Benzimidazole and Pyridylimidazole Derivatives

Abstract

This invention relates to benzimidazoles, pyridylimidazoles and related bicyclic heteroaryl compounds, all of which may be described by of Formula I The invention is particularly related to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABA A receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. Novel processes for preparing compounds of Formula I are disclosed. This invention also relates to the use of benzimidazoles, pyridylimidazoles and related bicyclic heteroaryl compounds of Formula I in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABA A receptors in tissue sections.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z 1  is nitrogen or CR 1 ; 
         Z 2  is nitrogen or CR 2 ; 
         Z 3  is nitrogen or CR 3 ; 
         Z 4  is nitrogen or CR 4 ; 
       
       provided that no more than two of Z 1 , Z 2 , Z 3 , and Z 4  are nitrogen;
 R 1 , R 2 , R 3 , and R 4  are independently selected from 
 i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy, 
 ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R 10 ), -N(R 10 )(R 11 ) hydroxyalkyl, aminoalkyl, (R 10 )NHalkyl-, (R 10 )(R 11 )Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R 20 ,
 wherein R 10  and R 11  are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and 
 
 iii) a group of the formula: 
 
       
         
           
           
               
               
           
         
         where G is a bond, alkyl, —O—, —C(O)—, or —CH 2 C(═O)—, and 
         R A  is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R 20 , 
         iv) a group of the formula 
       
       
         
           
           
               
               
           
         
         where J is N, CH, or C-alkyl, and 
         R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; 
         R B  and R C  and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
 a) one or more double bonds, 
 b) one or more of oxo, O, S, SO, SO 2 , or N—R D  wherein R D  is hydrogen, Ar 1 , alkyl, cycloalkyl, heterocycloalkyl, or Ar 1 alkyl; wherein Ar 1  is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, and/or 
 c) one or more substituents R 20 ; 
 
         v) —OC(═O)R E , —C(═O)OR E , —C(═O)NH 2 , —C(═O)NHR E , —C(═O)NR E R F , S(O) n R E , —S(O) n NH 2 , —S(O) n NHR E , —S(O) n NR E R F , —NHC(═O)R E , —C(═NR E )R F , —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NR E C(═O)R F , NHS(O) m R E , and —NR E S(O) m R F , where m is 0, 1 or 2, and
 R E  and R F  are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R 20 ; 
 R 20  is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl; 
 R 30  is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; 
 
         R 5  represents hydrogen or haloalkyl; or 
         R 5  represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R 30 , or 
         R 5  represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R 10 ), —N(R 10 )(R 11 ), carboxamido, (R 10 )NHcarbonyl, (R 10 )(R 11 )Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl;
 Q represents —C(R 6 )(R 7 ) or oxygen, 
 with the proviso that Q is not oxygen when X 2  is nitrogen; 
 R 5  and R 7  independently represent hydrogen, fluorine, or alkyl; 
 the group: 
 
       
       
         
           
           
               
               
           
         
         represents a 5 to 7 membered heteroaryl or heterocycloalkyl ring containing up to 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, said 5 to 7 membered heteroaryl or heterocycloalkyl ring is substituted at each carbon atom by R, and substituted at each nitrogen atom available for substitution by R′, wherein
 R is independently chosen at each occurrence from hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy; 
 R′ is independently chosen at each occurrence from alkyl, hydrogen, cycloalkyl, cycloalkyl(alkyl), and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which 3- to 7-membered carbocyclic or heterocyclic groups are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy; 
 X 1  and X 2  independently represent nitrogen, carbon or CH; 
 Y is nitrogen, oxygen, carbon, —CH—, —CH 2 —, or absent; and 
 
         W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R 30 , —CO 2 H, —C(═O)OR E , C(═O)NHR E , —C(═O)NR E R F , —C(O)R E , and —S(O) m R E , —OR E , where R 30  and R E  are as defined above and m is 0, 1, or 2. 
       
     
     
         2 - 164 . (canceled) 
     
     
         165 . A pharmaceutical composition comprising a compound or salt according to  claim 1  combined with at least one pharmaceutically acceptable carrier or excipient. 
     
     
         166 . A method for altering the signal-transducing activity of a GABA A  receptor, said method comprising contacting a cell expressing such a receptor with an amount of a compound or salt according to  claim 1  sufficient to detectably alter the electrophysiology of the cell, wherein a detectable alteration of the electrophysiology of the cell indicates an alteration of the signal-transducing activity of GABA A  receptors. 
     
     
         167 . A method for altering the signal-transducing activity of a GABA A  receptor, said method comprising contacting a cell expressing such receptors with an amount of a compound or salt according to  claim 1  to detectably alter the chloride conductance in vitro of cell expressing GABA A  receptors. 
     
     
         168 . The method of  claim 167  wherein the cell is recombinantly expresses a heterologous GABA A  receptor and the alteration of the electrophysiology of the cell is detected by intracellular recording or patch clamp recording. 
     
     
         169 . The method of  claim 167  wherein the cell is a neuronal cell that is contacted in vivo in an animal, the cell is contacted with the compound or salt dissolved in a body fluid, and the alteration in the electrophysiology of the cell is detected as a change in the animal's behavior. 
     
     
         170 . (canceled) 
     
     
         171 . A method for altering the signal-transducing activity of a GABA A  receptor, the method comprising exposing a cell expressing the GABA A  receptor to an amount of a compound or salt according to  claim 1  sufficient to inhibit RO15-1788 binding in vitro to cells expressing a human GABA A  receptor. 
     
     
         172 . A method for the treatment of anxiety, depression, a sleep disorder, schizophrenia, attention deficit-hyperactivity disorder, or for the enhancement of memory, comprising administering an effective amount of a compound or salt of  claim 1  to a patient. 
     
     
         173 . A method for demonstrating the presence of a GABA A  receptor in a cell or tissue sample, said method comprising:
 contacting a cell or tissue sample with a labeled compound or salt according to  claim 1 ;   washing the cell or tissue sample to remove unbound labeled compound or salt; and   detecting the presence of labeled compound or salt in the cell or tissue sample.   
     
     
         174 . The method of  claim 173  in which the cell or tissue sample is a tissue section. 
     
     
         175 . The method of  claim 173  in which the labeled compound or salt contains a radioactive label or a directly or indirectly luminescent label. 
     
     
         176 . The method of  claim 173  in which the cell or tissue sample is a tissue section, labeled compound or salt contains a radioactive label or a directly or indirectly luminescent label, and the labeled compound or salt is detected autoradiographically to generate an autoradiogram. 
     
     
         177 . A method for demonstrating the presence of a GABA A  receptor in a tissue section comprising:
 contacting the tissue section with a radiolabeled or luminescently labeled compound or salt according to  claim 1  to yield a contacted tissue section;   washing the tissue section to remove unbound labeled compound or salt;   detecting the labeled compound or salt in the tissue section; and   comparing the exposure density of the tissue section with the exposure density of a second tissue section that has not been contacted with a compound or salt according to  claim 1 .   
     
     
         178 - 182 . (canceled) 
     
     
         183 . A process for preparing a compound of  claim 1 , where the compound of  claim 1  has the formula 
       
         
           
           
               
               
           
         
         comprising reacting a compound of Formula B 
       
       
         
           
           
               
               
           
         
         with a compound of Formula C 
       
       
         
           
           
               
               
           
         
         wherein: 
         Z 1  is nitrogen or CR 2 ; 
         Z 2  is nitrogen or CR 2 ; 
         Z 3  is nitrogen or CR 3 ; 
         Z 4  is nitrogen or CR 4 ; 
         provided that no more than two of Z 2 , Z 2 , Z 3 , and Z 4  are nitrogen; 
         R 2 , R 2 , R 3 , and R 4  are independently selected from 
         i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy, 
         ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R 10 ), —N(R 10 )(R 11 ), hydroxyalkyl, aminoalkyl, (R 10 )NHalkyl, (R 10 )(R 11 )Nalkyl, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R 20 ,
 wherein R 10  and R 11  are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and 
 
         iii) a group of the formula: 
       
       
         
           
           
               
               
           
         
         where G is a bond, alkyl, —O—, —C(═O)—, or —CH 2 C(═O)—, and 
         R A  is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R 20 , and 
         iv) a group of the formula 
       
       
         
           
           
               
               
           
         
         where J is N, CH, or C-alkyl, and 
         R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; 
         R B  and R C  and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
 a) one or more double bonds, 
 b) one or more of oxo, O, S, SO, SO 2 , or N—R D  wherein R D  is hydrogen, Ar 1 , alkyl, cycloalkyl, heterocycloalkyl, or Ar 1 alkyl; wherein Ar 1  is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, and/or 
 c) one or more substituents R 20 ; 
 
         v) —OC(═O)R E , —C(═O)OR E , —C(═O)NH 2 , —C(═O)NHR E , —C(═O)NR E R F , S(O) n R E , —S(O) n NH 2 , —S(O) n NHR E , —S(O) n NR E R F , —NHC(═O)R E , —C(═NR E )R F , —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NR E C(═O)R F , —NHS(O) m R E , and —NR E S(O) m R F , where m is 0, 1 or 2, and
 R E  and R F  are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R 30 ; 
 R 20  is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl; 
 R 30  is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; 
 
         R 5  represents hydrogen or haloalkyl; or 
         R 5  represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R 30 , or 
         R 5  represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R 10 ), —N(R 10 )(R 11 ), carboxamido, (R 10 )NHcarbonyl, (R 10 )(R 11 )Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl;
 R 6  and R 7  independently represent hydrogen, fluorine, or alkyl; 
 
         R is independently chosen at each occurrence from hydrogen, halogen, amino, C 2 -C 6 alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C 2 -C 6 alkoxy, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 cycloalkyl)(C 1 -C 4 )alkyl, halo(C 2 -C 6 )alkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C 2-4 alkyl, and —O(C 2-4 alkyl); and 
         W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R 30 , —CO 2 H, —C(═O)OR E , —C(═O)NHR E , —C(═O)NR E R F , —C(O)R E , and —S(O) m R E , —OR E , where R 30  and R E  are as defined above and m is 0, 1, or 2. 
       
     
     
         184 - 210 . (canceled) 
     
     
         211 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         Hal represents a halogen; and 
         Z 2  is nitrogen or CR 1 ; 
         Z 2  is nitrogen or CR 2 ; 
         Z 3  is nitrogen or CR 3 ; 
         Z 4  is nitrogen or CR 4 ; 
         provided that no more than two of Z 1 , Z 2 , Z 3 , and Z 4  are nitrogen; 
         R 1 , R 2 , R 3 , and R 4  are independently selected from
 i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy, 
 ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R 10 ), —N(R 10 )(R 11 ), hydroxyalkyl, aminoalkyl, (R 10 )NHalkyl-, (R 10 )(R 11 )Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R 20 ,
 wherein R 10  and R 11  are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and 
 
 iii) a group of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             where G is a bond, alkyl, —O—, —C(═O)—, or —CH 2 C(═O)—, and 
             R A  is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R 20 , 
           
         
         iv) a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where J is N, CH, or C-alkyl, and 
           R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, 
           each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; 
           R B  and R C  and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
 a) one or more double bonds, 
 b) one or more of oxo, O, S, SO, SO 2 , or N—R D  wherein R D  is hydrogen, Ar 1 , alkyl, cycloalkyl, heterocycloalkyl, or Ar 1 alkyl; wherein Ar 1  is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, and/or 
 c) one or more substituents R 20 ; 
 
           v) —OC(═O)R E , —C(═O)OR E , —C(═O)NH 2 , —C(═O)NHR E , —C(═O)NR E R F , —S(O) n R E , —S(O) n NH 2 , —S(O) n NHR E , —S(O) n NR E R F , —NHC(═O)R E , —C(═NR E )R F , —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NR E C(═O)R F , —NHS(O) m R E , and —NR E S(O) m R F , where m is 0, 1 or 2, and
 R E  and R F  are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R 30 ; 
 
         
         R 20  is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl; 
         R 30  is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; and 
         R 5  represents hydrogen or haloalkyl; or 
         R 5  represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R 30 , or 
         R 5  represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R 10 ), —N(R 10 )(R 11 ), carboxamido, (R 10 )NHcarbonyl, (R 10 )(R 11 )Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl. 
       
     
     
         212 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         PROT represents a nitrogen protecting group; and 
         Z 1  is nitrogen or CR 2 ; 
         Z 2  is nitrogen or CR 2 ; 
         Z 3  is nitrogen or CR 3 ; 
         Z 4  is nitrogen or CR 4 ; 
         provided that no more than two of Z 1 , Z 2 , Z 3 , and Z 4  are nitrogen; 
         R 1 , R 2 , R 3 , and R 4  are independently selected from
 i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy, 
 ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R 10 ), —N(R 10 )(R 11 ), hydroxyalkyl, aminoalkyl, (R 10 )NHalkyl-, (R 10 )(R 11 )Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R 20 ,
 wherein R 10  and R 11  are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and 
 
 iii) a group of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             where G is a bond, alkyl, —O—, —C(═O)—, or —CH 2 C(═O)—, and 
             R A  is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R 20 , 
           
           iv) a group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           
             where J is N, CH, or C-alkyl, and 
             R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, 
             each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; 
           
           R B  and R C  and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
 a) one or more double bonds, 
 b) one or more of oxo, O, S, SO, SO 2 , or N—R D  wherein R D  is hydrogen, Ar 1  alkyl, cycloalkyl, heterocycloalkyl, or Ar 1 alkyl; wherein Ar 1  is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, and/or 
 c) one or more substituents R 20 ; 
 
           v) —OC(═O)R E , —C(═O)OR E , —C(═O)NH 2 , —C(═O)NHR E , —C(═O)NR E R F , —S(O) n R E , —S(O) n NH 2 , —S(O) n NHR E , —S(O) n NR E R F , —NHC(═O)R E , —C(═NR E )R F , —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NR E C(═O)R F , —NHS(O) m R E , and —NR E S(O) m R F , where m is 0, 1 or 2, and
 R E  and R F  are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R 30 ; 
 
         
         R 20  is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl; 
         R 30  is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; and 
         R 5  represents hydrogen or haloalkyl; or 
         R 5  represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R 30 , or 
         R 5  represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R 10 ), —N(R 10 )(R 11 ), carboxamido, (R 10 )NHcarbonyl, (R 10 )(R 11 )Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl. 
       
     
     
         213 . A compound according to  claim 212  wherein PROT is butoxycarbonyl. 
     
     
         214 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R H  represents a halogen or hydrogen; 
         Z 1  is nitrogen or CR 1 ; 
         Z 2  is nitrogen or CR 2 ; 
         Z 3  is nitrogen or CR 3 ; 
         Z 4  is nitrogen or CR 4 ; 
         provided that no more than two of Z 1 , Z 2 , Z 3 , and Z 4  are nitrogen; 
         R 1 , R 2 , R 3 , and R 4  are independently selected from
 i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy, 
 ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R 10 ), —N(R 10 )(R 11 ), hydroxyalkyl, aminoalkyl, (R 10 )NHalkyl-, (R 10 )(R n )Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R 20 ,
 wherein R 10  and R 11  are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and 
 
 iii) a group of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             where G is a bond, alkyl, —O—, —C(═O)—, or —CH 2 C(═O)—, and 
             R A  is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R 20 , 
           
           iv) a group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           
             where J is N, CH, or C-alkyl, and 
             R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, 
             each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; 
           
           R E , and R c  and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
 a) one or more double bonds, 
 b) one or more of oxo, O, S, SO, SO 2 , or N—R D  wherein R D  is hydrogen, Ar 1 , alkyl, cycloalkyl, heterocycloalkyl, or Ar 1 alkyl; wherein Ar 1  is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, and/or 
 c) one or more substituents R 20 ; 
 
           v) —OC(═O)R E , —C(═O)OR E , —C(═O)NH 2 , —C(═O)NHR E , —C(═O)NR E R F , —S(O) n R E , —S(O) n NH 2 , —S(O) n NHR E , —S(O) n NR E R F , —NHC(═O)R E , —C(═NR E )R F , —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NR E C(═O)R F , —NHS(O) m R E , and —NR E S(O) m R F , where m is 0, 1 or 2, and
 R E  and R F  are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R 30 ; 
 
         
         R 20  is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl; 
         R 30  is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; 
         R 5  represents hydrogen or haloalkyl; or 
         R 5  represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R 30 , or 
         R 5  represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R 10 ), —N(R 10 )(R 11 ), carboxamido, (R 10 )NHcarbonyl, (R 10 )(R 11 )Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl; and 
         W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R 30 , —CO 2 H, —C(═O)OR E , —C(═O)NHR E , —C(═O)NR E R F , —C(O)R E , and —S(O) m R E , —OR E , where R 30  and R E  are as defined above; and m is 0, 1, or 2. 
       
     
     
         215 . A compound according to  claim 214  wherein R H  is hydrogen. 
     
     
         216 . A compound according to  claim 214  wherein R H  is halogen.