Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them

Abstract

The present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them. The present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the Formula (1), their analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, appropriate N-oxide, pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.

1 - 80 . (canceled) 
   
   
       81 . A method for the preparation of a compound of Formula (1) 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently selected for each occurrence from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , S(O) q —NR a R a , —NR a R a , —OR a , and —SR a , or when two R 3  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 R 4  is —NR 5 R 6 , with the proviso that R 4  is not NH 2 ; 
 R 5  and R 6  may be the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, halogen, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —C(═NR a )—R a , —C(═NR a )—NR a R a , —C(═S)—NR a R a , —C(═S)—R a , —N═C(R a R a ), —NR a R a , —OR a , —SR a , and a protecting group or when R 5  and R 6  are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered cyclic ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring; 
 X is O or S(O) q ; 
 Y is —C(O)NR 7 ; 
 R 7  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR a , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring; 
 P is selected from the group consisting of O and S; 
 m is 0-3; 
 n is 1-4; 
 q is 0, 1 or 2; 
 R a  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , —OR a  and —SR a ; 
 
     or an analog thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a pharmaceutically acceptable solvate thereof, the method comprising the steps of:
 a) reacting a compound of Formula (10) with a compound of Formula (11) in the presence of a base 
 
     
       
         
         
             
             
         
       
     
     wherein Z is a halogen and W is a halogen, to obtain an intermediate of Formula (12);
 b) cyclizing the intermediate of Formula (12) to form a tricyclic intermediate of Formula (13) 
 
     
       
         
         
             
             
         
       
       c) oxidizing the tricyclic intermediate of Formula (13) to form an intermediate of Formula (14) 
     
     
       
         
         
             
             
         
       
       d) activating the carboxylic acid group of the intermediate of formula (14) and reacting the activated carboxylic acid with an optionally substituted aryl or heteroaryl amine (ArNHR 7 ) under basic conditions to form the intermediate of formula (15), wherein Y is —CONR 7   
     
     
       
         
         
             
             
         
       
       e) reducing the intermediate of Formula (15) to the intermediate of Formula (16) 
     
     
       
         
         
             
             
         
       
       f) converting the intermediate of Formula (16) to the desired compound of Formula (1) wherein Y is —CONR 7  and R 4  is —NR 5 R 6   
     
     
       
         
         
             
             
         
       
       g) optionally converting the compound of Formula (I) into a corresponding salt and/or N-oxide. 
     
   
   
       82 . A method for the preparation of a compound of Formula (1) 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently selected for each occurrence from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , —OR a , and —SR a , or when two R 3  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 R 4  is —NR 5 R 6 , with the proviso that R 4  is not NH 2 ; 
 R 5  and R 6  may be the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, halogen, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , S(O) q —R a , —S(O) q —NR a R a , —C(═NR a )—R a , —C(═NR a )—NR a R a , —C(═S)—NR a R a , —C(═S)—R a , —N═C(R a R a ), —NR a R a , —OR a , —SR a , and a protecting group or when R 5  and R 6  are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered cyclic ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring; 
 X is O or S(O) q ; 
 Y is —C(O)NR 7 ; 
 R 7  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR a , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring; 
 P is selected from the group consisting of O and S; 
 m is 0-3; 
 n is 1-4; 
 q is 0, 1 or 2; 
 R a  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , —OR a  and —SR a ; 
 
     or an analog thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a pharmaceutically acceptable solvate thereof, the method comprising the steps of:
 a) reacting a compound of Formula (17) with a compound of Formula (18) in the presence of a base 
 
     
       
         
         
             
             
         
       
     
     wherein Z is a halogen, W is a halogen, and FG is chosen from the group consisting of CHO, COCH 3 , CN, and COOR a , under basic conditions to obtain the intermediate of Formula (19) 
     
       
         
         
             
             
         
       
       b) cyclizing the intermediate of Formula (19) to form a tricyclic intermediate of Formula (20) 
     
     
       
         
         
             
             
         
       
       c) oxidizing the tricyclic intermediate of Formula (20) if FG is CHO or COCH 3 , or hydrolysing the intermediate of Formula (20) if FG is CN or COOR a , to form the intermediate of Formula (14) 
     
     
       
         
         
             
             
         
       
       d) activating the carboxylic acid group of the intermediate of formula (14) and reacting the activated carboxylic acid with an optionally substituted aryl or heteroaryl amine (ArNHR 7 ) under basic conditions to form the intermediate of formula (15), wherein Y is —CONR 7   
     
     
       
         
         
             
             
         
       
       e) reducing the intermediate of Formula (15) to the intermediate of Formula (16) 
     
     
       
         
         
             
             
         
       
       f) converting the intermediate of Formula (16) to the desired compound of Formula (1) wherein Y is —CONR 7  and R 4  is —NR 5 R 6   
     
     
       
         
         
             
             
         
       
       g) optionally converting the compound of Formula (I) into a corresponding salt and/or N-oxide. 
     
   
   
       83 . A method for the preparation of a compound of Formula (1) 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently selected for each occurrence from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , —OR a , and —SR a , or when two R 3  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 R 4  is —NR 5 R 6 , with the proviso that R 4  is not NH 2 ; 
 R 5  and R 6  may be the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, halogen, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , S(O) q —R a , —S(O) q —NR a R a , —C(═NR a )—R a , —C(═NR a )—NR a R a , —C(═S)—NR a R a , —C(═S)—R a , —N═C(R a R a ), —NR a R a , —OR a , —SR a , and a protecting group or when R 5  and R 6  are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered cyclic ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring; 
 X is O or S(O) q ; 
 Y is C(O)NR 7 ; 
 R 7  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR a , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring; 
 P is selected from the group consisting of O and S; 
 m is 0-3; 
 n is 1-4; 
 q is 0, 1 or 2; 
 R a  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , OR a  and —SR a ; 
 
     or an analog thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a pharmaceutically acceptable solvate thereof, the method comprising the steps of:
 a) reacting a compound of Formula (21) with a compound of Formula (22) in the presence of a base 
 
     
       
         
         
             
             
         
       
     
     wherein Z is a halogen, to obtain the intermediate of Formula (23) 
     
       
         
         
             
             
         
       
       b) reducing the intermediate of Formula (23) to form the intermediate of Formula (24) 
     
     
       
         
         
             
             
         
       
       c) cyclizing the intermediate of Formula (24) to form a tricyclic intermediate of Formula (25) 
     
     
       
         
         
             
             
         
       
       d) converting the acetyl group of the tricyclic intermediate of Formula (25) to an acetamido group to obtain the intermediate of Formula (26) 
     
     
       
         
         
             
             
         
       
       e) formulating the intermediate of Formula (26) to obtain the intermediate of Formula (27) 
     
     
       
         
         
             
             
         
       
       f) oxidizing the intermediate of Formula (27) to form the intermediate of Formula (28) 
     
     
       
         
         
             
             
         
       
       g) activating the carboxylic acid group of the intermediate of formula (28) and reacting the activated carboxylic acid with an optionally substituted aryl or heteroaryl amine (ArNHR 7 ) to form a compound of formula (I), wherein R 4  is —NHC(O)CH 3 ; 
       h) optionally converting the —NHC(O)CH 3  group to a group of the formula —NR 5 R 6 ; and 
       i) optionally converting the compound formed in step (g) or (h) into a corresponding salt and/or N-oxide. 
     
   
   
       84 . The method according to  claim 81 , wherein R 1  is substituted or unsubstituted alkyl. 
   
   
       85 . The method according to  claim 81 , wherein R 1  is —CHF 2 . 
   
   
       86 . The method according to  claim 81 , wherein P is O. 
   
   
       87 . The method according to  claim 81 , wherein X═O. 
   
   
       88 . The method according to  claim 81 , wherein Ar is selected from the group consisting of substituted or unsubstituted 4-pyridyl, substituted or unsubstituted 4-pyridyl-N-oxide, or substituted or unsubstituted 3-pyridyl. 
   
   
       89 . The method according to  claim 81 , wherein Ar is 
     
       
         
         
             
             
         
       
     
   
   
       90 . The method according to  claim 81 , wherein R 4  is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
   
   
       91 . The method according to  claim 81 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt thereof. 
   
   
       92 . The method according to  claim 81 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide sodium salt. 
   
   
       93 . The method according to  claim 81 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide monosodium salt. 
   
   
       94 . The method according to  claim 81 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxide or a pharmaceutically acceptable salt thereof. 
   
   
       95 . The method according to  claim 82 , wherein R 1  is substituted or unsubstituted alkyl. 
   
   
       96 . The method according to  claim 82 , wherein R 1  is —CHF 2 . 
   
   
       97 . The method according to  claim 82 , wherein P is O. 
   
   
       98 . The method according to  claim 82 , wherein X═O. 
   
   
       99 . The method according to  claim 82 , wherein Ar is selected from the group consisting of substituted or unsubstituted 4-pyridyl, substituted or unsubstituted 4-pyridyl-N-oxide, or substituted or unsubstituted 3-pyridyl. 
   
   
       100 . The method according to  claim 82 , wherein Ar is 
     
       
         
         
             
             
         
       
     
   
   
       101 . The method according to  claim 82 , wherein R 4  is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
   
   
       102 . The method according to  claim 82 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt thereof. 
   
   
       103 . The method according to  claim 82 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide sodium salt. 
   
   
       104 . The method according to  claim 82 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide monosodium salt. 
   
   
       105 . The method according to  claim 82 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxide or a pharmaceutically acceptable salt thereof. 
   
   
       106 . The method according to  claim 83 , wherein R 1  is substituted or unsubstituted alkyl. 
   
   
       107 . The method according to  claim 83 , wherein R 1  is —CHF 2 . 
   
   
       108 . The method according to  claim 83 , wherein P is O. 
   
   
       109 . The method according to  claim 83 , wherein X═O. 
   
   
       110 . The method according to  claim 83 , wherein Ar is selected from the group consisting of substituted or unsubstituted 4-pyridyl, substituted or unsubstituted 4-pyridyl-N-oxide, or substituted or unsubstituted 3-pyridyl. 
   
   
       111 . The method according to  claim 83 , wherein Ar is 
     
       
         
         
             
             
         
       
     
   
   
       112 . The method according to  claim 83 , wherein R 4  is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
   
   
       113 . The method according to  claim 83 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceutically acceptable salt thereof. 
   
   
       114 . The method according to  claim 83 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide sodium salt. 
   
   
       115 . The method according to  claim 83 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide monosodium salt. 
   
   
       116 . The method according to  claim 83 , wherein the compound of Formula (1) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxide or a pharmaceutically acceptable salt thereof. 
   
   
       117 . A method for the preparation of a compound of Formula (1) 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1 , R 2  and R 3  may be the same or different and are independently selected for each occurrence from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , NR a R a , OR a , and SR a  or when two R 3  substitutents are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 R 4  is —NR 5 R 6 , with the proviso that R 4  is not NH 2 ; 
 R 5  and R 6  may be the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, halogen, —C(O)—R a , —C(O)O—R a , C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —C(═NR a )—R a , —C(═NR a )—NR a R a , —C(═S)—NR a R a , —C(═S)—R a , —N═C(R a R a ), —NR a R a , —OR a , —SR a , and a protecting group or when R 5  and R 6  are ortho to each other, they may be joined to a form a saturated or unsaturated 3-7 membered cyclic ring, which may optionally include up to two heteroatoms which may be the same or different selected from O, NR a  or S; 
 Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring; 
 X is O or S(O) q ; 
 Y is —C(O)NR 7 ; 
 R 7  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR a , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring; 
 P is selected from the group consisting of O and S; 
 m is 0-3; 
 n is 1-4; 
 q is 0, 1 or 2; 
 R a  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, —OH, cyano, formyl, acetyl, halogen, a protecting group, —C(O)—R a , —C(O)O—R a , —C(O)NR a R a , —S(O) q —R a , —S(O) q —NR a R a , —NR a R a , —OR a  and —SR a ; 
 or an analog thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a pharmaceutically acceptable solvate thereof, the method comprising the step of: 
 converting a compound of 
 
     
       
         
         
             
             
         
       
     
     (wherein FG is chosen from the group consisting of CHO, COCH 3 , CN, and COOR a ); 
     
       
         
         
             
             
         
       
     
     (wherein FG is chosen from the group consisting of CHO, COCH 3 , CN, and COOR a ); 
     
       
         
         
             
             
         
       
     
     to the compound of Formula (1).