Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues

Abstract

Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) and other disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 n is 1, 2 or 3; 
 R 1  is C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, or (3- to 8-membered heterocycloalkyl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, nitro, halogen, amino, cyano, hydroxy, aminocarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 2 -C 6 allyl ether, C 1 -C 6 alkanoyl, C 3 -C 6 alkanone, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl; 
 or R 1  and R 3  are taken together to form a fused 5- to 7-membered cycloalkyl or heterocycloalkyl ring, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy; 
 R 2  represents from 0 to 4 substituents independently chosen from:
 (i) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl, C 1 -C 6 haloalkyl, and groups that are taken together to form a C 1 -C 3 alkylene bridge; 
 (ii) phenylC 0 -C 4 alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen and C 1 -C 6 alkyl; and 
 (iii) groups that are taken together to form a spiro C 3 -C 7 cycloalkyl or a Spiro 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from C 1 -C 6 alkyl; 
 
 R 3  represents from 0 to 4 substituents independently chosen from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, groups that are taken together to form a C 1 -C 3 alkylene bridge and groups that are taken together to form a fused 5- to 7-membered cycloalkyl or heterocycloalkyl ring, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; 
 
       
         
           
           
               
               
           
         
          represents a pyrazole ring, which rings is substituted with 0 or 1 R x , and each of which rings is further substituted with from 0 to 3 substituents independently chosen from R y ; 
         R x  is:
 (i) halogen, cyano, aminocarbonyl, or COOH; or 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, (C 3 -C 0 cycloalkyl)-J-C 0 -C 4 alkyl, (3- to 10-membered heterocycloalkyl)-J-C 0 -C 4 alkyl, phenyl-J-C 0 -C 4 alkyl, naphthyl-J-C 0 -C 4 alkyl or (5- to 12-membered heteroaryl)-J-C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from:
 (a) oxo, halogen, cyano, hydroxy, amino, nitro and aminocarbonyl; and 
 (b) groups of the formula D-J-E- 
 wherein: 
 D represents C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from halogen, cyano, hydroxy, amino, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 alkoxy; 
 Each J is independently absent, O, CH 2 O, OCH 2 , C(═O), OC(═O), C(═O)O, S(O) m , N(R z ), C(═O)N(R z ), N(R z )C(═O), N(R z )S(O) m  or S(O) m N(R z ), wherein each m is independently 0, 1 or 2 and each R z  is independently hydrogen or C 1 -C 6 alkyl; and 
 E is absent or represents C 1 -C 6 alkylene or C 1 -C 6 alkoxy; and 
 
 
         Each R y  is independently oxo, amino, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, phenylC 0 -C 2 alkyl or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl. 
       
     
     
         2 . A compound or salt according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       represents a pyrazole ring, which rings is substituted with exactly one R x , and each of which rings is further substituted with 0 or 1 substituent chosen from R y . 
     
     
         3 . A compound or salt according to  claim 1 , wherein n is 1. 
     
     
         4 . (canceled) 
     
     
         5 . A compound or salt according to  claim 1 , wherein R 2  and R 3  independently represent 0 substituents or 1 or 2 methyl substituents. 
     
     
         6 - 16 . (canceled) 
     
     
         17 . A compound or salt according to  claim 1 , wherein the compound satisfies the formula: 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       are each a 5-membered heteroaryl, such that
 U is N; 
 Y is N; and 
 Q and R x  are independently chosen from CR x  and CR 4 ; 
 R 1  is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl or (3- to 8-membered heterocycloalkyl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, nitro, halogen, amino, cyano, hydroxy, aminocarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 3 -C 6 alkanone, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl; and 
 each R 4  is independently hydrogen, amino, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl or mono- or di-(C 1 -C 6 alkyl)amino. 
 
     
     
         18 - 20 . (canceled) 
     
     
         21 . A compound or salt according to  claim 17 , wherein:
 R x  is:
 (i) halogen, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di(C 1 -C 6 alkyl)aminocarbonyl; or 
 (ii) C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from:
 (a) hydroxy, cyano, halogen and oxo; and 
 (b) C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 cyanoalkyl, C 1 -C 8 alkoxy, C 1 -C 8 haloalkoxy, C 1 -C 8 alkylthio, C 2 -C 8 allyl ether, C 1 -C 6 alkylsulfonyl, mono- or di(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, phenoxy, phenyl, and 4- to 7-membered heterocycloalkyl, each of which is unsubstituted or substituted with 1 or 2 substituents independently chosen from oxo, C 1 -C 4 allyl and C 1 -C 4 alkoxy; and 
 
   R 4  is hydrogen, amino, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, mono- or di-(C 1 -C 6 alkyl)amino, phenylC 0 -C 2 alkyl or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl.   
     
     
         22 . A compound or salt according to  claim 21 , wherein:
 R x  is mono- or di-(C 1 -C 6 alkyl)amino, 4- to 7-membered heterocycloalkyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from:
 (a) hydroxy, cyano, halogen and oxo; and 
 (b) C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 cyanoalkyl, C 1 -C 8 alkoxy, C 1 -C 8 haloalkoxy, C 1 -C 8 alkylthio, C 2 -C 8 alkyl ether, C 1 -C 6 alkylsulfonyl, mono- or di(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, phenoxy, phenyl, and 4- to 7-membered heterocycloalkyl, each of which is unsubstituted or substituted with 1 or 2 substituents independently chosen from oxo, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and 
   R 1  is C 3 -C 8 cycloalkylC 0 -C 2 alkyl, 4- to 7-membered heterocycloalkyl or C 2 -C 8 alkyl, each of which is unsubstituted or substituted with 1 or 2 substituents independently chosen from C 1 -C 4 alkyl and C 1 -C 4 alkoxy.   
     
     
         23 . A compound or salt according to  claim 21 , wherein:
 R x  is:
 (i) C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, or mono- or di(C 1 -C 6 alkyl)aminocarbonyl; or 
 (ii) phenyl or 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, and mono- or di(C 1 -C 6 alkyl)aminocarbonyl; and 
   R 4  is hydrogen.   
     
     
         24 . A compound or salt according to any one of  claims 17 - 23 , wherein R x  is phenyl, pyridyl or pyrimidinyl, each of which is substituted with one substituent chosen from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 1 -C 4 alkanoyl. 
     
     
         25 . A compound or salt according to any one of  claims 17 - 24 , wherein R 1  is C 3 -C 6 alkyl, or (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl. 
     
     
         26 . A compound or salt according to  claim 25 , wherein R 1  is isopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         27 - 45 . (canceled) 
     
     
         46 . A pharmaceutical composition, comprising at least one compound or salt according to  claim 1  in combination with a physiologically acceptable I carrier or excipient. 
     
     
         47 . A pharmaceutical composition according to  claim 46 , wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch. 
     
     
         48 . A method for treating a condition responsive to H3 receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of a compound or salt according to  claim 1 , and thereby alleviating the condition in the patient. 
     
     
         49 . (canceled) 
     
     
         50 . A method according to  claim 48  or  claim 49 , wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, dementia, schizophrenia, a cognitive disorder, epilepsy, migraine, excessive daytime sleepiness, shift work sleep disorder, jet lag, narcolepsy, sleep apnea, allergic rhinitis, vertigo, motion sickness, a memory disorder, or Parkinson's disease. 
     
     
         51 . A method according to  claim 48 , wherein the condition is obesity, an eating disorder or diabetes. 
     
     
         52 . A method according  claim 48 , wherein the patient is a human. 
     
     
         53 . A compound or salt according to  claim 1 , wherein the compound or salt is radiolabeled. 
     
     
         54 - 55 . (canceled) 
     
     
         56 . A packaged pharmaceutical preparation, comprising:
 (a) a pharmaceutical composition according to  claim 46  in a container; and   (b) instructions for using the composition to treat a condition responsive to H3 receptor modulation in a patient.   
     
     
         57 . A packaged pharmaceutical preparation according to  claim 56 , wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, dementia, schizophrenia, a cognitive disorder, epilepsy, migraine, excessive daytime sleepiness, shift work sleep disorder, jet lag, narcolepsy, sleep apnea, allergic rhinitis, vertigo, motion sickness, a memory disorder, or Parkinson's disease. 
     
     
         58 . A packaged pharmaceutical preparation according to  claim 56 , wherein the condition is obesity, an eating disorder or diabetes. 
     
     
         59 - 61 . (canceled)