Heteroaryl amide derivatives

Abstract

Heteroaryl amide derivatives 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.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein: 
         T, U and V are independently chosen from CR 3 , CR A  and N, such that exactly one of T, U and V is CR A ; 
         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, (4- to 10-membered heterocycle)C 0 -C 1 alkyl, and phenylC 0 -C 2 alkyl; 
 (ii) substituents that taken together with the atom to which they are attached or with the atoms through which they are connected form a 3- to 8-membered cycloalkyl or heterocycloalkyl ring; and 
 (iii) a substituent that taken together with R 4  and the atoms through which they are connected forms 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 hydroxyalkl, 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, or (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl, or R 4  taken together with a substituent of X and the atoms through which they are connected forms a 4- to 7-membered heterocycloalkyl; 
         R A  is a group of the formula -L-A, 
       
       
         
           
           
               
               
           
         
          or a group chosen from M, such that R A  is not absent, 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, and which alkylene is optionally substituted with oxo; and 
 A is absent or CO, O, NR 6 , S, SO, SO 2 , CONR 6 , NR 6 CO, (C 4 -C 12 cycloalkyl), (4 to 7-membered heterocycle), phenyl-E-, or (5- or 6-membered heterocycle)-E-; wherein R 6  is hydrogen or C 1 -C 6 alkyl and E is O, S, SO 2  or NH; 
 
         such that each -L-A is substituted with from 1 to 6 groups independently chosen from M; and 
         each M is;
 (i) hydroxy, halogen, cyano, amino, imino, hydroxyimino, aminocarbonyl, aminosulfonyl or COOH; 
 (ii) C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, (3- to 12-membered carbocycle)C 0 -C 4 alkyl, (4- to 10-membered heterocycle)C 0 -C 4 alkyl, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 1 -C 6 alkanoylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonylamino, C 1 -C 6 alkylsulfonylaminoC 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyloxy, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkyl)aminocarbonylC 0 -C 1 alkyl or C 1 -C 6 alkylsilyloxy; each of which is substituted with from 0 to 6 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, COOH, C 1 -C 6 alkyl optionally substituted with COOH, amino, cyano, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, imino, hydroxyimino, C 1 -C 6 alkoxy that is optionally substituted with C 1 -C 6 alkanoyloxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 1 -C 6 alkylcarbonyl, 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, phenyl optionally substituted with halogen or C 1 -C 6 haloalkyl, cycloalkyl, and 4- to 7-membered heterocycle; or 
 (iii) two M taken together with the atoms through which they are connected form a bridge of the Formula —(CH 2 ) q —P—(CH 2 ) r —, wherein and r are independently 0 or 1 and P is CH 2 , O, NH or S, the bridge optionally substituted with from 0 to 2 substituents independently chosen from oxo and C 1 -C 4 alkyl; or 
 (iv) when -L-A- is substituted by at least two M at the same atom of -L-A-, two M taken together with the atom to which they are attached form a 3- to 7-membered carbocyclic or heterocycloalkyl ring that is substituted with from 0 to 2 substituents independently chosen from oxo and C 1 -C 4 alkyl; 
 
         such that: (i) R A  is not C 1 -C 6 alkoxy: (ii) R A  is a group of the formula -L-A and L is not absent if a group represented by M is aromatic and Y is aromatic or a 6-membered heterocycloalkyl; and (iii) if Y is optionally substituted phenyl, then R A  is not C 1 -C 4 alkoxycarbonyl;
 o is an integer ranging from 0 to 4; 
 p is 0 or 1; and 
 R 11  and R 12  are:
 (i) independently chosen from:
 (a) hydrogen, 
 (b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkyl ether, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and phenylC 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, 4- to 7-membered heterocycloalkyl that is optionally substituted with one or two methyl groups, and 5- or 6-membered heteroaryl; or 
 
 (ii) taken together to form a 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, aminocarbonyl, aminosulfonyl, COOH, oxo, 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 3 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, 4- to 7-membered heterocycloalkyl that is optionally substituted with one or two methyl groups, and 5- or 6-membered heteroaryl. 
 
 
       
     
     
         2 - 61 . (canceled)