Pyridazinone derivatives

Abstract

The present invention is directed to novel pyridazinone derivatives that mediate enzymatic activity. In particular, the compounds may be effective in the treatment of diseases or disease states related to the activity of the histamine H3 receptor, including, for example, neurodegenerative disorders, sleep/wake disorders, attention deficit hyperactivity disorder and cognition.

1 . A compound according to formula I*: 
       
         
           
           
               
               
           
         
         or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof; 
         wherein: 
         X and X a  are each CH; 
         Y is S(O) q , O, or NR 15 ; 
         R 1  is NR 10 R 11  or a 4- to 9-membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms and optionally substituted with 1 to 3 R 20  groups; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 2  is meta or para to the Y—(CHR 4 ) m —R 1  group 
 
         
         each R 3  is
 independently H, F, Cl, Br, I, OR 21 , NR 23 R 24 , NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C(═O)R 21 , CO 2 R 21 , or C(═O)NR 23 R 24 ; 
 
       
       
         
           
           
               
               
           
         
         each R 4  is independently H, C 1 -C 6 -alkyl, or OR 21 , wherein the alkyl group is optionally substituted with 1 to 3 R 20  groups; 
         R 10  and R 11  are each independently H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with 1 to 3 R 20  groups; 
         R 13  and R 14  are each independently H, C 1 -C 6 alkyl, aryl, arylalkyl C 1 -C 6 alkoxyl, S(═O) y —C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl; 
         or R 13  and R 14 , taken together with the carbon atoms through which they are connected form a fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, or C 3 -C 6 cycloalkyl ring; and wherein the fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, or cycloalkyl ring is optionally substituted with 1 to 3 R 20  groups; 
         R 15  is H, C 1 -C 6  alkyl, C(═O)R 25 , CO 2 R 25 ; 
         R 20  at each occurrence is independently, H, F, Cl, Br, I, OR 21 , OR 22 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6  alkyl optionally substituted with OR 26 , C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7 cycloalkylC 0 -C 4 alkyl, 3- to 7-membered heterocycloalkylC 0 -C 4 alkyl, phenyl, 5- or 6-membered heteroarylC 0 -C 4 alkyl, arylalkyl, (═O), C(═O)R 21 , CO 2 R 21 , OC(═O)R 21 , C(═O)NR 23 R 24 , NR 27 C(═O)R 21 , NR 27 C(═O)OR 21 , OC(═O)NR 23 R 24 , NR 27 C(═S)R 21 , or S(O) q R 21 ; 
         each R 21  is independently H, C 1 -C 6 alkyl, aryl, or arylalkyl; 
         each R 22  is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; 
         each R 23  and R 24  is independently selected from H, C 1 -C 6 alkyl, and aryl, or R 23  and R 24 , together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocyclic ring optionally substituted with ═O; 
         R 25  is C 1 -C 6 alkyl, aryl, or alkylaryl; 
         R 26  is H, C 1 -C 6 alkyl, aryl, or alkylaryl; 
         R 27  is H or C 1 -C 6 alkyl; 
         m is 1, 2, 3, 4, or 5 when R 1  is attached via a nitrogen atom, and m is 0, 1, 2, 3, 4, or 5 when R 1  is attached via a carbon atom; 
         n is 1, 2, or 3; 
         q is 0, 1, or 2; 
         y is 0, 1, or 2. 
       
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein Y is O. 
     
     
         5 . (canceled) 
     
     
         6 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 1  is a 4- to 9-membered heterocycloalkyl ring containing 1 nitrogen atom. 
     
     
         7 . The compound according to  claim 6 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 1  is a piperidinyl or pyrrolidinyl ring, optionally substituted with 1 to 3 R 20  groups. 
     
     
         8 . The compound according to  claim 7 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein the piperidinyl or pyrrolidinyl ring is attached to Y through a ring nitrogen atom. 
     
     
         9 . The compound according to  claim 8 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein the piperidinyl or pyrrolidinyl ring is substituted with one or two alkyl groups. 
     
     
         10 . The compound according to  claim 7 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein the piperidinyl ring is attached to Y through a ring carbon atom. 
     
     
         11 . The compound according to  claim 10 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein the piperidinyl ring is N-substituted with cycloalkyl. 
     
     
         12 . The compound according to  claim 11 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein the piperidinyl ring is N-substituted with cyclobutyl. 
     
     
         13 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 2  is para to the Y—(CHR 4 ) m —R 1  group. 
     
     
         14 . (canceled) 
     
     
         15 . The compound according to  claim 13 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 13  and R 14 , taken together with the carbon atoms through which they are connected form a fused phenyl, thienyl, oxazolyl, pyridinyl, or C 3 -C 6 cycloalkyl ring; and wherein the fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, or cycloalkyl ring is optionally substituted with 1 to 3 R 20  groups. 
     
     
         16 - 30 . (canceled) 
     
     
         31 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1 when R 1  is attached to Y through a ring carbon atom. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein m is 3 when R 1  is attached to Y through a ring nitrogen atom. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The compound according to  claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         38 . The compound according to  claim 9 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound according to  claim 38 , or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         40 - 43 . (canceled) 
     
     
         44 . The compound according to  claim 4 , wherein one of R 13  cyclopropyl. 
     
     
         45 - 52 . (canceled) 
     
     
         53 . The compound according to  claim 1 , selected from the group consisting of:
 2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenyl-2H-pyridazin-3-one;   6-methyl-2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one;   2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-phthalazin-1-one;   2-[6-(1-cyclobutyl-piperidin-4-yloxy)-pyridin-3-yl]-6-phenyl-2H-pyridazin-3-one;   2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-pyridin-3-yl-2H-pyridazin-3-one;   6-cyclopropyl-2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one;   and a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         54 - 57 . (canceled) 
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 1  or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
         59 . A method for treating a disorder selected from the group consisting of narcolepsy or sleep/wake disorders, feeding behavior, eating disorders, obesity, cognition, arousal, memory, mood disorders, mood attention alteration, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain, stress, migraine, motion sickness, depression, psychiatric disorders, epilepsy, gastrointestinal disorders, respiratory disorders, inflammation, and myocardial infarction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to  claim 1 , 
       
         
           
           
               
               
           
         
         or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof. 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         60 - 67 . (canceled)