Heteroaryl amide analogues as p2x7 antagonists

Abstract

Heteroaryl amide analogues are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

What is claim is: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 T, U and V are independently chosen from CR 3 , CR A  and N, such that
 (i) exactly one of T, U and V is CR; and 
 (ii) if X is CH 2 , Y is phenyl, and U and V are both substituted carbon, then T is not N; 
 
 W is —C(═O)NR 4 —, —NR 4 C(═O)— or —NR 4 —NR 4 —C(═O)—; 
 X is absent or C 1 -C 6 alkylene that is substituted with from 0 to 4 substituents independently chosen from:
 (i) C 1 -C 4 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl and phenylC 0 -C 2 alkyl; 
 (ii) substituents that are taken together to form a 3- to 7-membered cycloalkyl or heterocycloalkyl ring; and 
 (iii) substituents that are taken together with R 4  to form a 4- to 7-membered heterocycloalkyl; 
 
 Y is C 3 -C 16 cycloalkyl, 4- to 16-membered heterocycloalkyl, 6- to 16-membered aryl or 5- to 16-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from hydroxy, halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 Z 1  and Z 3  are independently N or CR 2 ; 
 Z 2  is N, CR 2  or CR A ; 
 Each R 2  and each R 3  is independently chosen from hydrogen, halogen, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkanoyl, C 2 -C 6 alkyl ether, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 Each R 4  is independently hydrogen, C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl or taken together with a substituent of X to form a 4- to 7-membered heterocycloalkyl; 
 R A  is a group of the formula -L-A-M, wherein:
 L is absent or C 1 -C 6 alkylene that is optionally modified by the replacement of a carbon-carbon single bond with a double or triple carbon-carbon bond, which alkylene is optionally substituted with oxo, —COOH, —SO 2 N, —PO 3 H 2 , tetrazole or oxadizaolone; 
 A is absent or CO, O, NR 6 , S. SO, SO 2 , CONR 6 , NR 6 CO, (C 4 -C 7 cycloalkyl)C 0 -C 4 alkylene or (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkylene; wherein R 6  is hydrogen or C 1 -C 6 alkyl; and 
 M is:
 (i) hydroxy, cyano, amino, aminocarbonyl, aminosulfonyl or COOH; or 
 (ii) C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 5- to 10-membered carbocycle, 4- to 10-membered heterocycle, C 1 -C 6 alkanoyloxy, C 1 -C 6 alkanoylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, C 1 -C 6 alkylsulfonyloxy, mono- or di-C 1 -C 6 alkylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, or mono- or di-(C 1 -C 6 alkyl)aminocarbonyl; each of which is optionally substituted and each of which is preferably substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle. 
 
 
 
     
     
         2 . A compound or salt thereof according to  claim 1 , wherein: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound or sail thereof according to  claim 2 , wherein: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound or salt thereof according to  claim 1 , wherein each R 3  is independently hydrogen or C 1 -C 4 alkyl. 
     
     
         5 . A compound or salt thereof according to  claim 1 , wherein R A  is C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyl ether, phenylC 0 -C 4 alkyl, (4- to 10-membered heterocycle)C 0 -C 4 alkyl, (C 1 -C 6 alkylsulfonylamino)C 0 -C 4 alkyl, (C 1 -C 6 alkanoyloxy)C 0 -C 4 alkyl, (C 1 -C 6 alkylsulfonyloxy)C 0 -C 4 alkyl, (mono- or di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, and (mono- or di-C 1 -C 6 alkylaminocarbonyl)C 0 -C 4 alkyl; each of which is substituted with from 0 to 4 substituents independently chosen from:
 (i) oxo, halogen, amino, cyano, hydroxy, aminocarbonyl, aminosulfonyl and COOH; and   (ii) C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-C 1 -C 6 alkylaminocarbonyl, mono- or di-C 1 -C 6 alkylaminosulfonyl, phenyl and 4- to 7-membered heterocycle; each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, oxo, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.   
     
     
         6 . A compound or salt thereof according to  claim 5 , wherein R A  is C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 cyanoalkenyl, C 2 -C 6 alkyl ether, (mono- or di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, (mono- or di-C 1 -C 6 alkylaminocarbonyl)C 0 -C 4 alkyl, or (4- to 7-membered heterocycle)C 1 -C 4 alkyl; each of which is substituted with from 0 to 4 substituents independently chosen from amino, hydroxy, oxo, halogen, aminocarbonyl, aminosulfonyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkylsulfonyl; C 1 -C 6 alkylsulfonylamino, 4- to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
     
     
         7 . A compound or salt thereof according to  claim 5 , wherein R A  is a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 L is absent or C 1 -C 6 alkylene that is optionally substituted with oxo; 
 
       
         
           
           
               
               
           
         
       
       represents a 4- to 7-membered heterocycloalkyl that is optionally fused to phenyl or to a 5- or 6-membered heteroaryl, and
 R 7  represents from 0 to 4 substituents independently chosen from:
 (i) hydroxy, amino, oxo, aminocarbonyl, aminosulfonyl and COOH; 
 (ii) C 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonylC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonylaminoC 0 -C 4 alkyl, and 4- to 7-membered heterocycle; each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, oxo, aminocarbonyl, aminosulfonyl, COOK, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, and C 1 -C 6 alkylsulfonylamino; 
 (iii) substituents that are taken together to form a bridge, of the Formula —(CH 2 ) q —P—(CH 2 ) r —, wherein q and r are independently 0 or 1 and P is CH 2 , O, NH or 5; and 
 
 (iv) substituents that are taken together to form a spiro 4- to 7-membered heterocycloalkyl ring that is substituted with from 0 to 2 substituents independently chosen from oxo and C 1 -C 4 alkyl. 
 
     
     
         8 . A compound or salt thereof according to  claim 7 , wherein R A  is a group of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 L is C 1 -C 2 alkylene that is optionally substituted with oxo; 
 G is CHR 8 , NH or O; 
 s and t are independently 0, 1, 2, 3 or 4, such that the sum of s and t ranges from 2 to 5; and 
 R 8  is:
 (i) hydrogen, amino, aminocarbonyl, aminosulfonyl or COOH; or 
 C 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonylC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonylaminoC 0 -C 4 alkyl, or 4- to 7-membered heterocycle; each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, oxo, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, and C 1 -C 6 alkylsulfonylamino. 
 
 
     
     
         9 . A compound or salt thereof according to  claim 7 , wherein R A  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 J is CH or N; 
 B, D, E and F are independently chosen from, CH 2 , NH and O; and 
 R 9  represents from 0 to 2 substituents independently chosen from:
 (i) amino, aminocarbonyl and COOH; and 
 (ii) C 1 -C 6 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 2 alkyl, C 1 -C 6 alkylsulfonyl and C 1 -C 6 alkylsulfonylamino; each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, oxo and COOH. 
 
 
     
     
         10 . A compound or salt thereof according to  claim 5 , wherein R A  is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyl ether, or mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, each of which is substituted with from 1 to 4 substituents independently chosen hum halogen, hydroxy, cyano, amino, oxo, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkanoylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonyloxy, C 1 -C 6 alkylsulfonylamino, phenyl that is optionally substituted with halogen or C 1 -C 4 alkyl, and 4- to 7-membered heterocycle that is optionally substituted with C 1 -C 4 alkyl. 
     
     
         11 . A compound or salt thereof according to  claim 10 , wherein R A  is mono-(C 1 -C 6 alkyl)aminoC 0 -C 2 alkyl or C 2 -C 6 alkyl ether, each of which is substituted with from 1 to 4 substituents independently chosen from hydroxy, halogen, oxo, COOH, C 1 -C 4 alkyl and C 1 -C 4 alkoxy. 
     
     
         12 . A compound or salt thereof according to  claim 1 , wherein:
 L is not absent;   A is absent; and   M is phenyl or a 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, —C 1 -C 6 alkysulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle.   
     
     
         13 . A compound or salt thereof according to  claim 1 , wherein:
 L is C 0 -C 3 alkylene that is optionally substituted with oxo or COOH;   A is absent; and   M is phenyl that is substituted with amino, cyano, aminocarbonyl, aminosulfonyl, COOH or C 1 -C 6 alkyl.   
     
     
         14 . A compound or salt thereof according to  claim 1 , wherein:
 L is C 1 -C 2 alkylene that is optionally substituted with oxo;   A is absent; and   M is mono- or di-(C 1 -C 6 alkyl)amino that is substituted with a 5- or 6-membered heteroaryl, each of which heteroaryl is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle.   
     
     
         15 . A compound or salt thereof according to  claim 12  or  claim 14 , wherein the 5- or 6-membered heteroaryl is:
 (i) pyridyl or pyrimidinyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle; or 
 (ii) a heteroaryl chosen from: 
 
       
         
           
           
               
               
           
         
         
           each of which is substituted with from 0 to 2 substituents independently chosen from amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle. 
         
       
     
     
         16 . A compound or salt thereof according to  claim 1 , wherein each R 2  is hydrogen or C 1 -C 6 alkyl. 
     
     
         17 . A pharmaceutical composition, comprising at least one compound or salt thereof according to  claim 1  in combination with a physiologically acceptable carrier or excipient. 
     
     
         18 . A method for treating a condition responsive to P2X 7  receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or salt thereof according to  claim 1 , and thereby alleviating the condition in the patient.