3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands

Abstract

Compounds provided herein are 3,7-dihydro-purine-2,6-dione derivatives of Formula (I): Such compounds are particularly useful as CRF receptor ligands, and hence, in the treatment of various neurologically-related disorders such as affective disorder, anxiety and depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis or hypoglycemia.

What is claimed is:  
     
         1 . A method of treating a mammal afflicted with a disorder selected from affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis and hypoglycemia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is selected from the group consisting of H, C 1-4  alkyl, C 3-8  cycloalkyl, C 2-4  alkenyl and C 2-4  alkynyl, wherein each is optionally substituted with 0-3 substituents independently selected from the group consisting of —CN, hydroxy, halo and C 1-4  alkoxy;  
 alternatively R 1  is selected from the group consisting of —CN, —CF 3 , —C 2 F 5 , H, C 1 -C 6  alkyl-NR 1a R 1b , —NR 1a C(O)R 1b , —C(O)NR 1a R 1b , —OR 1a , S(O) n R 1a  and —OC(O)R 1a , wherein R 1a  and R 1b  are independently selected from the group consisting of H, C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl, and wherein R 1a  and R 1b  are each optionally substituted with 0-3 substituents independently selected from the group consisting of —CN, hydroxy, halo and C 1-4  alkoxy;  
 n is 0, 1 or 2;  
 R 2  is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6  alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, aryl, heteroaryl and C 5 -C 8  cycloalkenyl, wherein each is optionally substituted with 0 to 4 substituents independently selected at each occurrence from the group consisting of halogen, —OH, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 2 -C 4  cycloalkyl, C 1 -C 4  haloalkyl, —CO 2 R 5 —OC(O)R 5 , —COR 5 , —OC(O)OR 5 , —CO 2 H, —OR 5 , —NR 6 R 7 , —NR 5 COR 7 , —NHR 5 SO 2 R 7 , —OC(O)NR 5 R 6 , —N(COR 5 ) 2 , —NR 5 CONR 6 R 7 , —NR 5 CO 2 R 7 , —CONR 5 R 7 , —S(O) n R 5 , —SO2NR 5 R 7 , —SH, —CN, aryl, heteroaryl and heterocyclyl;  
 R 3  is selected from the group consisting of aryl and heteroaryl;  
 R 4  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-4  alkoxy-C 1-4  alkyl, aryl, heteroaryl, heterocyclyl and benzyl;  
 R 4  is optionally substituted with 0-1 substituents selected from the group consisting of —CN, —S(O) n R 9 , —COR 10 , —CO 2 R 10 , —NR 11 COR 10 , —N(COR 10 ) 2 , —NR 11 CONR 1 OR 12 , —NR 11 CO 2 R 9 , —CONR 10 R 12 , 1-naphthalenyl, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl and C 3-8  cycloalkyl, wherein 0-1 carbon atoms in the C 3-8  cycloalkyl is replaced by a group selected from the group consisting of —S(O) n —, —NR 10 —, —NCO 2 R 9 —, —NCOR 9 — and —NSO 2 R 9 —, and wherein N 4  in 1-piperazinyl is optionally substituted with 0-1 substituents selected from the group consisting of R 10 , CO 2 R 9 , COR 9  and SO 2 R 9 ;  
 alternatively R 4  is optionally substituted with 0-3 substituents independently selected at each occurrence from the group consisting of aryl, heteroaryl, heterocyclyl, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, Br, Cl, F, I, C 1-4  haloalkyl, —OR 10 , —NR 1 OR 12 , C 1-4  alkoxy-C 1-4  alkyl and C 3-8  cycloalkyl which is optionally substituted with 0-1 R 8  and wherein 0-1 carbon atoms in the C 3-8  cycloalkyl is replaced by —O—;  
 R 5  is selected from the group consisting of H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkyloxy-C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl-C 1 -C 4  alkyl, wherein one carbon atom in any cycloalkyl ring may be replaced with O, S or NR 6 , and wherein C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkyloxy-C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl-C 1 -C 4  alkyl are each optionally substituted with 0 to 2 substituents independently selected at each occurrence from the group consisting of —OH, C 1 -C 4  alkoxy and halogen;  
 R 6  is selected from the group consisting of H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl-C 1 -C 4  alkyl and C 1 -C 4  haloalkyl;  
 R 7  is selected from the group consisting of H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 1 -C 4  haloalkyl, aryl, C 1 -C 4  alkyloxy-C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl-C 1 -C 4  alkyl, wherein one carbon in any cycloalkyl ring may be replaced with O, S or NR 6 , and wherein C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 1 -C 4  haloalkyl, aryl, C 1 -C 4  alkyloxy-C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl-C 1 -C 4  alkyl are each optionally substituted with 0 to 2 substituents independently selected at each occurrence from the group consisting of C 1 -C 4  alkoxy and halogen;  
 R 8  is selected from the group consisting of H, C 1-4  alkyl, C 3-6  cycloalkyl-C 1-4  alkyl and C 3-8  cycloalkyl;  
 R 9  is selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl and C 3-6  cycloalkyl-C 1-6  alkyl;  
 R 10  is selected from the group consisting of H, benzyl, aryl, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl and C 3-6  cycloalkyl-C 1-6  alkyl;  
 R 11  is selected from the group consisting of H, C 1-4  alkyl, C 3-7  cycloalkyl and C 3-6  cycloalkyl-C 1-6  alkyl;  
 R 12  is selected from the group consisting of H, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl and C 3-6  cycloalkyl-C 1-6  alkyl;  
 R 13  is selected from the group consisting of H, C 1-6  alkyl, C 3-10  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-2  alkoxy-C 1-4  alkyl, C 1-4  haloalkyl, R 16 S(O) n —C 1-4  alkyl and R 9 R 1 ON—C 2-4  alkyl;  
 R 14  and R 15  are independently selected at each occurrence from the group consisting of H, C 1-6  alkyl, C 3-10  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-2  alkoxy-C 1-2  alkyl and C 1-4  haloalkyl;  
 alternatively, in an —NR 13 R 14  moiety, R 13  and R 15  taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N 4  in 1-piperazinyl is optionally substituted with 0-1 substituents selected from the group consisting of R 17 , CO 2 R 16 , COR 16  and SO 2 R 16 ;  
 R 16  is selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, aryl, aryl(C 1-4  alkyl)-, heteroaryl, heteroaryl(C 1-4  alkyl)- and benzyl, wherein each benzyl being optionally substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C 1-4  alkyl, Br, Cl, F, I, C 1-4  haloalkyl, nitro, C 1-4  alkoxy C 1-4  haloalkoxy and dimethylamino;  
 R 17  is selected from the group consisting of H, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, aryl, aryl(C 1-4  alkyl)-, heteroaryl and heteroaryl(C 1-4  alkyl)-;  
 R 18  is selected from the group consisting of H, C 1-4  alkyl, C 3-7  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl, phenyl and benzyl, each phenyl or benzyl being optionally substituted on the aryl moiety with 0-3 groups chosen from the group consisting of C 1-4  alkyl, Br, Cl, F, I, C 1-4  haloalkyl, nitro, C 1-4  alkoxy, C 1-4  haloalkoxy and dimethylamino;  
 R 19  is selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy-C 1-4  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-6  alkyl and benzyl, each benzyl being optionally substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C 1-4  alkyl, Br, Cl, F, I, C 1-4  haloalkyl, nitro, C 1-4  alkoxy, C 1-4  haloalkoxy and dimethylamino;  
 aryl is selected from the group consisting of phenyl, naphthyl, indanyl and indenyl, each aryl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6  alkyl, C 3-6  cycloalkyl, methylenedioxy, C 1-4  alkoxy-C 1-4  alkoxy, —OR 13 , Br, Cl, F, I, C 1-4  haloalkyl, —CN, —NO 2 , SH, —S(O) n Rl4, —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14 , —NR 13 R 15  and —CONR 13 R 15 ;  
 heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C 1-6  alkyl, C 3-6  cycloalkyl, Br, Cl, F, I, C 1-4  haloalkyl, —CN, nitro, —OR 13 , SH, —S(O) n R 14 , —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14 , —NR 13 R 15  and —CONR 13 R 15 , and wherein each heteroaryl is optionally substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R 18 , CO 2 R 19 , COR 19  and SO 2 R 19 ; and  
 heterocyclyl is saturated or partially saturated heteroaryl, morpholinyl, thiomorpholinyl, piperazinyl, each optionally substituted with 1-3 substituents independently selected at each occurrence from the group consisting of C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 4  haloalkyl, —CN, —OR 5 , —SH, —NO 2 , —OCF 3 , —S(O) n R 5 , —COR 5 , —CO 2 R 5 , —OC(O)R 5 , —NR 5 COR 6 , —N(COR 5 ) 2 , —NR 5 CONR 5 R 6 , —NR 5 CO 2 R 6 , —NR 5 R 6  and —CONR 5 R 6 .  
 
     
     
         2 . The method of  claim 1  wherein R 1  is selected from the group consisting of H and C 1-4  alkyl.  
     
     
         3 . The method of  claim 1  wherein R 1  is —OR 1a , wherein R 1a  is C 1 -C 4  alkyl.  
     
     
         4 . The method of  claim 1  wherein R 2  is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl.  
     
     
         5 . The method of  claim 1  wherein R 3  is selected from the group consisting of phenyl and pyridyl.  
     
     
         6 . The method of  claim 1  wherein R 4  is selected from the group consisting of C 1-10  alkyl, C 3-8  cycloalkyl and benzyl.  
     
     
         7 . The method of  claim 1  wherein R 10  is selected from the group consisting of H and benzyl.  
     
     
         8 . The method of  claim 1  wherein R 13  is selected from the group consisting of C 1-6  alkyl and C 1-4  haloalkyl.  
     
     
         9 . The method of  claim 1  wherein aryl is phenyl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6  alkyl, —OR 13 , Br, Cl, F, I and C 1-4  haloalkyl.  
     
     
         10 . The method of  claim 1  wherein heteroaryl is pyridyl optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C 1-6  alkyl and —OR 13 .  
     
     
         11 . The method of  claim 1  wherein: 
 R 1  is selected from the group consisting of C 1-4  alkyl, C 3-8  cycloalkyl, C 2-4  alkenyl and C 2-4  alkynyl, wherein each is optionally substituted with 0-3 substituents independently selected from the group consisting of —CN, hydroxy, halo and C 1-4  alkoxy;  
 R 2  is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 3 -C 6 -alkenyl, and C 3 -C 6 -alkynyl, wherein each is optionally substituted with 0 to 4 substituents independently selected at each occurrence from the group consisting of halogen, —OH, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 2 -C 4  cycloalkyl, C 1 -C 4  haloalkyl, —CO 2 R 5 —OC(O)R 5 , —COR 5 , —OC(O)OR 5 , —CO 2 H, —OR 5 , —NR 6 R 7 , —NR 5 COR 7 , —NHR 5 SO 2 R 7 , —OC(O)NR 5 R 6 , —N(COR 5 ) 2 , —NR 5 CONR 6 R 7 , —NR 5 CO 2 R 7 , —CONR 5 R 7 , —S(O) n R 5 , —SO 2 NR 5 R 7 , —SH, and —CN;  
 R 3  is phenyl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6  alkyl, C 3-6  cycloalkyl, methylenedioxy, C 1-4  alkoxy-C 1-4  alkoxy, —OR 13 , Br, Cl, F, I, C 1-4  haloalkyl, —CN, —NO 2 , SH, —S(O) n R 14 , —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14 , —NR 13 R 15  and —CONR 13 R 15 , or pyridyl optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C 1-6  alkyl, C 3-6  cycloalkyl, Br, Cl, F, I, C 1-4  haloalkyl, —CN, nitro, —OR 13 , SH, —S(O) n R 14 , —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14. —NR   13 R 15  and —CONR 13 R 15 ; and  
 R 4  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, and benzyl;  
 R 4  is optionally substituted with 0-1 substituents selected from the group consisting of —CN, —S(O) n R 9 , —COR 10 , and 1-naphthalenyl;  
 alternatively R 4  is optionally substituted with 0-3 substituents independently selected at each occurrence from the group consisting of aryl, C 1-6  alkyl, C 2-8  alkenyl, —OR 10 , —NR 10 R 12 , CF 3 , C 1-4  alkoxy-C 1-4  alkyl and C 3-8  cycloalkyl which is optionally substituted with 0-1 R 8  and wherein 0-1 carbon atoms in the C 3-8  cycloalkyl is replaced by —O—.  
 
     
     
         12 . The method of  claim 1  wherein: 
 R 1  is selected from the group consisting of C 1-4  alkyl, —CF 3 , —C 2 F 5 , CN, and OR 1a ;  
 R 1a  is selected from the group consisting of C 1-4  alkyl substituted with 0-3 halo;  
 R 2  is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl, each optionally substituted with 0 to 4 substituents independently selected at each occurrence from the group consisting of halogen, —OH, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 2 -C 4  cycloalkyl, C 1 -C 4  haloalkyl, —CO 2 R 5 —OC(O)R 5 , —COR 5 , —OC(O)OR 5 , —CO 2 H, —OR 5 , —NR 6 R 7 , —NR 5 COR 7 , —NHR 5 SO 2 R 7 , —OC(O)NR 5 R 6 , —N(COR 5 ) 2 , —NR 5 CONR 6 R 7 , —NR 5 CO 2 R 7 , —CONR 5 R 7 , —S(O) n R 5 , —SO2NR 5 R 7 , —SH, and —CN;  
 R 3  is phenyl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6  alkyl, C 3-6  cycloalkyl, methylenedioxy, C 1-4  alkoxy-C 1-4  alkoxy, —OR 13 , Br, Cl, F, I, C 1-4  haloalkyl, —CN, —NO 2 , SH, —S(O) n R 14 , —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14 , —NR 13 R 15  and —CONR 13 R 15 , or pyridyl optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C 1-6  alkyl, C 3-6  cycloalkyl, Br, Cl, F, I, C 1-4  haloalkyl, —CN, nitro, —OR 13 , SH, —S(O) n R 14 , —COR 13 , —CO 2 R 13 , —OC(O)R 14 , —NR 18 COR 13 , —N(COR 13 ) 2 , —NR 18 CONR 13 R 15 , —NR 18 CO 2 R 14 , —NR 13 R 15  and —CONR 13 R 15 ; and  
 R 4  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, and benzyl;  
 R 4  is optionally substituted with 0-1 substituents selected from the group consisting of —CN, —S(O) n R 9 , —COR 10 , and 1-naphthalenyl;  
 alternatively R 4  is optionally substituted with 0-3 substituents independently selected at each occurrence from the group consisting of aryl, C 1-6  alkyl, C 2-8  alkenyl, —OR 10 , —NR 1 OR 12 , CF 3 , C 1-4  alkoxy-C 1-4  alkyl and C 3-8  cycloalkyl which is optionally substituted with 0-1 R8 and wherein 0-1 carbon atoms in the C 3-8  cycloalkyl is replaced by —O—.  
 
     
     
         13 . A method of treating a mammal afflicted with affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis or hypoglycemia which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof, wherein: 
 R 1  is selected from the group consisting of C 1-4  alkyl, CN, and CF 3 ;  
 alternatively R 1  is —OR 1a , wherein R 1a  is C 1 -C 4  alkyl;  
 R 2  is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl;  
 R 3  is selected from the group consisting of aryl and heteroaryl;  
 R 4  is selected from the group consisting of C 1-10  alkyl, C 3-8  cycloalkyl and benzyl;  
 R 4  is optionally substituted with 0-1 1-naphthalenyl groups;  
 alternatively R 4  is optionally substituted with 0-3 substituents independently selected at each occurrence from the group consisting of aryl, C 1-6  alkyl, C 2-8  alkenyl, —OR 10 , —NR 1 OR 12 , CF 3 , C 1-4  alkoxy-C 1-4  alkyl and C 3-8  cycloalkyl;  
 R 10  is selected from the group consisting of H and benzyl;  
 R 13  is selected from the group consisting of C 1-6  alkyl and C 1-4  haloalkyl;  
 aryl is phenyl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C 1-6  alkyl, —OR 13 , Br, Cl, F, I and C 1-4  haloalkyl; and  
 heteroaryl is pyridyl optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C 1-6  alkyl and —OR 13 .  
 
     
     
         14 . The method of  claim 13  wherein R 1  is selected from the group consisting of ethyl.  
     
     
         15 . The method of  claim 13  wherein R 1  is methoxy.  
     
     
         16 . The method of  claim 13  wherein R 2  is selected from the group consisting of methyl, ethyl, propyl and cyclopropyl.  
     
     
         17 . The method of  claim 1  wherein the compound of formula (I) is selected from the group consisting of: 
 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;  
 3-(2,4-dichlorophenyl)-8-ethyl-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 7-(1-allyl-3-butenyl)-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 3-(2,4-dichlorophenyl)-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;  
 3-(2,4-dichlorophenyl)-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 3-(2,4-dichlorophenyl)-8-ethyl-7-(4-methoxybenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 3-[2-chloro-4-(isopropylphenyl)]-8-ethyl-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;  
 3-[2-chloro-4-(isopropylphenyl)]-8-ethyl-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 3-[2-chloro-4-(isopropylphenyl)]-1-methyl-7-(3-pentyl)-3,7-dihydro-1H-purine-2,6-dione;  
 3-[2-chloro-4-(isopropylphenyl)]-7-(4-heptyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 8-ethyl-7-(4-heptyl)-1-methyl-3-(2,4,6-trimethylphenyl)-3,7-dihydro-1H-purine-2,6-dione;  
 8-ethyl-7-(4-heptyl)-3-(4-methoxy-2-methylpyrid-3-yl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione;  
 or a pharmaceutically acceptable salt form thereof.  
 
     
     
         18 . The method of  claim 1  wherein said disorder is anxiety or depression.  
     
     
         19 . The method of  claim 1  wherein said disorder is irritable bowel syndrome.