,3-d]pyrimidine-; 
 (iv) when R 1  is phenyl, then R 2  is not —O-p-phenylene-NH—C(O)-3, -4-dimethoxyphenyl, —O—(CH 2 ) 2 —O-(4-methylphenyl), —O—(CH 2 ) 2 —Ophenyl, —O—(CH 2 ) 2 -(3-bromophenyl), —NH—(CH 2 ) 2 —NH(3-CF 3 -pyridin-2-yl), —S—(CH 2 ) 2 —O-(3-methylphenyl), —S—(CH 2 ) 2 —O-(4-Fphenyl), —S—(CH 2 ) 2 —O-(2,4-dichlorophenyl), —NH—(CH 2 ) 2 —NH(4-CF 3 -pyrimidin-2-yl), —NH—(CH 2 ) 2 —O-(3-acetylaminophenyl), —S—(CH 2 ) 3 -phenyl, —S—(CH 2 ) 4 -(1,3-dioxoisoindolin-1-yl), —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 3 -imidazol-1-yl, —NH—(CH 2 ) 3 -(2-oxo-pyrrolidin-1-yl), —N(CH 3 )—(CH 2 ) 2 -pyridin-2-yl, —NH—(CH 2 ) 2 -pyridin-2-yl, —S—(CH 2 ) 2 -(1,3-dioxoisoindolin-1-yl, —S—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 2 -(2-chlorophenyl), —NH—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 2 -(3,4-dimethoxyphenyl), —NH—(CH 2 ) 2 -thiophen-2-yl, or —NH—(CH 2 ) 2 -phenyl; 
 (v) when R 1  is 4-fluorophenyl, then R 2  is not chosen from —O—(CH 2 ) 2 —O-(2-chlorophenyl), —O—(CH 2 ) 2 —O-(4-fluorophenyl), —S—(CH 2 ) 3 -phenyl, —NH—(CH 2 ) 3 -phenyl, —NH—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 3 -(2-oxo-pyrrolidin-1-yl), —NH—(CH 2 ) 2 -morpholin-4-yl, —S—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 2 -azepan-1-yl, —S—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 2 -(3,4-methylenedioxyphenyl), —NH—(CH 2 ) 2 -thiophen-2-yl, and —NH—(CH 2 ) 2 -(3,4-ethylenedioxyphenyl); 
 (vi) when R 1  is 4-chlorophenyl, then R 2  is not chosen from —O-p-phenylene-O—CH 2 -phenyl, —O—(CH 2 ) 2 —O-(4-methylphenyl), —S—(CH 2 ) 4 -(1,3-dioxoisoindolin-1-yl), —S—(CH 2 ) 3 -phenyl, —S—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 3 -imidazol-1-yl, —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 2 -azepan-1-yl, —S—(CH 2 ) 2 -(1,3-dioxoisoindolin-1-yl), —NH—(CH 2 ) 2 -(3,4-methylenedioxyphenyl), —NH—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 2 -thiophen-2-yl, —NH—(CH 2 ) 2 -(3,4-ethylenedioxyphenyl), —S—(CH 2 ) 4 -(1,3-dioxoisoindolin-1-yl), —NH(CH 2 ) 3 -(2-oxo-pyrrolidin-1-yl), and —NH(CH 2 ) 2 -(3,4,-dimethoxyphenyl); 
 (vii) when R 1  is 3-methylphenyl, then R 2  is not —O—(CH 2 ) 2 —O-(phenyl); 
 (viii) when R 1  is 3-thiophen-2-yl, then R 2  is not chosen from —NH—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 2 -phenyl, and —NH—(CH 2 ) 2 -(3,4-dimethoxyphenyl); 
 (ix) when R 1  is 4-methoxyphenyl, then R 2  is not chosen from —S—(CH 2 ) 3 -phenyl, —NH—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 2 —(CH 3 ) 2 -morpholin-4-yl, —NHCH 2 C(CH 3 ) 2 -morpholin-4-yl, —N(CH 3 )—(CH 2 ) 2 -(3,4-dimethoxyphenyl), —S—(CH 2 ) 2 -phenyl, and —NH—(CH 2 ) 2 -(3,4-methylenedioxyphenyl); 
 (x) when R 1  is 3,4-dimethylphenyl, then R 2  is not chosen from —O-p-phenylene-O—CH 2 -phenyl, —S—(CH 2 ) 3 -phenyl, —S—(CH 2 ) 3 -morpholin-4-yl, —S—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 3 -(4-hydroxyphenyl), —O—(CH 2 ) 2 -(1,3-dioxoisoindolin-1-yl), —NH—(CH 2 ) 2 -morpholin-4-yl, —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 2 -(3,4-methylenedioxyphenyl), —S—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 2 -phenyl, —NH—(CH 2 ) 2 -thiophen-2-yl, and —NH—(CH 2 ) 2 -(3,4-methylenedioxyphenyl); 
 (xi) when R 1  is 4-bromophenyl, then R 2  is not chosen from —(CH 2 ) 3 -phenyl, —S—(CH 2 ) 3 -morpholin-4-yl, —S—(CH 2 ) 2 -phenyl, —S—(CH 2 ) 3 -phenyl, —NH—(CH 2 ) 3 -morpholin-4-yl, —NH—(CH 2 ) 3 -(2-oxo-pyrrolidin-1-yl), and —NH—(CH 2 ) 2 -(3,4-ethylenedioxyphenyl); and 
 (xii) when R 1  is 4-biphenyl, then R 2  is not —NH—(CH 2 ) 2 -(3,4-ethylenedioxyphenyl); 
 (xiii) when R 1  is 2,3-dihydro-1,4-benzodioxin-2-yl, then R 2  is not NH(CH 2 ) 2 -phenyl, and 
 (xiv) 5-(2-chlorophenyl)-4-[4-(phenylmethoxy)phenoxy]-thieno[2,3-d]pyrimidine. 
 
   
   
       64 - 81 . (canceled) 
   
   
       82 . The method of  claim 63  wherein the patient is suffering from a psychiatric or neurological syndrome. 
   
   
       83 . The method of  claim 63  wherein the patient is suffering from bipolar disorder, schizophrenia, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, multiple sclerosis, Huntington's disease, a disorder affecting the function of the basal ganglia, diabetes or obesity. 
   
   
       84 . The method of  claim 63 , wherein said patient is suffering from memory and/or cognitive impairment associated with Parkinson's disease, Alzheimer's disease, dementia, epilepsy, multiple sclerosis, or Huntington's disease.