Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4'-piperidines

Abstract

Substituted spiro[isobenzofuran-1,4′-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4′-piperidines capable of modulating NPY5 receptor activity are provided. Such compounds may be used to modulate ligand binding to NPY5 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders (e.g., eating disorders such as obesity or bulimia, psychiatric disorders, diabetes and cardiovascular disorders such as hypertension) in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such compounds for detecting NPY5 receptors.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 V, W, Y and Z are independently N or CR 1 ;  
 R 1  is independently selected at each occurrence from: 
 (i) hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH 2  and —COOH; and  
 (ii) L-R A -Q-G, wherein: 
 L is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) n —, —NR B —, —C(═O)NHR B —, —NHR B C(═O)—, —NR B S(O) n — or —S(O) n NR B —; n is 0, 1 or 2;  
 R A  is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )cycloalkynyl or (C 3 -C 8 )heterocycloalkyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl;  
 Q is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) n —, —CHR B —, —NR B —, —C(═O)NHR B —, —NHR B C(═O)—, —NR B S(O) n — or —S(O) n NR B —;  
 R B  is independently selected at each occurrence from hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl and (C 1 -C 8 )alkyl(C 3 -C 8 )cycloalkyl; and  
 G is: hydrogen; or 
 (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —NH(C 1 -C 8 )alkyl, —N((C 1 -C 8 )alkyl) 2 , —NHC(═O)(C 1 -C 8 )alkyl, —N(C 1 -C 8 ) alkylC(═O)(alkyl), —NHS(O) s (C 1 -C 8 )alkyl, —S(O) s (C 1 -C 8 )alkyl, —S(O) s NH(C 1 -C 8 )alkyl and —S(O) s N((C 1 -C 8 )alkyl) 2 , wherein s is 0, 1 or 2;  
 
 
 
 J is a bond or (C 1 -C 6 )alkyl; and  
 R G  is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from: 
 (i) hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH 2  and —COOH; and  
 (ii) T-RC-U-M, wherein: 
 T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) n —, —NR D —, —C(═O)NHR D —, —NHR D C(═O)—, —NR D S(O) n — or —S(O) n NR D —; n is independently chosen at each occurrence from 0, 1 or 2;  
 R C  is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or a 3-to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl;  
 U is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O) n —, —CHR D —, —NR D —, —C(═O)NHR D —, —NHR D C(═O)—, —NR D S(O) n — or —S(O) n NR D —;  
 R D  is independently selected at each occurrence from hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl and (C 1 -C 8 ) alkyl(C 3 -C 8 )cycloalkyl; and  
 M is: hydrogen; or 
 (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 ) cycloalkyl(C 1 -C 8 )alkyl or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 9 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —NH(C 1 -C 8 )alkyl, —N((C 1 -C 8 )alkyl) 2 , —NHC(═O)(C 1 -C 8 )alkyl, —N(C 1 -C 8 )alkylC(═O)(alkyl), —NHS(O) s (C 1 -C 8 )alkyl, —S(O) s (C 1 -C 8 )alkyl, —S(O) s NH(C 1 -C 8 )alkyl and —S(O) s N((C 1 -C 8 )alkyl) 2 , wherein s is 0, 1 or 2;  
 
 
 
 with the proviso that if R G , M or both are aromatic, then J is (C 1 -C 6 )alkyl.  
 
     
     
         2 . A compound according to  claim 1 , wherein Y and Z are CH, and V and W are CR 1 , wherein R 1  is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy.  
     
     
         3 . A compound according to  claim 1 , wherein R G  is cyclohexyl.  
     
     
         4 . A compound according to  claim 1 , wherein J is (C 1 -C 3 )alkyl and R G  is a 5- or 6-membered carbocyclic or heterocyclic group.  
     
     
         5 . A compound according to  claim 1 , wherein the compound is selected from: 1′-(4′-carboxycyclohexylmethyl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one; 1′-(1,4-dioxa-spiro[4,5]dec-8-yl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one; 1′-(3-phenylethyl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one; 1′-(cyclohexyl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one; and 1′-(4-bromo-3-phenylethyl-carbamoyl)-spiro [isobenzofuran-1,4′-piperidine]-3-one.