Aryloxy-and arylthiosubstituted pyrimidines and triazines and derivatives thereof

Abstract

The present invention provides novel compounds, and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsey, irritable bowl syndrome, immune supression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R 1 , R 3 , R 5 , Q, Z, Y, V, X and X′ are as defined herein.

What is claimed is:  
     
         1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Q═O, S(O)n;  
 R 1  is C 1 -C 4 -alkyl, -alkenyl, -alkynyl, C 1 -C 2  haloalkyl, halogen, NR 6 R 7 , OR 8 , SR 8 , CN;  
 R 3  is C 1 -C 8  alkyl, C 1 -C 2  haloalkyl, halogen, NR 6 R 7 , OR 8 , SR 8 ,(CH 2 ) k NR 6 R 7 , (CH 2 ) k OR 8 , CH(CHR 16 CHR 16 OR 8 ) 2 , CH(CN)AR, CH(CN) 2 ,  
 CHR 16  (CHR 16 ) p OR 8 , (CHR 16 ) p Ar wherein the aryl group is substituted with 1-3 R 18 , (CHR 16 ) p heteroaryl wherein the heteroaryl group is substituted with 1-3 R 18 , 1-tetrahydroquinolinyl, 2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with 0-3 groups chosen from hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, nitro, cyano, S(O)z—(C 1 -C 6 )alkyl;  
 V is N;  
 Y is CR 2  or N;  
 Z is N;  
 R 2  and is independently selected at each occurrence from the group consisting of hydrogen, halo, halomethyl, methyl cyano, nitro, NR 6 R 7 , NH(COR 9 ), N(COR 9 );  
 X and X′ are independently selected at each occurrence from the group consisting of alkyl, halogen, S(O) n R 8 , OR 8 , halomethyl, NR 14 R 15 , CN;  
 R 5  is H, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 3  haloalkyl, C 1 -C 6  alkoxy, (CHR 16 ) p OR 8 , (CHR 16 ) p S(O) n R 8 , (CHR 16 ) p NR 14 R 15 , C 3 -C 6  cycloalkyl, C 4 -C 6  cycloalkenyl, CN;  
 R 6  and R 7  are independently selected at each occurrence from the group consisting of: 
 hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloalkylalkyl, CH(R 16 ) (CHR 16 ) p OR 8 , (CHR 16 ) p OR 8 , —(C 1 -C 6  alkyl)-aryl, heteroaryl, —(C 1 -C 6  alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following:  
 hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, NHC(═O) (C 1 -C 6  alkyl), NH(C 1 -C 6  alkyl) N(C 1 -C 6  alkyl) 2 , nitro, CO 2 (C 1 -C 6  alkyl), cyano, S(O) z —(C 1 -C 6 -alkyl), or R 6  and R 7  can be taken together to form —(CH 2 ) q A(CH 2 ) r —, optionally substituted with 0-3 R 17 , or, when considered with the commonly attached nitrogen, R 6  and R 7  can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of:  
 hydrogen, C 1 -C 6  alkyl, (C 1 -C 6 )alkyl(C 1 -C 4 )alkoxy, hydroxy, or C 1 -C 6  alkoxy;  
 
 A is CH 2 , O, S(O) n , N(C(═O)R 24 ), N(R 19 ), C(H) (NR 14 R 15 ), C(H) (OR 20 ) C (H) (C(═O) R 21 ), N(S (O) n R 21 );  
 R 8  is hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) t R 22 , C 3 -C 10  cycloalkyl, cycloalkylalkyl, —(C 1 -C 6  alkyl)-aryl, heteroaryl, —(C 1 -C 6  alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following: 
 hydrogen, halogen, C 1 -C 6  alkyl C 1 -C 6  alkoxy, amino, NHC(═O)(C 1 -C 6  alkyl), NH(C 1 -C 6  alkyl) N(C 1 -C 6  alkyl) 2 , nitro, CO 2 (C 1 -C 6  alkyl), cyano; S(O) z (C 1 -C 6 -alkyl);  
 
 R 9  is independently selected at each occurrence from hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, C 2 -C 4  alkenyl, aryl substituted with 0-3 R 18 , and —(C 1 -C 6  alkyl)-aryl substituted with 0-3 R 18 ;  
 R 14  and R 15  are independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) t R 22 , aryl substituted with 0-3 R 18 ;  
 R 16  is hydrogen or C 1 -C 4  alkyl;  
 R 17  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo, OR 23 , SR 23 , NR 23 R 24 , (C 1 -C 6 ) alkyl, (C 1 -C 4 ) alkoxy;  
 R 18  is hydrogen, C 1 -C 4  alkyl, C 1 -C 2  haloalkyl, C 1 -C 4  alkoxy, C(═O)R 24 , NO 2 , halogen or cyano;  
 R 19  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) w R 22 , aryl substituted with 0-3 R 18 ;  
 R 20  is hydrogen, C(═O)R 22 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl;  
 R 21  is hydrogen, C 1 -C 4  alkoxy, NR 23 R 24 , hydroxyl or C 1 -C 4  alkyl;  
 R 22  is cyano, OR 24 , SR 24 , NR 23 R 24 , C 3 -C 6  cycloalkyl;  
 R 23  and R 24  are independently selected at each occurrence from hydrogen or C 1 -C 4  alkyl;  
 k is 1-4;  
 n is independently selected at each occurrence from 0-2;  
 p is 0-3;  
 q is 0-3;  
 r is 1-4;  
 t is independently selected at each occurrence from 1-6;  
 z=0-3;  
 w=1-6;  
 provided, however, that when Y is CR 2 , then R 3  is (CHR 16 ) p Ar wherein the aryl group is substituted with 1-3 R 18  or (CHR 16 ) p heteroaryl wherein the heteroaryl group is substituted with 1-3 R 18 .  
 
     
     
         2 . A compound of  claim 1  wherein: 
 R 3  is C 1 -C 4  alkyl, C 1 -C 2  haloalkyl, NR 6 R 7 , OR 8 , CH(CHR 16 CHR 16 OR 8 ) 2 , CH(CN)AR, CH(CN) 2 , CH(R 16 CHR 16 ) p OR 8 , (CHR 16 ) p Ar wherein the aryl group is substituted with 1-3 R 18 , (CHR 16 ) p heteroaryl wherein the heteroaryl group is substituted with 1-3 R 18 , 1-tetrahydroquinolinyl, 2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with 0-3 groups chosen from hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, nitro, cyano, S(O) z —(C 1 -C 6 )alkyl;  
 R 2  is independently selected at each occurrence from the group consisting of hydrogen, halo, methyl, nitro, cyano, NR6R7, NH(COR9), N(COR9)2;  
 R 6  and R 7  are independently selected at each occurrence from the group consisting of: 
 hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, cycloalkylalkyl, C 1 -C 6  alkoxy, (CHR 16 ) p OR 8 , (CHR 16 ) p OR 8 , —(C 1 -C 6  alkyl)-aryl, heteroaryl, —(C 1 -C 6  alkyl)-heteroaryl or aryl optionally substituted with 1-3 groups selected from the following:  
 hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, NHC(═O)(C 1 -C 6  alkyl), NH(C 1 -C 6  alkyl) N(C 1 -C 6  alkyl) 2 , CO 2 (C 1 -C 6  alkyl), cyano, or R 6  and R 7  can be taken together to form —(CH 2 ) q A(CH 2 ) r —, optionally substituted with 0-3 R 17 , or, when considered with the commonly attached nitrogen, R 6  and R 7  can be taken together to form a heterocycle, said heterocycle being substituted on carbon with 1-3 groups consisting of:  
 hydrogen, C 1 -C 6  alkyl, (C 1 -C 6 )alkyl(C 1 -C 4 )alkoxy, hydroxy, or C 1 -C 6  alkoxy;  
 
 R 8  is hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) t R 22 , C 3 -C 10  cycloalkyl, cycloalkylalkyl, —(C 1 -C 6  alkyl)-aryl, or hetero-aryl optionally substituted with 1-3 groups selected from the following: 
 hydrogen, halogen, C 1 -C 6  alkyl C 1 -C 6  alkoxy, NHC(═O)(C 1 -C 6  alkyl), NH(C 1 -C 6  alkyl) N(C 1 -C 6  alkyl) 2 , CO 2 (C 1 -C 6  alkyl);  
 
 R 14  and R 15  are independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl;  
 R 17  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, (C 1 -C 6 )alkyl(C 1 -C 4 )alkoxy;  
 R 18  is hydrogen, C 1 -C 4  alkyl, C 1 -C 2  haloalkyl, C 1 -C 4  alkoxy, or cyano;  
 R 19  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl substituted with 0-3 R 18 ;  
 R 22  is cyano, OR 24 , SR 24 , NR 23 R 24 , C 3 -C 6  alkyl or cycloalkyl;  
 R 23  and R 24  are independently selected at each occurrence from hydrogen or C 1 -C 4  alkyl;  
 t is independently selected at each occurrence from 1-3;  
 w is 1-3;  
 provided, however, that when Y is CR 2 , then R 3  is (CHR 16 ) p Ar wherein the aryl group is substituted with 1-3 R 18  or (CHR 16 ) p heteroaryl wherein the heteroaryl group is substituted with 1-3 R 18 .  
 
     
     
         3 . A compound of  claim 2  wherein: 
 R 1  is C 1 -C 2  alkyl, halide, NR 6 R 7 , OR 8 ;  
 R 3  is C 1 -C 4  alkyl, C 1 -C 2  haloalkyl, NR 6 R 7 , OR 8 , (CH 2 ) k NR 6 R 7 , (CH 2 ) k OR 8 ;  
 Y is N;  
 X and X′ are independently selected at each occurrence from the group consisting of methyl, hydrogen, Cl, Br, I, OR 8 , NR 14 R 15 , CN, S(O)nR 8 ;  
 R 5  is H, halo, C 1 -C 6  alkyl, C 1 -C 3  haloalkyl, C 1 -C 6  alkoxy, (CHR 16 ) p OR 8 , (CHR 16 ) p NR 14 R 15 , C 4 -C 6  cycloalkyl;  
 R 6  and R 7  are independently selected at each occurrence from the group consisting of: 
 C 1 -C 6  alkyl, (CHR 16 ) p R 8 ;  
 or can be taken together to form —(CH 2 ) q A(CH 2 ) r —, optionally substituted with CH 2 OCH 3 ;  
 
 A is CH 2 , O, S(O) n , N(C(═O)R 18 ), N(R 19 ), C(H) (OR 20 );  
 R 8  is hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) t R 22 ;  
 R 9  is hydroxy, C 1 -C 4  alkyl, or methoxy;  
 R 13  is OR 19 , SR 19 , NR 23 R 24 , C 3 -C 6  cycloalkyl;  
 R 14  and R 15  are independently is hydrogen, C 1 -C 2  alkyl, C 3 -C 6  cycloalkyl;  
 R 16  is hydrogen;  
 R 18  is hydrogen, C 1 -C 4  alkyl, C 1 -C 2  haloalkyl, C 1 -C 4  alkoxy, C(═O)R 24 , or cyano; R 19  is C 1 -C 3  alkyl;  
 R 20  is hydrogen, C 1 -C 2  alkyl or C 2 -C 3  alkenyl;  
 R 22  is OR 24 ;  
 R 23  and R 24  are independently selected at each occurrence from hydrogen or C 1 -C 2  alkyl;  
 k is 1-3;  
 m is 1-4;  
 n is independently selected at each occurrence from 0-2;  
 p is 0-2;  
 q is 0-2;  
 r is 1-2;  
 t is independently selected at each occurrence from 1-3;  
 w is 1-3.  
 
     
     
         4 . A compound of  claim 1  selected from the group: 
 a) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;  
 b) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine;  
 c) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazine;  
 d) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-homopiperidinyl)-1,3,5-triazine;  
 e) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(diethylamino)-1,3,5-triazine;  
 f) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(N-butyl-N-ethylamino)-1,3,5-triazine;  
 g) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;  
 h) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1-methoxybutyl)amino)-1,3,5-triazine;  
 i) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-piperidinyl)-1,3,5-triazine;  
 j) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1.2.3.4-tetrahydroquinolinyl))-1,3,5-triazine;  
 k) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-pyrrolidinyl)-1,3,5-triazine;  
 l) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-ethylpieridinyl))-1,3,5-triazine;  
 m) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(2-(1.2.3.4-tetrahydroisoquinolinyl))-1,3,5-triazine;  
 n) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(1,3,5,6-tetrahyropiperidinyl)-1,3,5-triazine;  
 o) 2-[2-Bromo-6-methoxy-4(1-methylethenyl)phenoxy]-4-methyl-6-(1-(2-trifluoromethylphenyl))-1,3,5-triazine;  
 p) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;  
 q) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine;  
 r) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazine;  
 s) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(1-homopiperidinyl)-1,3,5-triazine;  
 t) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(N-butyl-N-ethylamino)-1,3,5-triazine;  
 u) 2-[2-Bromo-6-methoxy-4(1-methylethyl)phenoxy]-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazine;  
 v) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-morpholinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;  
 w) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;  
 x) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;  
 y) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(diethylamino)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;  
 z) 1-[3-Bromo-5-methoxy-4-[[4-methyl-6-(1-piperidinyl)-1,3,5-triazinyl-2-yl]oxy]phenyl]ethanone;  
 aa) 3-Bromo-4-[[6-methyl-4(bis(2-methoxyethyl)amino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 bb) 3-Bromo-4-[[6-methyl-4(N-propyl-N-cyclopropylmethylamino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 cc) 3-Bromo-4-[[6-methyl-4(2-(1-methoxybutyl)amino)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 dd) 3-Bromo-4-[[6-methyl-4(4-thiomormopholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 ee) 3-Bromo-4-[[6-methyl-4(1-piperidinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 ff) 3-Bromo-4-[[6-methyl-4(1-homopiperidinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 gg) 3-Bromo-4-[[6-methyl-4(1-(2-trifluoromethylphenyl))-1,3,5-triazin-2-yl]oxy]-5-methoxy-alpha,alpha-dimethylbenzenemethanol;  
 hh) 2-(2,4,6-Triodophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;  
 ii) 2-(2,4,6-Trichlorophenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine;  
 jj) 2-(2-chloro-4,6-Dimethoxyphenoxy)-4-methyl-6-(4-morpholinyl)-1,3,5-triazine; and  
 kk) 2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy]-4-methyl-6-(N-ethyl-N-butylamino)-1,3,5-triazine uu) 2-[(2,6-Dibromo-4-(1-methylethyl))phenoxy]-4-methyl-6-(bis(2-methoxyethyl)amino)-1,3,5-triazine.  
 
     
     
         5 . A method of treating affective disorders, anxiety, or depression in mammals comprising administering to the mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         6 . A method of treating affective disorders, anxiety, or depression in mammals comprising administering to the mammal a therapeutically effective amount of a compound of  claim 2 .  
     
     
         7 . A method of treating affective disorders, anxiety, or depression in mammals comprising administering to the mammal a therapeutically effective amount of a compound of  claim 3 .  
     
     
         8 . A method of treating affective disorders, anxiety, or depression in mammals comprising administering to the mammal a therapeutically effective amount of a compound of  claim 4 .  
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 2 .  
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 3 .  
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 4 .  
     
     
         13 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim  5 .