N-ureidoalkyl-piperidines as modulators of chemokine receptor activity

Abstract

The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

1 - 34 . (canceled)  
     
     
         35 . A method for treating inflammation in an inflammatory disorder wherein the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, allergic colitis, eczema, conjunctivitis, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, and eosinophilic gastroenteritis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1,  
       
         
           
           
               
               
           
         
       
       or stereoisomers or pharmaceutically acceptable salts thereof, wherein: 
 M is selected from CH 2 , CHR 5 , CHR 13 , CR 13 R 13 , and CR 5 R 13 ;  
 Q is selected from CH 2 , CHR 5 , CHR 13 , CR 13 R 13 , and CR 5 R 13 ;  
 J and K are selected from CH 2 , CHR 5 , CHR 6 , CR 6 R 6  and CR 5 R 6 ;  
 L is CHR 5 ;  
 Z is selected from O and S;  
 E is selected from:  
                     
  ring A is a C 3-6  carbocyclic residue, provided that the C 3-6  carbocyclic residue is not phenyl;  
 R 1  and R 2  are independently selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, and a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R a ;  
 R a , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR b R b , (CH 2 ) r OH, (CH 2 ) r OR c , (CH 2 ) r SH, (CH 2 ) r SR c , (CH 2 ) r C(O)R b , (CH 2 ) r C(O)NR b R b , (CH 2 ) r NR b C(O)R b , (CH 2 ) r C(O)OR b , (CH 2 ) r OC(O)R c , (CH 2 ) r CH(═NR b )NR b R b , (CH 2 ) r NHC(═NR b )NR b R b , (CH 2 ) r S(O) p R c , (CH 2 ) r S(O) 2 NR b R b , (CH 2 ) r NR b S(O) 2 R c , and (CH 2 ) r phenyl;  
 R b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 R c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 alternatively, R 2  and R 3  join to form a 5, 6, or 7-membered ring substituted with 0-3 R a ;  
 R 3  is selected from a (CR 3′ R 3′ ) r —C 3-10  carbocyclic residue substituted with 0-5 R 15  and a (CR 3′ R 3′ ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;  
 R 3′  and R 3′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 4  is absent, taken with the nitrogen to which it is attached to form an N-oxide, or taken with the nitrogen to which it is attached to form a quaternary salt comprising a compound of formula (I) and a counterion and is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q C(O)R 4b , (CH 2 ) q C(O)NR 4a R 4a′ , (CH 2 ) q C(O)OR 4b , and a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 4c ;  
 R 4a  and R 4a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 4b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, (CH 2 ) r C 3-6  cycloalkyl, C 2-8  alkynyl, and phenyl;  
 R 4c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 4a R 4a′ , and (CH 2 ) r phenyl;  
 alternatively, R 4  joins with R 7 , R 9 , R 1l , or R 14  to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R a ;  
 R 5  is selected from a (CR 5′ R 5″ ) t —C 3-10  carbocyclic residue substituted with 0-5 R 16  and a (CR 5′ R 5′ ) t -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 16 ;  
 R 5′  and R 5″ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 6 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CF 2 ) r CF 3 , CN, (CH 2 ) r NR 6a R 6a′ , (CH 2 ) r OH, (CH 2 ) r OR 6b , (CH 2 ) r SH, (CH 2 ) r SR 6b , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 6b , (CH 2 ) r C(O)NR 6a R 6a′ , (CH 2 ) r NR 6d C(O)R 6a , (CH 2 ) r C(O)OR 6b , (CH 2 ) r OC(O)R 6b , (CH 2 ) r S(O) p R 6b , (CH 2 ) r S(O) 2 NR 6a R 6a′ , (CH 2 ) r NR 6d S(O) 2 R 6b , and (CH 2 ) t phenyl substituted with 0-3 R 6c ;  
 R 6a  and R 6a′ , at each occurrence, are selected from H, C 1-6 alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;  
 R 6b , at each occurrence, is selected from C 1-6  alkyl, C 3-6 cycloalkyl, and phenyl substituted with 0-3 R 6c ;  
 R 6c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 6d R 6d ;  
 R 6d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 with the proviso that when either of J or K is CR 6 R 6  and R 6  is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R 6  is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;  
 R 7 , is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 7d , (CH 2 ) q SR 7d , (CH 2 ) q NR 7a R 7a′ , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(CH 2 ) q NR 7a C(O)R 7a , (CH 2 ) q NR 7a C(O)H, (CH 2 ) r C(O)OR 7b , (CH 2 ) q OC(O)R 7b , (CH 2 ) q S(O) p R 7b , (CH 2 ) q S(O) 2 NR 7a R 7a′ , (CH 2 ) q NR 7a S(O) 2 R 7b , C 1-6  haloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 7c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 7c ;  
 R 7a  and R 7a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 7e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 7e ;  
 R 7b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-2 R 7e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 7e ;  
 R 7c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 7f R 7f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r SC 1-4  alkyl, (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7f R 7f , (CH 2 ) r NR 7f C(O)R 7a , (CH 2 ) r C(O)OC 1-4  alkyl, (CH 2 ) r OC(O)R 7b , (CH 2 ) r C(═NR 7f )NR 7f R 7f , (CH 2 ) r S(O) p R 7b , (CH 2 ) r NHC(═NR 7f )NR 7f R 7f , (CH 2 ) r S(O) 2 NR 7f R 7f , (CH 2 ) r NR 7f S(O) 2 R 7b , and (CH 2 ) r phenyl substituted with 0-3 R 7e ;  
 R 7d , at each occurrence, is selected from C 1-6  alkyl substituted with 0-3 R 7e , alkenyl, alkynyl, and a C 3-10  carbocyclic residue substituted with 0-3 R 7c ;  
 R 7e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;  
 R 7f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 8  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) t phenyl substituted with 0-3 R 8a ;  
 R 8a , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;  
 alternatively, R 7  and R 8  join to form C 3-7  cycloalkyl, or ═NR 8b ;  
 R 8b  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, OH, CN, and (CH 2 ) r -phenyl;  
 R 9 , is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, F, Cl, Br, I, NO 2 , CN, (CH 2 ) r OH, (CH 2 ) r SH, (CH 2 ) r OR 9d , (CH 2 ) r SR 9d , (CH 2 ) r NR 9a R 9a′ , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 9b , (CH 2 ) r C(O)NR 9a R 9a′ , (CH 2 ) r NR 9a C(O)R 9a , (CH 2 ) r NR 9a C(O)H, (CH 2 ) r NR 9a C(O)NHR 9a , (CH 2 ) r C(O)OR 9b , (CH 2 ) r OC(O)R 9b , (CH 2 ) r OC(O)NHR 9a , (CH 2 ) r S(O) p R 9b , (CH 2 ) r S(O) 2 NR 9a R 9a′ , (CH 2 ) r NR 9a S(O) 2 R 9b , C 1-6  haloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 9c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 9c ;  
 R 9a  and R 9a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 9e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 9e ;  
 R 9b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-2 R 9e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 9e ;  
 R 9c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 9f R 9f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r SC 1-14  alkyl, (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 9b , (CH 2 ) r C(O)NR 9f R 9f , (CH 2 ) r NR 9f C(O)R 9a , (CH 2 ) r C(O)OC 1-14  alkyl, (CH 2 ) r OC(O)R 9b , (CH 2 ) r C(═NR 9f )NR 9f R 9f , (CH 2 ) r S(O) p R 9b , (CH 2 ) r NHC(═NR 9f )NR 9f R 9f , (CH 2 ) r S(O) 2 NR 9f R 9f , (CH 2 ) r NR 9f S(O) 2 R 9b , and (CH 2 ) r phenyl substituted with 0-3 R 9e ;  
 R 9d , at each occurrence, is selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, a C 3-10  carbocyclic residue substituted with 0-3 R 9c , and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R 9c ;  
 R 9e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 9f R 9f , and (CH 2 ) r phenyl;  
 R 9f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 10 , is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, F, Cl, Br, I, NO 2 , CN, (CH 2 ) r OH, (CH 2 ) r OR 10d , (CH 2 ) r SR 10d , (CH 2 ) r NR 10a R 10a′ , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 10b , (CH 2 ) r C(O)NR 10a R 10a′ , (CH 2 ) r NR 10a C(O)R 10a , (CH 2 ) r NR 10a C(O)H, (CH 2 ) r C(O)OR 10b , (CH 2 ) r OC(O)R 10b , (CH 2 ) r S(O) p R 10b , (CH 2 ) r S(O) 2 NR 10a R 10a′ , (CH 2 ) r NR 10a S(O) 2 R 10b , C 1-6  haloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 10c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 10c ;  
 R 10a  and R 10a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 10e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 10e ;  
 R 10b  at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-2 R 10e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 10e ;  
 R 10c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 10f R 10f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r SC 1-14  alkyl, (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 10b , (CH 2 ) r C(O)NR 10f R 10f , (CH 2 ) r NR 10f C(O)R 10a , (CH 2 ) r C(O)OC 1-14  alkyl, (CH 2 ) r OC(O)R 10b , (CH 2 ) r C(═NR 10f )NR 10f R 10f , (CH 2 ) r S(O) p R 10b , (CH 2 ) r NHC(═NR 10f )NR 10f R 10f , (CH 2 ) r S(O) 2 NR 10f R 10f , (CH 2 ) r NR 10f S(O) 2 R 10b , and (CH 2 ) r phenyl substituted with 0-3 R 10e ;  
 R 10d , at each occurrence, is selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, a C 3-10  carbocyclic residue substituted with 0-3 R 10c , and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R 10c ;  
 R 10e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 10f R 10f , and (CH 2 ) r phenyl;  
 R 10f , at each occurrence, is selected from H, C 1-5  alkyl, and C 3-6  cycloalkyl;  
 alternatively, R 9  and R 10  join to form C 3-7  cycloalkyl, 5-6-membered cyclic ketal or ═O;  
 with the proviso that when R 10  is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R 9  is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;  
 R 11 , is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 11d , (CH 2 ) q SR 11d , (CH 2 ) q NR 11a R 11a′ , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11a R 11a′ , (CH 2 ) q NR 11a C(O)R 11a , (CH 2 ) q NR 11a C(O)NHR 11a , (CH 2 ) r C(O)OR 11b , (CH 2 ) q OC(O)R 11b , (CH 2 ) q S(O) p R 11b , (CH 2 ) q S(O) 2 NR 11a R 11a′ , (CH 2 ) q NR 11a S(O) 2 R 11b , C 1-6  haloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 11c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 11c ;  
 R 11a  and R 11a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 11e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 11e ;  
 R 11b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-2 R 11e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 11e ;  
 R 11c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 11f R 11f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r SC 1-4  alkyl, (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11f R 11f , (CH 2 ) r NR 11f  C(O)R 11a , (CH 2 ) r C(O)OC 1-4  alkyl, (CH 2 ) r OC(O)R 11b , (CH 2 ) r C(═NR 11f )NR 11f R 11f , (CH 2 ) r NHC(═NR 11f )NR 11f R 11f , (CH 2 ) r S(O) p R 11b , (CH 2 ) r S(O) 2 NR 11f R 11f , (CH 2 ) r NR 11f  S(O) 2 R 11b , and (CH 2 ) r phenyl substituted with 0-3 R 11e ;  
 R 11d , at each occurrence, is selected from C 1-6  alkyl substituted with 0-3 R 11e , C 2-6  alkenyl, C 2-6  alkynyl, and a C 3-10  carbocyclic residue substituted with 0-3 R 11c ;  
 R 11e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 11f R 11f , and (CH 2 ) r phenyl;  
 R 11f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 12  is selected from H, C 1-6  alkyl, (CH 2 ) q OH, (CH 2 ) r C 3-6  cycloalkyl, and (CH 2 ) t phenyl substituted with 0-3 R 12a ;  
 R 12a , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 9f R 9f , and (CH 2 ) r phenyl;  
 alternatively, R 11  and R 12  join to form C 3-7  cycloalkyl;  
 R 13 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, (CF 2 ) w CF 3 , (CH 2 )NR 13a R 13a′ , (CH 2 ) r OH, (CH 2 ) r OR 13b , (CH 2 ) r SH, (CH 2 ) r SR 13b , (CH 2 ) w C(O)OH, (CH 2 ) w C(O)R 13b , (CH 2 ) w C(O)NR 13a R 13a′ , (CH 2 ) r NR 13d C(O)R 13a , (CH 2 ) w C(O)OR 13b , (CH 2 ) r OC(O)R 13b , (CH 2 ) w S(O) p R 13b , (CH 2 ) w S(O) 2 NR 13a R 13a′ , (CH 2 ) r NR 13d S(O) 2 R 13b , and (CH 2 ) w -phenyl substituted with 0-3 R 13c ;  
 R 13a  and R 13a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;  
 R 13b , at each occurrence, is selected from C 1-6  alkyl, C 3-6 cycloalkyl, and phenyl substituted with 0-3 R 13c ;  
 R 13c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 13d R 13d ;  
 R 13d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 14 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 14a R 14a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 14d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 14d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 14b , (CHR′) r C(O)NR 14a R 14a′ , (CHR′) r NR 14f C(O) (CHR′) r R 14b , (CHR′) r C(O)O(CHR′) r R 14d , (CHR′) r OC(O) (CHR′) r R 14b , (CHR′) r C(═NR 14f )NR 14a R 14a′ , (CHR′) r NHC(═NR 14f )NR 14f R 14f , (CHR′) r S(O) p (CHR′) r R 14b , (CHR′) r S(O) 2 NR 14a R 14a′ , (CHR′) r NR 14f S(O) 2 (CHR′) r R 14b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, (CHR′) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e , or two R 14  substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R 15e ;  
 R′, at each occurrence, is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with R 14e ;  
 R 14a  and R 14a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 14e ;  
 R 14b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-3 R 14e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 14e ;  
 R 14d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 14e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 14e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 14e ;  
 R 14e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 14f R 14f , and (CH 2 ) r phenyl;  
 R 14f  at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 alternatively, R 14  joins with R 4  to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, the spirocycle substituted with 0-3 R a ;  
 R 15 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 15a R 15a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 15d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 15d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 15b , (CHR′) r C(O)NR 15a R 15a′ , (CHR′)NR 15f C(O) (CHR′) r R 15b , (CHR′) r C(O)O(CHR′) r R 15d , (CHR′) r OC(O) (CHR′) r R 15b , (CHR′) r C(═NR 15f )NR 15a R 15a′ , (CHR′) r NHC(═NR 15f )NR 15f R 15f , (CHR′) r S(O) p (CHR′) r R 15b , (CHR′) r S(O) 2 NR 15a R 15a′ , (CHR′) r NR 15f S(O) 2 (CHR′) r R 15b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, (CHR′) r phenyl substituted with 0-3 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15a  and R 15a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-3 R 15e ; and (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 15e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 15e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15e ;  
 R 15e  at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 15f R 15f  and (CH 2 ) r phenyl;  
 R 15f , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 R 16 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 16a R 16a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 16d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 16d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 16b , (CHR′) r C(O)NR 16a R 16a′ , (CHR′) r NR 16f C(O) (CHR′) r R 16b , (CHR′) r C(O)O(CHR′) r R 16d , (CHR′) r OC(O) (CHR′) r R 16b , (CHR′) r C(═NR 16f )NR 16a R 16a′ , (CHR′) r NHC(═NR 16f )NR 16f R 16f , (CHR′) r S(O) p (CHR′) r R 16b , (CHR′) r S(O) 2 NR 16a R 16a′ , (CHR′) r NR 6f S(O) 2 (CHR′) r R 16b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, and (CHR′) r phenyl substituted with 0-3 R 16e ;  
 R 16a  and R 16a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 16e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 16e ;  
 R 16b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r C 3-6  carbocyclic residue substituted with 0-3 R 16e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 16e ;  
 R 16d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 16e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 16e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 16e ;  
 R 16e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 16f R 16f , and (CH 2 ) r phenyl;  
 R 16f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl, and phenyl;  
 g is selected from 0, 1, 2, 3, and 4;  
 t is selected from 1 and 2;  
 w is selected from 0 and 1;  
 r is selected from 0, 1, 2, 3, 4, and 5;  
 q is selected from 1, 2, 3, 4, and 5; and  
 p is selected from 0, 1, 2, and 3.  
 
     
     
         36 . The method of  claim 35 , wherein: 
 Z is selected from O and S;    E is selected from:                          R 4  is absent, taken with the nitrogen to which it is attached to form an N-oxide, or taken with the nitrogen to which it is attached to form a quaternary salt comprising a compound of formula (I) and a counterion and is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and (CH 2 ) r -phenyl substituted with 0-3 R 4c ;    R 4c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 4a R 4a′ , and (CH 2 ) r phenyl;    alternatively, R 4  joins with R 7  R 9  R 14  to form a 5, 6 or 7 membered piperidinium spirocycle substituted with 0-3 R a ;    R 1  and R 2  are independently selected from H and C 1-4  alkyl;    R 6 , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CF 2 ) r CF 3 , CN, (CH 2 ) r OH, (CH 2 ) r OR 6b , (CH 2 ) r C(O)R 6b , (CH 2 ) r C(O)NR 6a R 6a′ , (CH 2 ) r NR 6d C(O)R 6a , and (CH 2 ) t phenyl substituted with 0-3 R 6c ;    R 6a  and R 6a′ , at each occurrence, are selected from H, C 1-6 alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;    R 6b , at each occurrence, is selected from C 1-6  alkyl, C 3-6 cycloalkyl, and phenyl substituted with 0-3 R 6c ;    R 6c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 6d R 6d ;    R 6d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;    R 7 , is selected from H, C 1-3  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q OH, (CH 2 ) q OR 7d , (CH 2 ) q NR 7a R 7a′ , (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7a R 7a′ , (CH 2 ) q NR 7a C(O)R 7a , C 1-6  haloalkyl, (CH 2 ) r phenyl with 0-2 R 7c ;    R 7a  and R 7a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7c , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 7f R 7f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7f R 7f , (CH 2 ) r  NR 7f C(O)R 7a , (CH 2 ) r S(O) p R 7b , (CH 2 ) r S(O) 2 NR 7f R 7f , (CH 2 ) r NR 7f S(O) 2 R 7b , and (CH 2 ) r phenyl substituted with 0-2 R 7e ;    R 7d , at each occurrence, is selected from C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;    R 7f , at each occurrence, is selected from H, C 1-5  alkyl, and C 3-6  cycloalkyl;    R 8  is H or joins with R 7  to form C 3-7  cycloalkyl or ═NR 8b ;    R 11 , is selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q OH, (CH 2 ) q OR 11d , (CH 2 ) q NR 11a R 11a′ , (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11a R 11a′ , (CH 2 ) q NR 11a C(O)R 11a , C 1-6  haloalkyl, (CH 2 ) r phenyl with 0-2 R 11c , (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;    R 11a  and R 11a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r phenyl substituted with 0-3 R 11e ;    R 11b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 11e ;    R 11c , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 11f R 11f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11f R 11f , (CH 2 ) r NR 11f C(O)R 11a , (CH 2 ) r S(O) p R 11b , (CH 2 ) r S(O) 2 NR 11f R 11f , (CH 2 ) r NR 11f S(O) 2 R 11b , and (CH 2 ) r phenyl substituted with 0-2 R 11e ;    R 11d , at each occurrence, is selected from C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 11e ;    R 11e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 11f R 11f , and (CH 2 ) r phenyl;    R 11f , at each occurrence, is selected from H, C 1-5  alkyl and C 3-6  cycloalkyl;    R 12  is H or joins with R 11  to form C 3-7  cycloalkyl;    R 13 , at each occurrence, is selected from C 1-4  alkyl, C 3-6  cycloalkyl, (CH 2 )NR 13a R 13a′ , (CH 2 )OH, (CH 2 )OR 13b , (CH 2 ) w C(O)R 13b , (CH 2 ) w C(O)NR 13a R 13a′ , (CH 2 )NR 13d C(O)R 13a , (CH 2 ) w S(O) 2 NR 13a R 13a′ , (CH 2 )NR 13d S(O) 2 R 13b , and (CH 2 ) w -phenyl substituted with 0-3 R 13c ;    R 13a  and R 13a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;    R 13b , at each occurrence, is selected from C 1-6  alkyl, C 3-6 cycloalkyl, and phenyl substituted with 0-3 R 13c ;    R 13c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, and (CH 2 ) r NR 13d R 13d ;    R 13d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;    q is selected from 1, 2, and 3; and    r is selected from 0, 1, 2, and 3.    
     
     
         37 . The method of  claim 36 , wherein: 
 ring A is selected from:                          R 3  is selected from a (CR 3′ H) r -carbocyclic residue substituted with 0-5 R 15 , wherein the carbocyclic residue is selected from phenyl, C 3-6  cycloalkyl, naphthyl, and adamantyl; and a (CR 3′ H) r -heterocyclic system substituted with 0-3 R 15 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 5  is selected from (CR 5′ H) t -phenyl substituted with 0-5 R 16 ; and a (CR 5′ H) t -heterocyclic system substituted with 0-3 R 16 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.    
     
     
         38 . The method of  claim 37 , wherein the compound of formula (I) is:  
       
         
           
           
               
               
           
         
         R 16 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 16a R 16a′ , NO 2 , CN, OH, (CH 2 ) r OR 16d , (CH 2 ) r C(O)R 16b , (CH 2 ) r C(O)NR 16a R 16a′ , (CH 2 ) r NR 16f C(O)R 16b , (CH 2 ) r S(O) p R 16b , (CH 2 ) r S(O) 2 NR 16a R 16a′ , (CH 2 ) r NR 16f S(O) 2 R 16b , and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16a  and R 16a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16d , at each occurrence, is selected from C 1-6  alkyl and phenyl; 
 R 16e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl; and  
 R 16f , at each occurrence, is selected from H, and C 1-5  alkyl.  
 
       
     
     
         39 . The method of  claim 38 , wherein: 
 R 5  is CH 2 phenyl substituted with 0-3 R 16 ;    R 9 , is selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, F, Cl, CN, (CH 2 ) r OH, (CH 2 ) r OR 9d , (CH 2 ) r NR 9a R 9a′ , (CH 2 ) r OC(O)NHR 9a , (CH 2 ) r phenyl substituted with 0-5 R 9e , and a heterocyclic system substituted with 0-2 R 9e , wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;    R 9a  and R 9a , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 9e ;    R 9d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 9e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl;    R 10  is selected from H, C 1-5  alkyl, OH, and CH 2 OH;    alternatively, R 9  and R 10  join to form C 3-7  cycloalkyl, 5-6-membered cyclic ketal or ═O;    with the proviso that when R 10  is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R 9  is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;    R 11  is selected from H, C 1-8  alkyl, (CH 2 ) r phenyl substituted with 0-5 R 11e , and a (CH 2 ) r -heterocyclic system substituted with 0-2 R 11e , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 11e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl;    R 12  is H;    alternatively, R 11  and R 12  join to form C 3-7  cycloalkyl;    R 14 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 14a R 14a′ , NO 2 , CN, OH, (CH 2 ) r OR 14d , (CH 2 ) r C(O)R 14b , (CH 2 ) r C(O)NR 14a R 14a′ , (CH 2 ) r NR 14f C(O)R 14b , (CH 2 ) r S(O) p R 14b , (CH 2 ) r S(O) 2 NR 14a R 14a′ , (CH 2 ) r NR 14f S(O) 2 R 14b , (CH 2 ) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ; or two R 14  substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R 15e ;    R 14a  and R 14a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;    R 14b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14e ;    R 14d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 14e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-15  alkyl; and    R 14f , at each occurrence, is selected from H, and C 1-5  alkyl; and    r is selected from 0, 1, and 2.    
     
     
         40 . The method of  claim 38 , wherein: 
 J is selected from CH 2  and CHR 5 ;    K is selected from CH 2  and CHR 5 ;    R 3  is a C 3-10  carbocyclic residue substituted with 0-3 R 15 , wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR 3′ H) r -heterocyclic system substituted with 0-3 R 15 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 15 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 15a R 15a′ , NO 2 , CN, OH, (CH 2 ) r OR 15d , (CH 2 ) r C(O)R 15b , (CH 2 ) r C(O)NR 15a R 15a′ , (CH 2 ) r NR 15f C(O)R 15b , (CH 2 ) r S(O) p R 15b , (CH 2 ) r S(O) 2 NR 15a R 15a′ , (CH 2 ) r NR 15f S(O) 2 R 15b  (CH 2 ) r phenyl substituted with 0-3 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;    R 15a  and R 15a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 15e ;    R 15b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 15e ;    R 15d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 15e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl; and    R 15f , at each occurrence, is selected from H, and C 1-5  alkyl.    
     
     
         41 . A method for treating inflammation in an inflammatory disorder wherein the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, allergic colitis, eczema, conjunctivitis, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, and eosinophilic gastroenteritis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1,  
       
         
           
           
               
               
           
         
       
       or stereoisomers or pharmaceutically acceptable salts thereof, wherein: 
 M is selected from CH 2 , CHR 5 , CHR 13 , CR 13 R 13 , and CR 5 R 13 ;  
 Q is selected from CH 2 , CHR 5 , CHR 13 , CR 13 R 13 , and CR 5 R 13 ;  
 J and L are selected from CH 2 , CHR 5 , CHR 6 , CR 6 R 6  and CR 5 R 6 ;  
 K is CHR 5 ;  
 Z is selected from O and S;  
 E is  
                     
  ring A is a C 3-6  carbocyclic residue, provided that the C 3-6  carbocyclic residue is not phenyl;  
 R 1  and R 2  are independently selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, and a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R a ;  
 R a , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR b R b , (CH 2 ) r OH, (CH 2 ) r OR c , (CH 2 ) r SH, (CH 2 ) r SR c , (CH 2 ) r C(O)R b , (CH 2 ) r C(O)NR b R b , (CH 2 ) r NR b C(O)R b , (CH 2 ) r C(O)OR b , (CH 2 ) r OC(O)R c , (CH 2 ) r CH(═NR b )NR b R b , (CH 2 ) r NHC(═NR b )NR b R b , (CH 2 ) r S(O) p R c , (CH 2 ) r S(O) 2 NR b R b , (CH 2 ) r NR b S(O) 2 R c , and (CH 2 ) r phenyl;  
 R b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 R c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 alternatively, R 2  and R 3  join to form a 5, 6, or 7-membered ring substituted with 0-3 R a ;  
 R 3  is selected from a (CR 3′ R 3″ ) r —C 3-10  carbocyclic residue substituted with 0-5 R 15  and a (CR 3′ R 3″ ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;  
 R 3′  and R 3″ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 4  is absent, taken with the nitrogen to which it is attached to form an N-oxide, or taken with the nitrogen to which it is attached to form a quaternary salt comprising a compound of formula (I) and a counterion and is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q C(O)R 4b , (CH 2 ) q C(O)NR 4a R 4a′ , (CH 2 ) q C(O)OR 4b , and a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 4c ;  
 R 4a  and R 4a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 4b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, (CH 2 ) r C 3-6  cycloalkyl, C 2-8  alkynyl, and phenyl;  
 R 4c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 4a R 4a′ , and (CH 2 ) r phenyl;  
 alternatively, R 4  joins with R 7 , R 9 , R 11  or R 14  to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with 0-3 R a ;  
 R 5  is selected from a (CR 5′ R 5′ ) t —C 3-10  carbocyclic residue substituted with 0-5 R 16  and a (CR 5′ R 5″ ) t -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 16 ;  
 R 5′  and R 5″ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and phenyl;  
 R 6 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CF 2 ) r CF 3 , CN, (CH 2 ) r NR 6a R 6a′ , (CH 2 ) r OH, (CH 2 ) r OR 6b , (CH 2 ) r SH, (CH 2 ) r SR 6b , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 6b , (CH 2 ) r C(O)NR 6a R 6a′ , (CH 2 ) r NR 6d C(O)R 6a , (CH 2 ) r C(O)OR 6b , (CH 2 ) r OC(O)R 6b , (CH 2 ) r S(O) p R 6b , (CH 2 ) r S(O) 2 NR 6a R 6a′ , (CH 2 ) r NR 6d S(O) 2 R 6b , and (CH 2 ) t phenyl substituted with 0-3 R 6c ;  
 R 6a  and R 6a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;  
 R 6b , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;  
 R 6c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 6d R 6d ;  
 R 6d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 with the proviso that when any of J or L is CR 6 R 6  and R 6  is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R 6  is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;  
 R 7 , is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 7d , (CH 2 ) q SR 7d , (CH 2 ) q NR 7a R 7a′ , (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7a R 7a′ , (CH 2 ) q NR 7a C(O)R 7a , (CH 2 ) q NR 7a C(O)H, (CH 2 ) r C(O)OR 7b , (CH 2 ) q OC(O)R 7b , (CH 2 ) q S(O) p R 7b , (CH 2 ) q S(O) 2 NR 7a R 7a′ , (CH 2 ) q NR 7a S(O) 2 R 7b , C 1-6  haloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 7c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 7c ;  
 R 7a  and R 7a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 7e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 7e ;  
 R 7b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-2 R 7e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 7e ;  
 R 7c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 7f R 7f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r SC 1-4  alkyl, (CH 2 ) r C(O)OH, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7f R 7f , (CH 2 ) r NR 7f C(O)R 7a , (CH 2 ) r C(O)OC 1-14  alkyl, (CH 2 ) r OC(O)R 7b , (CH 2 ) r C(═NR 7f )NR 7f R 7f , (CH 2 ) r S(O) p R 7b , (CH 2 ) r NHC(═NR 7f )NR 7f R 7f , (CH 2 ) r S(O) 2 NR 7f R 7f , (CH 2 ) r NR 7f S(O) 2 R 7b , and (CH 2 ) r phenyl substituted with 0-3 R 7e ;  
 R 7d , at each occurrence, is selected from C 1-6  alkyl substituted with 0-3 R 7e , alkenyl, alkynyl, and a C 3-10  carbocyclic residue substituted with 0-3 R 7c ;  
 R 7e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;  
 R 7f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 8  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) t phenyl substituted with 0-3 R 8a ;  
 R 8a , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-15  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;  
 alternatively, R 7  and R 8  join to form C 3-7  cycloalkyl, or ═NR 8b ;  
 R 8b  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, OH, CN, and (CH 2 ) r -phenyl;  
 R 13 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, (CF 2 ) w CF 3 , (CH 2 ) r NR 13a R 13a′ , (CH 2 ) r OH, (CH 2 ) r OR 13b , (CH 2 ) r SH, (CH 2 ) r SR 13b , (CH 2 ) w C(O)OH, (CH 2 ) w C(O)R 13b , (CH 2 ) w C(O)NR 13a R 13a′ , (CH 2 ) r NR 13d C(O)R 13a , (CH 2 ) w C(O)OR 13b , (CH 2 ) r OC(O)R 13b , (CH 2 ) w S(O) 2 R 13b , (CH 2 ) w S(O) 2 NR 13a R 13a′ , (CH 2 ) r NR 13d S(O) 2 R 13b , and (CH 2 ) w -phenyl substituted with 0-3 R 13c ;  
 R 13a  and R 13a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;  
 R 13b , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;  
 R 13c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 13d R 13d ;  
 R 13d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;  
 R 14 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 14a R 14a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 14d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 14d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 14b , (CHR′) r C(O)NR 14a R 14a′ , (CHR′) r NR 14f C(O) (CHR′) r R 14b , (CHR′) r C(O)O(CHR′) r R 14d , (CHR′) r OC(O) (CHR′) r R 14b , (CHR′) r C(═NR 14f )NR 14a R 14a′ , (CHR′) r NHC(═NR 14f )NR 14f R 14f , (CHR′) r S(O) p (CHR′) r R 14b , (CHR′) r S(O) 2 NR 14a R 14a′ , (CHR′) r NR 14f S(O) 2 (CHR′) r R 14b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, (CHR′) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ; or two R 14  substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R 15e ;  
 R′, at each occurrence, is selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with R 14e ;  
 R 14a  and R 14a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 14e ;  
 R 14b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-3 R 14e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 14e ;  
 R 14d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 14e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 14e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 14e ;  
 R 14e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 14f R 14f , and (CH 2 ) r phenyl;  
 R 14f , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 alternatively, R 14  joins with R 4  to form a 5, 6 or 7 membered piperidinium spirocycle or pyrrolidinium spirocycle fused to ring A, the spirocycle substituted with 0-3 R a ;  
 R 15 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 15a R 15a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 15d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 15d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 15b , (CHR′) r C(O)NR 15a R 15a′ , (CHR′) r NR 15f C(O) (CHR′) r R 15b , (CHR′) r C(O)O(CHR′) r R 15d , (CHR′) r OC(O) (CHR′) r R 15b , (CHR′) r C(═NR 15f )NR 15a R 15a′ , (CHR′) r NHC(═NR 15f )NR 15f R 15f , (CHR′) r S(O) p (CHR′) r R 15b , (CHR′) r S(O) 2 NR 15a R 15a′ , (CHR′) r NR 15f S(O) 2 (CHR′) r R 15b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, (CHR′) r phenyl substituted with 0-3 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15a  and R 15a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15b  at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r —C 3-6  carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;  
 R 15d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 15e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 15e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15e ;  
 R 15e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 15f R 15f , and (CH 2 ) r phenyl;  
 R 15f , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl;  
 R 16 , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, NO 2 , CN, (CHR′) r NR 16a R 16a′ , (CHR′) r OH, (CHR′) r O(CHR′) r R 16d , (CHR′) r SH, (CHR′) r C(O)H, (CHR′) r S(CHR′) r R 16d , (CHR′) r C(O)OH, (CHR′) r C(O) (CHR′) r R 16b , (CHR′) r C(O)NR 16a R 16a′ , (CHR′) r NR 16f C(O) (CHR′) r R 16b , (CHR′) r C(O)O(CHR′) r R 16d , (CHR′) r OC(O) (CHR′) r R 16b , (CHR′) r C(═NR 16f )NR 16a R 16a′ , (CHR′) r NHC(═NR 16f )NR 16f R 16f , (CHR′) r S(O) p (CHR′) r R 16b , (CHR′) r S(O) 2 NR 16a R 16a′ , (CHR′) r NR 16f S(O) 2 (CHR′) r R 16b , C 1-6  haloalkyl, C 2-8  alkenyl substituted with 0-3 R′, C 2-8  alkynyl substituted with 0-3 R′, and (CHR′) r phenyl substituted with 0-3 R 16e ;  
 R 16a  and R 16a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a. (CH 2 ) r -C 3-10  carbocyclic residue substituted with 0-5 R 16e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 16e ;  
 R 16b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, a (CH 2 ) r C 3-6  carbocyclic residue substituted with 0-3 R 16e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 16e ;  
 R 16d , at each occurrence, is selected from C 2-8  alkenyl, C 2-8  alkynyl, C 1-6  alkyl substituted with 0-3 R 16e , a (CH 2 ) r —C 3-10  carbocyclic residue substituted with 0-3 R 16e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 16e ;  
 R 16e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl,  
 Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 16f R 16f , and (CH 2 ) r phenyl;  
 R 16f , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl, and phenyl;  
 g is selected from 0, 1, 2, 3, and 4;  
 t is selected from 1 and 2;  
 w is selected from 0 and 1;  
 r is selected from 0, 1, 2, 3, 4, and 5;  
 q is selected from 1, 2, 3, 4, and 5; and  
 p is selected from 0, 1, 2, and 3.  
 
     
     
         42 . The method of  claim 41 , wherein: 
 Z is selected from O and S;    R 4  is absent, taken with the nitrogen to which it is attached to form an N-oxide, or taken with the nitrogen to which it is attached to form a quaternary salt comprising a compound of formula (I) and a counterion and is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, and (CH 2 ) r -phenyl substituted with 0-3 R 4c ;    R 4c , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 4a R 4a′ , and (CH 2 ) r phenyl;    alternatively, R 4  joins with R 7 , R 9 , or R 14  to form a 5, 6 or 7 membered piperidinium spirocycle substituted with 0-3 R a ;    R 1  and R 2  are independently selected from H and C 1-4  alkyl;    R 6 , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CF 2 ) r CF 3 , CN, (CH 2 ) r OH, (CH 2 ) r OR 6b , (CH 2 ) r C(O)R 6b , (CH 2 ) r C(O)NR 6a R 6a′ , (CH 2 ) r NR 6d C(O)R 6a , and (CH 2 ) r phenyl substituted with 0-3 R 6c ;    R 6a  and R 6a′ , at each occurrence, are selected from H, C 1-6 alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;    R 6b , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 6c ;    R 6c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-15  alkyl, (CH 2 ) r OH, (CH 2 ) r SC 1-5  alkyl, and (CH 2 ) r NR 6d R 6d ;    R 6d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;    R 7 , is selected from H, C 1-3  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q OH, (CH 2 ) q OR 7d , (CH 2 ) q NR 7a R 7a′ , (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7a R 7a′ , (CH 2 ) q NR 7a C(O)R 7a , C 1-6  haloalkyl, (CH 2 ) r phenyl with 0-2 R 7c ;    R 7a  and R 7a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7c , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 7f R 7f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r C(O)R 7b , (CH 2 ) r C(O)NR 7f R 7f , (CH 2 ) r NR 7f C(O)R 7a , (CH 2 ) r S(O) p R 7b , (CH 2 ) r S(O) 2 NR 7f R 7f , (CH 2 ) r NR 7f S(O) 2 R 7b , and (CH 2 ) r phenyl substituted with 0-2 R 7e ;    R 7d , at each occurrence, is selected from C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 7e ;    R 7e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;    R 7f , at each occurrence, is selected from H, C 1-5  alkyl, and C 3-6  cycloalkyl;    R 8  is H or joins with R 7  to form C 3-7  cycloalkyl or ═NR 8b ;    R 11 , is selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) q OH, (CH 2 ) q OR 11d , (CH 2 ) q NR 11a R 11a′ , (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11a R 11a′ , (CH 2 ) q NR 11a C(O)R 11a , C 1-6  haloalkyl, (CH 2 ) r phenyl with 0-2 R 11c , (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;    R 11a  and R 11a′ , at each occurrence, are selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, a (CH 2 ) r phenyl substituted with 0-3 R 11e .    R 11b , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 11e ;    R 11c , at each occurrence, is selected from C 1-4  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, (CH 2 ) r C 3-6  cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , NO 2 , CN, (CH 2 ) r NR 11f R 11f , (CH 2 ) r OH, (CH 2 ) r OC 1-4  alkyl, (CH 2 ) r C(O)R 11b , (CH 2 ) r C(O)NR 11f R 11f , (CH 2 ) r NR 11f C(O)R 11a , (CH 2 ) r S(O) p R 11b , (CH 2 ) r S(O) 2 NR 11f R 11f , (CH 2 ) r NR 11f S(O) 2 R 11b , and (CH 2 ) r phenyl substituted with 0-2 R 11e ;    R 11d , at each occurrence, is selected from C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, (CH 2 ) r phenyl substituted with 0-3 R 11e ;    R 11e , at each occurrence, is selected from C 1-6  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, OH, SH, (CH 2 ) r SC 1-5  alkyl, (CH 2 ) r NR 11f R 11f , and (CH 2 ) r phenyl;    R 11f , at each occurrence, is selected from H, C 1-5  alkyl and C 3-6  cycloalkyl;    R 12  is H or joins with R 11  to form C 3-7  cycloalkyl;    R 13 , at each occurrence, is selected from C 1-4  alkyl, C 3-6  cycloalkyl, (CH 2 )NR 13a R 13a′ , (CH 2 )OH, (CH 2 )OR 13b , (CH 2 ) w C(O)R 13b , (CH 2 ) w C(O)NR 13a R 13a′ , (CH 2 )NR 13d C(O)R 13a , (CH 2 ) w S(O) 2 NR 13a R 13a′ , (CH 2 )NR 13d S(O) 2 R 13b , and (CH 2 ) w -phenyl substituted with 0-3 R 13c ;    R 13a  and R 13a , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;    R 13b , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, and phenyl substituted with 0-3 R 13c ;    R 13c , at each occurrence, is selected from C 1-6  alkyl, C 3-6  cycloalkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC 1-5  alkyl, (CH 2 ) r OH, and (CH 2 ) r NR 13d R 13d ;    R 13d , at each occurrence, is selected from H, C 1-6  alkyl, and C 3-6  cycloalkyl;    q is selected from 1, 2, and 3; and    r is selected from 0, 1, 2, and 3.    
     
     
         43 . The method of  claim 42 , wherein: 
 ring A is selected from:                          R 3  is selected from a (CR 3′ H) r -carbocyclic residue substituted with 0-5 R 15 , wherein the carbocyclic residue is selected from phenyl, C 3-6  cycloalkyl, naphthyl, and adamantyl; and a (CR 3′ H) r -heterocyclic system substituted with 0-3 R 15 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 5  is selected from (CR 5′ H) t -phenyl substituted with 0-5 R 16 ; and a (CR 5′ H) t -heterocyclic system substituted with 0-3 R 16 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.    
     
     
         44 . The method of  claim 43 , wherein the compound of formula (I) is:  
       
         
           
           
               
               
           
         
         R 16 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 16a R 16a′ , NO 2 , CN, OH, (CH 2 ) r OR 16d , (CH 2 ) r C(O)R 16b , (CH 2 ) r C(O)NR 16a R 16a′ , (CH 2 ) r NR 16f C(O)R 16b , (CH 2 ) r S(O) p R 16b , (CH 2 ) r S(O) 2 NR 16a R 16a′ , (CH 2 ) r NR 16f S(O) 2 R 16b , and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16a  and R 16a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 16e ;  
         R 16d , at each occurrence, is selected from C 1-6  alkyl and phenyl;  
         R 16e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl; and  
         R 16f , at each occurrence, is selected from H, and C 1-5  alkyl.  
       
     
     
         45 . The method of  claim 44 , wherein: 
 R 5  is CH 2 phenyl substituted with 0-3 R 16 ;    R 9 , is selected from H, C 1-6  alkyl, (CH 2 ) r C 3-6  cycloalkyl, F, Cl, CN, (CH 2 ) r OH, (CH 2 ) r OR 9d , (CH 2 ) r NR 9a R 9a′ , (CH 2 ) r OC(O)NHR 9a , (CH 2 ) r phenyl substituted with 0-5 R 9e , and a heterocyclic system substituted with 0-2 R 9e , wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;    R 9a  and R 9a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 9e ;    R 9d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 9e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl;    R 10  is selected from H, C 1-5  alkyl, OH, and CH 2 OH;    alternatively, R 9  and R 10  join to form C 3-7  cycloalkyl, 5-6-membered cyclic ketal or ═O;    with the proviso that when R 10  is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, R 9  is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;    R 11  is selected from H, C 1-8  alkyl, (CH 2 ) r phenyl substituted with 0-5 R 11e , and a (CH 2 ) r -heterocyclic system substituted with 0-2 R 11e , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 11e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl;    R 12  is H;    alternatively, R 11  and R 12  join to form C 3-7  cycloalkyl;    R 14 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 14a R 14a′ , NO 2 , CN, OH, (CH 2 ) r OR 14d , (CH 2 ) r C(O)R 14b , (CH 2 ) r C(O)NR 14a R 14a′ , (CH 2 ) r NR 14f C(O)R 14b , (CH 2 ) r S(O) p R 14b , (CH 2 ) r S(O) 2 NR 14a R 14a′ , (CH 2 ) r NR 14f S(O) 2 R 14b  (CH 2 ) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ; or two R 14  substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R 15e ;    R 14a  and R 14a′ , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;    R 14b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14e ;    R 14d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 14e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl; and    R 14f , at each occurrence, is selected from H, and C 1-5  alkyl; and    r is selected from 0, 1, and 2.    
     
     
         46 . The method of  claim 45 , wherein: 
 J is selected from CH 2  and CHR 5 ;    L is selected from CH 2  and CHR 5 ;    R 3  is a C 3-10  carbocyclic residue substituted with 0-3 R 15 , wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR 3′ H) r -heterocyclic system substituted with 0-3 R 15 , wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and    R 15 , at each occurrence, is selected from C 1-8  alkyl, (CH 2 ) r C 3-6  cycloalkyl, CF 3 , Cl, Br, I, F, (CH 2 ) r NR 15a R 15a , NO 2 , CN, OH, (CH 2 ) r OR 15d , (CH 2 ) r C(O)R 15b , (CH 2 ) r C(O)NR 15a R 15a′ , (CH 2 ) r NR 15f C(O)R 15b , (CH 2 ) r S(O) p R 15b , (CH 2 ) r S(O) 2 NR 15a R 15a′ , (CH 2 ) r NR 15f S(O) 2 R 15b  (CH 2 ) r phenyl substituted with 0-3 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;    R 15a  and R 15a , at each occurrence, are selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 15e ;    R 15b , at each occurrence, is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 15e ;    R 15d , at each occurrence, is selected from C 1-6  alkyl and phenyl;    R 15e , at each occurrence, is selected from C 1-6  alkyl, Cl, F, Br, I, CN, NO 2 , (CF 2 ) r CF 3 , OH, and (CH 2 ) r OC 1-5  alkyl; and    R 15f , at each occurrence, is selected from H, and C 1-5  alkyl.