5-Substituted-2-Arylpyridines

Abstract

Novel 5-substituted-2-arylpyridine compounds are provided. Such compounds can act as selective modulators of CRP receptors. The 5-substituted-2-arylpyridine compounds provided herein are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds provided are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 Ar is mono-, di-, or tri-substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring and from 1 to about 3 heteroatoms in at least one of said rings;  
 R is oxygen or absent;  
 R 2  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono or dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted mono or dialkylcarboxamide, optionally substituted aryl or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring and from 1 to about 3 heteroatoms in at least one of said rings;  
 R 1 , R 3 , and R 4  are independently chosen from hydrogen, halogen, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono- or di-alkylamino, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)oxy, optionally substituted (cycloalkyl)alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted mono- or dialkylcarboxamide,  
 with the proviso that not all of R 1 , R 2 , R 3 , and R 4  are unsubstituted alkyl and not all of R 5 , R 3 , and R 4  are hydrogen.  
 
     
     
         2 . (canceled)  
     
     
         3 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 Ar is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, and thiophenyl, each of which is substituted with up to 5 R A  groups;  
 R is oxygen or absent;  
 R 1 , R 3 , and R 4  are independently selected from hydrogen, halogen, hydroxy, amino, nitro, 
 C 1 -C 6 carbhydryl 1 , C 1 -C 6 carbhydryl 1 -O—, mono- or di-C 1 -C 6 carbhydryl 1 amino, C 3 -C 7 cycloalkyl 2 (C 0 -C 4 -carbhydryl 1 ), C 3 -C 7 cycloalkenyl 2 (C 0 -C 4 -carbhydryl 1 ), C 3 -C 7 cycloalkyl 2 (C 0 -C 4 -carbhydryl 1 )—O—, C 3 -C 7 cycloalkenyl 2 (C 0 -C 4 -carbhydryl 1 )—O—, haloC 1 -C 6 carbhydryl 1 , haloC 1 -C 6 carbhydryl 1 -O—, and —S(O) n (C 1 -C 6 carbhydryl 1 ), 
 where each carbhydryl 1  is independently straight or branched, contains 0or 1 or more double or triple bonds, and is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 alkyl)amino, and  
 where each C 3 -C 7 cycloalkyl 2  and C 3 -C 7 cycloalkenyl 2  is optionally substituted by one or more substituents independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(CV C 4 )alkylamino,  
 
 
 R 2  is selected from the group consisting of —XR C  and Y;  
 X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —C(═O)—, —C(═O) n —, —S(O) n —, —NH—, —NR D —, —C(═O)NH—, —C(═O)NR D —, —S(O) n NH—, —S(O) n NR D —, —OC(═S)S—, —NHC(═O)—, —NR D C(═O)—, —NHS(O) n —, and —NR D S(O) n —;  
 Y and Z are independently selected at each occurrence from: 3- to 7-membered carbocyclic or heterocyclic groups, which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, and —S(O) n (alkyl), 
 wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon;  
 
 R A  is independently selected at each occurrence from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl substituted with 0-2 R B , C 2 -C 6 alkenyl substituted with 0-2 R B , C 2 -C 6 alkynyl substituted with 0-2 R B , C 3 -C 7 cycloalkyl substituted with 0-2 R B , (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl substituted with 0-2 R B , 
 C 1 -C 6 alkoxy substituted with 0-2 R B , —NH(C 1 -C 6 alkyl) substituted with 0-2 R B , N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) where each C 1 -C 6 alkyl is independently substituted with 0-2 R B , —XR C , and Y;  
 
 R B  is independently selected at each occurrence from halogen, hydroxy, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —S(O) n (alkyl), halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, —CO(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —XR C , and Y;  
 R C  and R D , are the same or different, and are independently selected at each occurrence from:  
 hydrogen, and  
 straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), —NHS(O) n (C 1 -C 6 alkyl), —S(O) n (C 1 -C 6 alkyl), —S(O) n NH(C 1 -C 6 alkyl), —S(O) n N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and Z; and  
 n is independently selected at each occurrence from 0, 1, and 2;  
 with the proviso that not all of R 1 , R 2 , R 3 , and R 4  are unsubstituted alkyl and not all of R 1 , R 3 , and R 4  are hydrogen.  
 
     
     
         4 . (canceled)  
     
     
         5 . A compound or salt according to  claim 3 , wherein R is absent and Ar is pyridyl, which is substituted with R A  in at least 1 position ortho to the point of attachment of Ar in Formula I, and optionally substituted with up to 2 additional R A  groups.  
     
     
         6 . A compound or salt according to  claim 5  wherein 
 R is absent;    R 1 , R 3 , and R 4  are independently selected from the group consisting of i) hydrogen, ii)halogen, iii) C 1 -C 3 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from hydroxy, amino, cyano, and halogen.    
     
     
         7 . A compound or salt according to  claim 3 , wherein: 
 R is absent;    Ar is pyridyl, which is substituted with R A  in at least 1 position ortho to the point of attachment of Ar in Formula I, and optionally substituted with up to 2 additional R A  groups; and    R C  and R D , which may be the same or different, are independently selected at each occurrence from straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which alkyl groups may contain one or more double or triple bonds.    
     
     
         8 . A compound or salt according to  claim 7 , wherein: 
 R 1 , R 3  and R 4  are independently selected from the group consisting of i) hydrogen, ii) halogen, iii) C 1 -C 3 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy,    wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from hydroxy, amino, cyano, and halogen.    
     
     
         9 . A compound or salt according to  claim 3 , wherein: 
 R is absent;    Ar pyridyl which is substituted in at least one position ortho to the point of attachment of Ar in Formula I with a substituent selected from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 alkoxy, and mono- or di-(C 1 -C 6 alkyl)amino and optionally substituted with up to 2 additional substituents independently selected from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 alkoxy, and mono- or di-(C 1 -C 6 alkyl)amino;    R 1 , R 3  and R 4  are independently selected from the group consisting of i) hydrogen, ii)halogen, iii) C 1 -C 3 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy,    wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from hydroxy, amino, cyano, and halogen.    
     
     
         10 . A compound or salt according to  claim 9 , wherein 
 R 2  is —XR C ;    X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —C(═O)—, —NH—, —NR D —, —C(═O)NH—, —C(═O)NR D —, —NHC(═O)—, —NR D C(═O)—,    R C  and R D , are the same or different, and are independently selected at each occurrence from:    hydrogen, and    straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, and mono- and di(C 1 -C 6 alkyl)amino.    
     
     
         11 . A compound or salt according to  claim 10 , wherein 
 X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —NH—, - and NR D —;    R C  and R D , are the same or different, and are independently selected at each occurrence from: 
 hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds.  
   
     
     
         12 . A compound or salt according to  claim 3  of Formula II  
       
         
           
           
               
               
           
         
       
       wherein: 
 R X  and R Y  are the same or different and are independently selected from:  
 a) hydrogen,  
 b) —(C═O)C 1 -C 8 alkyl; and  
 c) straight or branched alkyl groups, cycloalkyl groups, or (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from:  
 i) halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(CV C 4 alkyl)amino, and  
 ii) 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino, wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon.  
 
     
     
         13 . A compound or salt according to  claim 12 , wherein: 
 R X  and R Y  are the same or different and are independently selected from: 
 a) hydrogen,  
 b) —(C═O)C 1 -C 8 alkyl, and  
 c) straight or branched alkyl groups, cycloalkyl groups, or (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from: halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(CV C 4 alkyl)amino,  
   Ar is pyridyl which is mono-, di-, or tri-substituted with R A , with the proviso that at least one of the positions ortho to the point of attachment of Ar shown in Formula II is substituted;    X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —C(═O)—, —C(═O)O—, —NH—, —NR D —, —C(═O)NH—, —C(═O)NR D —, —NHC(═O)—, and —NR D C(═O)—;    Y and Z are independently selected at each occurrence from: 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon; and    R C  and R D , are the same or different, and are independently selected at each occurrence from:    hydrogen, and    straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), and Z.    
     
     
         14 . A compound or salt according to  claim 12 , wherein: 
 R 1 , R 3  and R 4  are independently selected from the group consisting of i) hydrogen, ii)halogen, iii) C 1 -C 4 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, yl) (C 3 -C 7 Cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)CV C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy,    wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 alkyl)amino.    
     
     
         15 . A compound or salt according to  claim 13 , wherein 
 R X  is a) hydrogen or    b) a straight or branched alkyl group, a cycloalkyl groups, or (cycloalkyl)alkyl group, each of which groups having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    R Y  is a straight or branched alkyl group, a cycloalkyl groups, or (cycloalkyl)alkyl group, each of which groups having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    Ar is pyridyl, mono-, di-, or tri-substituted with substituents independently selected at each occurrence from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(d-C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 alkoxy, and mono- or di-(C 1 -C 6 alkyl)amino; and    R 1 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, mono- or di-(C 1 -C 3 alkyl)amino, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy.    
     
     
         16 . A compound or salt according to  claim 15 , wherein 
 R X  is hydrogen, C 1 -C 6 alkyl, a C 3 -C 7 cycloalkyl, or (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl;    R Y  a C 1 -C 6 alkyl, a C 3 -C 7 cycloalkyl, or (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl;    Ar is phenyl mono-, di-, or tri-substituted with substituents independently selected at each occurrence from halogen, halo(C 1 -C 2 )alkyl, halo(C 1 -C 2 )alkoxy, hydroxy, amino, C 1 -C 3  alkyl, C 1 -C 2 alkoxy, and mono- or di-(C 1 -C 2 alkyl)amino; and    R 1  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono- or di-(C 1 -C 3 alkyl)amino, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; and    R 3  is hydrogen, halogen, or methyl.    
     
     
         17 . A compound or salt according to  claim 12  of Formula III:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is N; and  
 R 5 , R 6 , and R 7  are independently  
 i) hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy) C 1 -C 4 alkoxy, or mono- or di(C 1 -C 4 alkyl)amino, or  
 ii) C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which is further substituted with a 3- to 7-membered carbocyclic or heterocyclic groups which is saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino;  
 wherein at least one of R 5  and R 7  is not hydrogen.  
 
     
     
         18 . A compound or salt according to  claim 17 , wherein: 
 R X  is a) hydrogen or    b) a straight or branched alkyl group, a cycloalkyl group, or (cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    R Y  is a straight or branched alkyl group, a cycloalkyl group, or (cycloalkyl)alkyl group, each having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    R 1  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkoxy, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, and C 1 -C 6 alkyl, which C 1-6 alkyl is unsubstituted or substituted by one to three substituents independently selected from hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di(C 1 -C 4 )alkylamino,    R 3  is hydrogen, halogen, methyl, or methoxy; and    R 5 , R 6 , and R 7  are independently selected from hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy)C 1 -C 4 alkoxy, and mono- or di(C 1 -C 4 alkyl)amino.    
     
     
         19 . A compound or salt according to  claim 3  of Formula IV  
       
         
           
           
               
               
           
         
       
       wherein R X  and R Y  are joined to form a saturated 5 to 7 membered heterocycloalkyl ring containing 0 or 1 additional heteroatom selected from N, O, and S, wherein said saturated 5 to 7 membered heterocycloalkyl ring is optionally substituted with from 1 to 4 groups independently chosen from halogen, hydroxy, methyl and methoxy.  
     
     
         20 . A compound or salt according to  claim 12  of Formula V:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar is pyridyl which is mono-, di-, or tri-substituted with R A , with the proviso that at least one of the positions ortho to the point of attachment of Ar shown in Formula V is substituted;  
 R 1  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkoxy, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, C 1 -C 6 alkyl, and mono- and di-(C 1 -C 4 alkyl)amino; and  
 R 9  is selected from straight or branched alkyl groups, cycloalkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 )alkylamino.  
 
     
     
         21 . A compound or salt according to  claim 20  of Formula VI:  
       
         
           
           
               
               
           
         
       
       wherein, A is N; and 
 R 5 , R 6 , and R 7  are independently  
 i) hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, Q-C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy) C 1 -C 4 alkoxy, or mono- or di(C 1 -C 4 alkyl)amino, or  
 ii) C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which is further substituted with a 3- to 7-membered carbocyclic or heterocyclic groups which is saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino;  
 wherein at least one of R 5  and R 7  is not hydrogen.  
 
     
     
         22 . A compound or salt according to  claim 20 , of Formula VII:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is N;  
 q is an integer from 1 to 4;  
 G is hydrogen, hydroxy, C 1 -C 4 alkoxy, mono- or di(C 1 -C 4 alkyl)amino, or a 3- to 7-membered carbocyclic or heterocyclic group which is saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino and —S(O) n (alkyl), wherein said 3- to 7-membered heterocyclic group contains from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon, and n is 0, 1, or 2; and  
 J and K are independently selected from hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy)C 1 -C 4 alkoxy, and mono- or di(C 1 -C 4 alkyl)amino.  
 
     
     
         23 . A compound or salt according to  claim 3  of Formula VIII  
       
         
           
           
               
               
           
         
       
       wherein: 
 R X  is a straight or branched alkyl group, cycloalkyl group, or (cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from:  
 i) halogen, hydroxy, amino, cyano, d-C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino,  
 ii) 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino, wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon.  
 
     
     
         24 . A compound or salt according to  claim 23 , wherein: 
 Ar is pyridyl which is mono-, di-, or tri-substituted with R A , with the proviso that at least one of the positions ortho to the point of attachment of Ar shown in Formula VIII is substituted;    X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —C(═O)—, —C(═O)—, —NH—, —NR D —, —C(═O)NH—, —C(═O)NR D —, —NHC(═O)—, and —NR D C(═O)—;    Y and Z are independently selected at each occurrence from: 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, —O(C 1 -C 4 alkyl), and —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon; and    R C  and R D , are the same or different, and are independently selected at each occurrence from:    hydrogen, and    straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), and Z.    
     
     
         25 . A compound or salt according to  claim 23 , wherein: 
 R 1 R 3  and R 4  are independently selected from the group consisting of i) hydrogen, ii)halogen, iii) C 1 -C 4 alkyl, iv) C 1 -C 3 alkoxy, v) (C 1 -C 3 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy,    wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 alkyl)amino.    
     
     
         26 . A compound or salt according to  claim 24 , wherein 
 R X  is a straight or branched alkyl group, a cycloalkyl groups, or (cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    Ar is pyridyl, mono-, di-, or tri-substituted with substituents independently selected at each occurrence from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 alkoxy, and mono- or di-(C 1 -C 6 alkyl)amino; and    R 1 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, mono- or di-(C 1 -C 3 alkyl)amino, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy.    
     
     
         27 . A compound or salt according to  claim 26 , wherein 
 R X  is a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl group;    Ar is phenyl or pyridyl, mono-, di-, or tri-substituted with substituents independently selected at each occurrence from halogen, halo(C 1 -C 2 )alkyl, halo(C 1 -C 2 )alkoxy, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, and mono- or di-(C 1 -C 2 alkyl)amino; and    R 1  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono- or di-(C 1 -C 3 alkyl)amino, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; and    R 3  is hydrogen, halogen, or methyl.    
     
     
         28 . A compound or salt according to  claim 23  of Formula IX:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is N; and  
 R 5 , R 6 , and R 7  are independently  
 i) hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy) C 1 -C 4 alkoxy, or mono- or di(C 1 -C 4 alkyl)amino, or  
 ii) C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each of which is further substituted with a 3- to 7-membered carbocyclic or heterocyclic groups which is saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino, wherein said 3- to 7-membered heterocyclic group contains from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon;  
 wherein at least one of R 5  and R 7  is not hydrogen.  
 
     
     
         29 . A compound or salt according to  claim 28 , wherein: 
 R X  is a straight or branched alkyl group, a cycloalkyl group, or (cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zero or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 )alkylamino;    R 1  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkoxy, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, and C 1 -C 6 alkyl, which C 1-6 alkyl is unsubstituted or substituted by one to three substituents independently selected from hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di(C 1 -C 4 )alkylamino,    R 3  is hydrogen, halogen, methyl, or methoxy; and    R 5 , R 6 , and R 7  are independently selected from hydrogen, halogen, cyano, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy)C 1 -C 4 alkoxy, and mono- or di(C 1 -C 4 alkyl)amino.    
     
     
         30 - 32 . (canceled)  
     
     
         33 . A method for treating anxiety, depression, irritable bowel syndrome, Crohn's disease, or stress comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt according to  claim 3 .  
     
     
         34 . (canceled)  
     
     
         35 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of  claim 3 .  
     
     
         36 . A pharmaceutical composition according to  claim 35 , wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup or a transdermal patch.  
     
     
         37 . A package comprising a pharmaceutical composition of  claim 35  in a container and further comprising at least one of: 
 instructions for using the composition to treat a patient suffering from anxiety, or    instructions for using the composition to treat a patient suffering from stress, or    instructions for using the composition to treat a patient suffering from depression or    instructions for using the composition to treat a patient suffering from Crohn's disease, or    instructions for using the composition to treat a patient suffering from irritable bowel syndrome.    
     
     
         38 - 44 . (canceled)