Substituted phenoxypropylcycloamine derivatives as histamine-3 (h3) receptor ligands

Abstract

The present invention provides compounds of formula I: their use as H 3 antagonists/inverse agonists, processes for their preparation, and pharmaceutical compositions thereof.

1 - 33 . (canceled) 
     
     
         34 . A method of treating a subject afflicted with a disorder which is narcolepsy, obstructive sleep apnea/hypopnea syndrome, shift work sleep disorder, a wake disorder, a feeding behavior, an eating disorder, obesity, a cognition disorder, arousal, a memory disorder, a mood disorder, mood attention alteration, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain, stress, migraine, motion sickness, depression, a psychiatric disorder, epilepsy, a gastrointestinal disorder, a respiratory disorder, inflammation, or myocardial infarction, comprising administering to the subject a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is a 4 to 10 membered heterocycloalkyl ring containing 1 nitrogen atom and optionally a second nitrogen atom or an oxygen atom, wherein R 1  is optionally substituted with one to three R 20  groups; 
 R 2  at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NO 2 , CN, CF 3 , C 1 -C 6  alkyl, C(═O)R 25 , CO 2 R 25 , or C(═O)NR 23 R 24 ; 
 R 3  is H or C 1 -C 6  alkyl, or R 3  can combine with A to form a 5 or 6 membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms, wherein said heterocycloalkyl ring is optionally substituted with one to three R 20  groups; 
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  is 
 
       
         
           
           
               
               
           
         
         wherein R 5  is para or meta to Y; 
         X is O or NOR 10 ; 
         Y is selected from S(O) q , O, and NR 11 ; 
         R 10  is H, C 1 -C 4  alkyl, cycloalkyl, or arylalkyl; 
         R 11  is H, C 1 -C 6  alkyl, C(═O)R 25 , CO 2 R 25 ; 
         A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4yl; 2,3-dihydro-indol-1-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-isoquinolin-2-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; indol-1-yl; and benzoimidazol-1-yl; wherein A can be optionally substituted with one to three R 20  groups; or A can combine with R 3  to form a 5 or 6 membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms, wherein said heterocycloalkyl ring is optionally substituted with one to three R 20  groups; 
         R 20  at each occurrence is independently, 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 21 , C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5 or 6 membered heteroaryl, arylalkyl, (═O), C(═O)R 26 , CO 2 R 28 , OC(═O)R 25 , C(═O)NR 23 R 24 , NR 27 C(═O)R 25 , NR 27 CO(═O)R 25 , OC(═O)NR 23 R 24 , NR 27 C(═S)R 25 , or S(O)R 25 , wherein said aryl groups are optionally substituted with one to three R 30  groups; 
         R 21  at each occurrence is independently H, C 1 -C 6  alkyl, aryl, or arylalkyl; 
         R 22  at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; 
         R 23  and R 24  at each occurrence are each 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  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl; 
         R 26  at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30  groups; 
         R 27  at each occurrence is independently H or C 1 -C 6  alkyl; 
         R 28  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30  groups; 
         R 30  at each occurrence is independently F, Cl, Br, I, OR 21 , OR 22 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6  alkyl, aryl, or arylalkyl; 
         n is 0, 1, 2, 3, or 4; 
         m is 0, 1, 2, 3, 4, or 5; 
         q is 0, 1, or 2. 
       
     
     
         35 . The method of  claim 34 , wherein in the compound X is O. 
     
     
         36 . The method of  claim 34 , wherein in the compound X is NOR 10 . 
     
     
         37 . The method of  claim 34 , wherein in the compound Y is O and m is 3. 
     
     
         38 . The method of  claim 34 , wherein in the compound X is O, Y is O, and m is 3. 
     
     
         39 . The method of  claim 34 , wherein in the compound R 1  is a pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group, wherein said groups are optionally substituted with 1 to 3 R 20  groups. 
     
     
         40 . The method of  claim 38 , wherein in the compound R 1  is a pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group, wherein said groups are optionally substituted with 1 to 3 R 20  groups. 
     
     
         41 . The method of  claim 40 , wherein in the compound R 1  is a pyrrolidin-1-yl or piperidin-1-yl group, wherein said groups are optionally substituted with 1 to 3 R 20  groups. 
     
     
         42 . The method of  claim 41 , wherein in the compound R 1  is 2-methyl-pyrrolidin-1-yl. 
     
     
         43 . The method of  claim 34 , wherein in the compound A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl wherein said groups are optionally substituted with 1 to 3 R 20  groups. 
     
     
         44 . The method of  claim 38 , wherein in the compound A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or thiomorpholin-4-yl wherein said groups are optionally substituted with 1 to 3 R 20  groups. 
     
     
         45 . The method of  claim 36 , wherein in the compound Y is O, m is 3 and A is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or piperazin-1-yl. 
     
     
         46 . The method of  claim 38 , wherein in the compound A is 3,4-dihydro-1H-isoquinolin-2-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 2,3,4,5-tetrahydrobenzo[b]azepin-1-yl; or 2-methyl-benzoimidazol-1-yl. 
     
     
         47 . The method of  claim 34 , wherein in the compound X is O, Y is O, and m is 0. 
     
     
         48 . The method of  claim 47 , wherein in the compound R 1  is piperidin-4-yl. 
     
     
         49 . The method of  claim 34 , wherein the compound has the structure of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,3-dihydroisoindol-2-yl, hexahydro-pyrrolo[1,2-a]pyrazin-2-yl, or octahydro-pyrido[1,2-a]pyrazin-2-yl, wherein R 1  is optionally substituted with one to three R 20  groups; 
 R 2  at each occurrence is independently F, Cl, OR 21 , or C 1 -C 6  alkyl; 
 R 3  is H or C 1 -C 6  alkyl, or R 3  can combine with A to form a 5 or 6 membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms, wherein said heterocycloalkyl ring is optionally substituted with one to three R 20  groups; 
 R 4  is H or C 1 -C 6  alkyl; 
 X is O or NOR 10 ; 
 R 10  is H, C 1 -C 4  alkyl, cycloalkyl, or arylalkyl; 
 A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-isoquinolin-2-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; and benzoimidazol-1-yl; 
 wherein A can be optionally substituted with one to three R 20  groups; 
 or A can combine with R 3  to form a 5 or 6 membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms, wherein said heterocycloalkyl ring is optionally substituted with one to three R 20  groups; 
 R 20  at each occurrence is independently, F, CN, CF 3 , C 1 -C 6  alkyl optionally substituted with OR 21 , phenyl, 5 or 6 membered heteroaryl, (═O), C(═O)R 26 , CO 2 R 28 , C(═O)NR 23 R 24 , or S(O) 2 R 25 , wherein said phenyl group is optionally substituted with one to three R 30  groups; 
 R 21  at each occurrence is independently H, C 1 -C 6  alkyl, aryl, or arylalkyl; 
 R 23  and R 24  at each occurrence are each independently H or C 1 -C 6  alkyl; 
 R 25  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl; 
 R 26  at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30  groups; 
 R 28  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30  groups; 
 R 30  at each occurrence is independently F, Cl, CF 3 , C 1 -C 6  alkyl or phenyl; 
 n is 0, 1, or 2; 
 m is 0, 1, 2, or 3; 
 or a stereoisomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         50 . The method of  claim 34 , wherein the compound has the structure of Formula Id: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, wherein R 1  is optionally substituted with one to three R 20  groups; 
 R 2  at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NO 2 , CN, CF 3 , C 1 -C 6  alkyl, C(═O)R 25 , CO 2 R 25 , or C(═O)NR 23 R 24 ; 
 R 3  is H or C 1 -C 6  alkyl; 
 R 4  is H or C 1 -C 6  alkyl; 
 X is O or NOR 10 ; 
 R 10  is H, C 1 -C 4  alkyl, cycloalkyl, or arylalkyl; 
 A is selected from pyrrolidin-1-yl; piperidin-1-yl; morpholin-4-yl; piperazin-1-yl; thiomorpholin-4-yl; 1,3-dihydro-isoindol-2-yl; 3,4-dihydro-2H-quinolin-1-yl; 3,4-dihydro-1H-quinolin-1-yl; 2,3,4,5-tetrahydro-benzo[b]azepin-1-yl; and benzoimadazol-1-yl;
 wherein A can be optionally substituted with one to three R 20  groups; 
 
 R 20  at each occurrence is independently, F, CN, CF 3 , C 1 -C 6  alkyl optionally substituted with OR 21 , phenyl, 5 or 6 membered heteroaryl, (═O), C(═O)R 26 , CO 2 R 28 , or S(O) 2 R 25 , wherein said phenyl group is optionally substituted with one to three R 30  groups; 
 R 21  at each occurrence is independently H, C 1 -C 6  alkyl, aryl, or arylalkyl; 
 R 23  and R 24  at each occurrence are each 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  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl; 
 R 26  at each occurrence is independently NR 23 R 24 , CF 3 , C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-10 membered heteroaryl, or arylalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one to three R 30  groups; 
 R 28  at each occurrence is independently C 1 -C 6  alkyl, aryl, or arylalkyl, wherein said groups are optionally substituted with one to three R 30  groups; 
 R 30  at each occurrence is independently F, Cl, Br, I, OR 21 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6  alkyl, aryl, or arylalkyl; 
 n is 0, 1, or 2; 
 or a stereoisomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         51 . The method of  claim 34 , wherein the compound is selected from Examples 1 through 171, and the pharmaceutically acceptable salts thereof. 
     
     
         52 . The method of  claim 34 , wherein the disorder is narcolepsy, obstructive sleep apnea/hypopnea syndrome, or shift work sleep disorder. 
     
     
         53 . The method of  claim 34 , wherein the disorder is attention deficit hyperactivity disorder.