Substituted 1-Benzyl-4-Substituted Piperazine Analogues

Abstract

Compounds of Formula I are provided, in which variables are as described herein: Such compounds may be used to modulate MCH binding to MCH receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting MCH receptors (e.g., receptor localization studies).

1 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 V is absent or —(C═O)—;  
 Y, is CH or nitrogen;  
 Y 3  and Y 4  are independently CR 1  or nitrogen; and Z is nitrogen or CR 2 ; such that at least one of Y 3 , Y 4  and Z is nitrogen, and at least one of Y 3 , Y 4  and Z is substituted carbon;  
 each R 1  is independently: 
 (i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, aminoC 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 6 alkyl or (4-to 7-membered heterocycloalkyl)C 0 -C 6 alkyl; or  
 (ii) taken together with R 2  to form a fused 5-or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl and haloC 1 -C 4 alkoxy;  
 
 R 2  is halogen, nitro, cyano, amino, acetyl, carboxamide, imino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 2 -C 6 alkyloxime, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, mono- or di-alkylcarboxamide, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, aminoC 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 6 alkyl; or  
 R 2  is (4-to 7-membered heterocycloalkyl)C 0 -C 6 alkyl, phenylC 0 -C 2 alkyl, phenylC 1 -C 2 alkoxy or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, C 1 -C 2 alkoxy and C 1 -C 2 alkyl; or  
 R 2  is taken together with a R 1  to form a fused 5-or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl and haloC 1 -C 4 alkoxy;  
 R 3  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or haloC 1 -C 6 alkyl;  
 R 4  is hydrogen, C 1 -C 6 alkyl or haloC 1 -C 6 alkyl;  
 R 5  is  
 taken together with R 6  to form a methylene or ethylene bridge;  
 P is N or CR 7 ;  
 Q is N or CR 8 ;  
 U is N or CR 9 ;  
 T is N or CR 10 ;  
 X is N or CR 11 ;  
 R 7  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 8  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 8  is: (i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) talken together with R 7  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 9  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 10  or R 11  to form a fused 5-to 10-membered carbocycle or heterocycle;  
 
 R 10  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 9  to form a fused carbocycle or heterocycle;  
 
 R 11  is: (i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 9  to form a fused carbocycle or heterocycle;  
 
 R 12  is hydrogen, halogen, hydroxy, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino or aminoC 1 -C 6 alkyl;  
 each L is independently a single covalent bond, N(R 13 ), O, C(═O), SO 2 , SO 2 NH, C(═O)N(R 13 ) or N(R 13 )C(═O), wherein each R 13  is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or haloC 1 -C 6 alkyl; and  
 each M is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl;  
 such that if Y 1  and Y 3  are both nitrogen and R 11  is trifluoromethyl, then R 2  is not amino.  
 
   
   
       2 . A compound or salt of  claim 1 , wherein Q is CR 8  and X is CR 11 .  
   
   
       3 . A compound or salt of  claim 2 , wherein P is CR 7 .  
   
   
       4 . A compound or salt of  claim 3 , wherein R 7  is not hydrogen.  
   
   
       5 . A compound or salt of  claim 1 , wherein R 11  is C 1 -C 4 alkoxy.  
   
   
       6 . A compound or salt of  claim 5 , wherein U is CR 9  and T is CR 10 .  
   
   
       7 . A compound or salt of  claim 1 , wherein R 7  and R 8  are each chosen from C 1 -C 4 alkyl.  
   
   
       8 . A compound or salt of  claim 1 , wherein R 3  is methyl and R 4  is hydrogen.  
   
   
       9 . (canceled)  
   
   
       10 . A compound or salt of  claim 1 , wherein V is C═O.  
   
   
       11 . A compound or salt of  claim 1 , wherein Z is CR 2 .  
   
   
       12 . A compound or salt of  claim 11 , wherein 
 R 2  is halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, haloC 1 -C 4 alkyl, mono- or di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl or (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl, or R 2  is taken together with a R 1  to form a fused 5- or 6-membered carbocycle or heterocycle.    
   
   
       13 . A compound or salt of  claim 12 , wherein 
 R 2  is halogen, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl or mono- or di-methylamino.    
   
   
       14 . A compound or salt of  claim 1 , wherein the compound has the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Y 1  is CH, C—CH 3  or nitrogen;  
 Y 3  and Y 4  are independently CR 1  or nitrogen, such that at least one of Y 3  and Y 4  is nitrogen, and Y 1  is carbon if Y 3  is nitrogen;  
 each R 1  is independently: 
 (i) hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl; or  
 (ii) taken together with R 2  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 2  is halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, haloC 1 -C 4 alkyl, mono- or di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, or (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl or taken together with a R 1  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 R 3  is hydrogen or C 1 -C 4 alkyl;  
 R 5  is taken together with R 6  to form a methylene bridge;  
 R 7  is hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy;  
 R 8  is halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy; and  
 R 11  is halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy or aminoC 1 -C 6 alkyl.  
 
   
   
       15 . A compound or salt of  claim 14 , wherein R 7  is not hydrogen.  
   
   
       16 . A compound or salt of  claim 14 , wherein R 9  is C 1 -C 4 alkyl.  
   
   
       17 . A compound or salt of any one of claims  14 , wherein R 11  is C 1 -C 4 alkoxy.  
   
   
       18 - 20 . (canceled)  
   
   
       21 . A compound or salt of  claim 1 , wherein the compound has the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Y 1  is CH or nitrogen;  
 Y 3  and Y 4  are independently CR 1  or nitrogen, such that at least one of Y 3  and Y 4  is nitrogen, and Y 1  is carbon if Y 3  is nitrogen;  
 each R 1  is independently: 
 (i) hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl; or  
 (ii) taken together with R 2  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 2  is halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, haloC 1 -C 4 alkyl, mono- or di-(C 1 -C 4 alkyl)amino, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl or (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl or taken together with a R 1  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 R 3  hydrogen or C 1 -C 4 alkyl;  
 R 5  is taken together with R 6  to form a methylene bridge;  
 R 7  is hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy;  
 R 8  is halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy; and  
 R 11  is halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy or aminoC 1 -C 6 alkyl.  
 
   
   
       22 . A compound or salt of  claim 21 , wherein R 7  is not hydrogen.  
   
   
       23 . A compound or salt of  claim 21 , wherein R 8  is C 1 -C 4 alkyl.  
   
   
       24 . A compound or salt of  claim 21 , wherein R 11  is C 1 -C 4 alkoxy.  
   
   
       25 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 Y 1 , Y 3  and Y 4  are independently CR 1  or nitrogen, and Z is nitrogen or CR 2 , such that at least one of Y 3 , Y 4  and Z is nitrogen;  
 each R 1  is independently: 
 (i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, aminoC 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 6 alkyl or (4- to 7-membered heterocycloalkyl)C 0 -C 6 alkyl; or  
 (ii) taken together with R 2  to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl and haloC 1 -C 4 alkoxy;  
 
 R 2  is hydrogen, halogen, nitro, cyano, amino, acetyl, carboxamide, imino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 2 -C 6 alkyloxime, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, mono- or di-alkylcarboxamide, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, aminoC 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 6 alkyl; or  
 R 2  is (4- to 7-membered heterocycloalkyl)C 0 -C 6 alkyl, phenylC 0 -C 2 alkyl, phenylC 1 -C 2 alkoxy or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl and haloC 1 -C 4 alkoxy; or  
 R 2  is taken together with a R 1  to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, haloC 1 -C 4 alkyl and haloC 1 -C 4 alkoxy;  
 R 5  is taken together with R 6  to form a methylene or ethylene bridge;  
 P is N or CR 7 ;  
 Q is N or CR 8 ;  
 U is N or CR 9 ;  
 T is N or CR 10 ;  
 X is N or CR 11 ;  
 R 7  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formla L-M; or 
 (ii) taken together with R 8  or R 12  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 8  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 7  to form a fused 5- or 6-membered carbocycle or heterocycle;  
 
 R 9  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 10  or R 11  to form a fused 5- to 10-membered carbocycle or heterocycle;  
 
 R 10  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 3  or R 9  to form a fused carbocycle or heterocycle;  
 
 R 11  is: (i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M; or 
 (ii) taken together with R 9  to form a fused carbocycle or heterocycle;  
 
 R 12  is hydrogen, halogen, hydroxy, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino or aminoC 1 -C 6 alkyl;  
 each L is independently a single covalent bond, N(R 13 ), O, C(═O), SO 2 , SO 2 NH, C(═O)N(R 13 ) or N(R 13 )C(═O), wherein each R 13  is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or haloC 1 -C 6 alkyl; and  
 each M is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl.  
 
   
   
       26 . (canceled)  
   
   
       27 . A compound of salt of  claim 25 , of the formula  
     
       
         
         
             
             
         
       
     
   
   
       28 .- 39 . (canceled)  
   
   
       40 . A pharmaceutical composition, comprising a compound or salt of  claim 1 , in combination with at least one physiologically acceptable carrier or excipient.  
   
   
       41 . The pharmaceutical composition of  claim 40 , 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.  
   
   
       42 . A packaged pharmaceutical preparation, comprising: a pharmaceutical composition of  claim 40  in a container; and instructions for using the composition to treat a patient suffering from a disorder associated with MCH receptor activation.  
   
   
       43 . The packaged pharmaceutical preparation of  claim 42 , wherein the disorder is an eating disorder, a sexual disorder, obesity, diabetes, heart disease or stroke.  
   
   
       44 .- 54 . (canceled)  
   
   
       55 . A method for treating a disease or disorder associated with MCH receptor activation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of  claims 1  to  39 .  
   
   
       56 . The method of claim  54  or  55 , wherein the disease or disorder is an eating disorder, sexual disorder, diabetes, heart disease or stroke.  
   
   
       57 .- 61 . (canceled)  
   
   
       62 . A method for treating obesity, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of  claims 1  to  39 .  
   
   
       63 .- 69 . (canceled)