Dihydrooxazol-2-amine derivatives

Abstract

The invention relates to compounds of formula wherein R 1 , R 2 , R 3 , R 4 , X, Ar, and are defined herein or to a pharmaceutically acceptable acid addition salt thereof. Compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds can be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm and cardiovascular disorders.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl;
 X is a bond or CH(CF 3 )—; and 
 Ar is heteroaryl, optionally substituted by one or more R 3 ; 
 
       or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         2 . The compound of  claim 1 , having formula Ia 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl; and
 Ar is heteroaryl, optionally substituted by one or more R 3 ; 
 
       or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         3 . The compound of  claim 2 , wherein Ar is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolinyl. 
     
     
         4 . The compound of  claim 3 , selected from the group consisting of
 (S)-4-(4-(Quinolin-8-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (S)-4-(4-(5-Fluoropyridin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (S)-4-(4-(6-Methylquinolin-8-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-trifluoromethyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-chloro-pyridin-2-yl)-amine;   6-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenylamino}-nicotinonitrile;   (S)-4-(4-(6-(Trifluoromethyl)pyrimidin-4-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-chloro-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-fluoro-pyrimidin-2-yl)-amine;   
       and
 {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(3-fluoro-pyridin-2-yl)-amine. 
 
     
     
         5 . The compound of  claim 3 , selected from the group consisting of
 {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-fluoro-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-trifluoromethyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-methyl-pyrimidin-4-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-methyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-trifluoromethyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-pyrazin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-methyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-methoxy-pyridin-2-yl)-amine;   
       and
 6-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenylamino}-pyrazine-2-carbonitrile. 
 
     
     
         6 . The compound of  claim 3 , selected from the group consisting of
 {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-pyrimidin-4-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-methoxy-pyrimidin-4-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(2-methyl-pyrimidin-4-yl)-amine;   (S)-4-(4-(Pyrimidin-4-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-methoxy-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-ethyl-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-methoxy-pyrimidin-2-yl)-amine;   5-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenylamino}-pyrazine-2-carbonitrile;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-trifluoromethyl-pyrimidin-2-yl)-amine; and   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(3-chloro-pyrazin-2-yl)-amine.   
     
     
         7 . The compound of  claim 3 , selected from the group consisting of
 {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-4-trifluoromethyl-pyridin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-methyl-pyrazin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-2-methoxy-pyrimidin-4-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-methylsulfanyl-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-methyl-pyrimidin-2-yl)-amine;   1-(2-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenylamino}-pyrimidin-5-yl)-ethanone;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(4-methyl-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-propyl-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(2-chloro-pyrimidin-5-yl)-amine;   
       and
 {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-bromo-pyrimidin-2-yl)-amine. 
 
     
     
         8 . The compound of  claim 3 , selected from the group consisting of
 {4-[2-((4S,5S)-2-Amino-5-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-chloro-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-cyclopropyl-pyrimidin-2-yl)-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(5-ethoxy-pyrimidin-2-yl)-amine;   (S)-4-(4-(5-(Trifluoromethyl)pyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (S)-4-(4-(5-tert-Butylpyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (S)-4-(4-(5-(Pentan-3-yl)pyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   2-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenylamino}-pyrimidine-5-carbonitrile;   (S)-4-(4-(5-Cyclobutylpyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (S)-4-(4-(5-Isopropylpyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   {4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-2-methyl-phenyl}-(5-chloro-pyrimidin-2-yl)-amine and   (S)-4-(4-(5-(2,2,2-Trifluoroethoxy)pyrimidin-2-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine.   
     
     
         9 . The compound of  claim 1 , having formula Ib 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl;
 Ar is heteroaryl, optionally substituted by one or more R 3 ; and 
 
       or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         10 . The compound of  claim 9 , selected from the group consisting of:
 (4S)-4-(4-(1-(4-Chlorophenyl)-2,2,2-trifluoroethylamino)phenethyl)-4,5-dihydrooxazol-2-amine (1:1 mixture of epimers);   (+)-(S)-4-(4-((S)-1-(4-Chlorophenyl)-2,2,2-trifluoroethylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   (−)-(S)-4-(4-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethylamino)phenethyl)-4,5-dihydrooxazol-2-amine;   -4-(4-(2,2,2-Trifluoro-1-(3-fluorophenyl)ethylamino)phenethyl)-4,5-dihydrooxazol-2-amine and   (4S)-4-(4-(2,2,2-Trifluoro-1-(4-(trifluoromethyl)phenyl)ethylamino)phenethyl)-4,5-dihydrooxazol-2-amine.   
     
     
         11 . The compound of  claim 9 , wherein Ar is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and quinolinyl. 
     
     
         12 . The compound of  claim 11 , which compound is {5-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-pyridin-2-yl}-(5-chloro-pyrimidin-2-yl)-amine. 
     
     
         13 . A pharmaceutical composition comprising a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl;
 X is a bond or CH(CF 3 )—; and 
 Ar is heteroaryl, optionally substituted by one or more R 3 ; 
 
       or a pharmaceutically acceptable acid addition salt thereof 
       and a pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 13 , wherein the compound of formula I is a compound of formula Ia. 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl; and
 Ar is heteroaryl, optionally substituted by one or more R 3 ; 
 
       or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         15 . The composition of  claim 13 , wherein the compound of formula I is a compound of formula Ib. 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is hydrogen; 
 R 3  is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, cyano, S-lower alkyl, S(O)-lower alkyl, S(O) 2 -lower alkyl, C(O)-lower alkyl or C 3-6 -cycloalkyl; 
 R 4  is hydrogen or lower alkyl; 
 
       
         
           
           
               
               
           
         
       
       is phenyl;
 Ar is heteroaryl, optionally substituted by one or more R 3 ; and 
 
       or a pharmaceutically acceptable acid addition salt thereof.