Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

1 . A compound of Formula III having the following structure: 
       
         
           
           
               
               
           
         
       
       all salts, prodrugs, tautomers, and isomers thereof,
 wherein: 
 Q has a structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         in which 
       
       
         
           
           
               
               
           
         
       
       indicates the attachment point of Q to A of Formula III;
 Z 2  is N or CR 12 ; 
 Z 4  is N or CR 14 ; 
 Z 5  is N or CR 15 ; 
 Z 6  is N or CR 16 ; 
 L 2  is selected from the group consisting of —(CR 10 R 11 ) p —NR 25 —(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —O—(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —S—(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —C(O)—(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —C(S)—(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —S(O)—(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —S(O) 2 —(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —C(O)NR 25 —(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —C(S)NR 25 —(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —S(O) 2 NR 25 —(CR 10 R 11 ) q —, —(CR 10 R 11 ) p —NR 25 C(O)—(CR 10 R 11 ) q — —(CR 10 R 11 ) p —NR 25 C(S)—(CR 10 R 11 ) q —, and —(CR 10 R 11 ) p —NR 25 S(O) 2 —(CR 10 R 11 ) q —; 
 p and q are independently 0, 1, or 2 provided, however, that at least one of p and q is 0; 
 s is 1 or 2; 
 X is O or S; 
 A is selected from the group consisting of —O—, —S—, —CR a R b —, —NR 1 —, —C(O)—, —C(S)—, —S(O)—, and —S(O) 2 —;
 R a  and R b  at each occurrence are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro; or 
 R a  and R b  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 1  is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)R 7 , —C(S)R 7 , —S(O) 2 R 7 , —C(O)NHR 7 , —C(S)NHR 7 , and —S(O) 2 NHR 7 , wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro, further provided that when R 1  is lower alkyl, any substitution on the lower alkyl carbon bound to the N of —NR 1 — is fluoro, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 7  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , provided, however, that any substitution of the alkyl carbon bound to the N of —C(O)NHR 7 , —C(S)NHR 7  or —S(O) 2 NHR 7  is fluoro, wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro, and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 4 , R 5 , R 6 , R 12 , R 14 , R 15 , R 16 , R 42 , R 43 , R 45 , R 46  and R 47  are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —CR a R b R 26 , and -LR 26 ; 
 L at each occurrence is independently selected from the group consisting of -(alk) a -S-(alk) b -, -(alk) a -O-(alk) b -, -(alk) a -NR 25 -(alk) b -, -(alk) a -C(O)-(alk) b -, -(alk) a -C(S)-(alk) b -, -(alk) a -S(O)-(alk) b -, -(alk) a -S(O) 2 -(alk) b -, -(alk) a -OC(O)-(alk) b -, -(alk) a -C(O)O-(alk) b -, -(alk) a -OC(S)-(alk) b -, -(alk) a -C(S)O-(alk) b -, -(alk) a -C(O)NR 25 -(alk) b -, -(alk) a -C(S)NR 25 -(alk) b -, -(alk) a -S(O) 2 NR 25 -(alk) b -, -(alk) a -NR 25 C(O)-(alk) b -, -(alk) a -NR 25 C(S)-(alk) b -, -(alk) a -NR 25 S(O) 2 -(alk) b -, -(alk) a -NR 25 C(O)O-(alk) b -, -(alk) a -NR 25 C(S)O-(alk) b -, -(alk) a -OC(O)NR 25 -(alk) b -, -(alk) a -OC(S)NR 25 -(alk) b -, -(alk) a -NR 25 C(O)NR 25 -(alk) b -, -(alk) a -NR 25 C(S)NR 25 -(alk) b -, and -(alk) a -NR 25 S(O) 2 NR 25 -(alk) b -; 
 a and b are independently 0 or 1; 
 alk is C 1-3  alkylene or C 1-3  alkylene substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein lower alkyl or the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro; 
 R 25  at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 26  at each occurrence is independently selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of S(O), S(O)2, C(O) or C(S) of L, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 26  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted lower alkynyl, provided, however, that when R 26  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 10  and R 11  at each occurrence are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, and lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
 any two of R 10  and R 11  on the same or adjacent carbon atoms combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, and any others of R 10  and R 11  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, and lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 8  and R 9  combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; 
 R 17  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl and —OR 18 ; 
 R 31  and R 33  are independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; 
 R 36  is selected from the group consisting of substituted methyl, optionally substituted C 2-6  alkyl, optionally substituted lower alkenyl, provided, however, that when R 36  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to the S(O) 2 of S(O) 2 R 36 , optionally substituted lower alkynyl, provided, however, that when R 36  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to the S(O) 2 of S(O) 2 R 36 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR 19 R 20 ; 
 R 19 , R 20 , R 34 , R 35 , R 37 , and R 38  are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 19 , R 20 , R 34 , R 35 , R 37 , or R 38  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to the N of NR 19 R 20 , NR 34 R 35  or NR 37 R 38 , optionally substituted lower alkynyl, provided, however, that when R 19 , R 20 , R 34 , R 35 , R 37 , or R 38  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to the N of NR 19 R 20 , NR 34 R 35  or NR 37 R 38 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or 
 R 34  and R 35  together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; or 
 R 37  and R 38  together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; 
 R 32  is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and —OR 18 ; 
 R 82  is selected from hydrogen or lower alkyl; and 
 R 18  is hydrogen or optionally substituted lower alkyl; 
 provided, however, that the compound is not 3-{3-[2-(tetrahydropyran-2-yloxy)-ethoxy]-benzyl}-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, which has the structure 
 
 
       
         
           
           
               
               
           
         
       
       or
   4-(4-methyl-piperazin-1-ylmethyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-benzamide, which has the structure   
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1  having structure of Formula IIIa: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2  having structure of Formula IIIb: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
         Z 12  is N or CR 52 ; 
         Z 16  is N or CR 56 ;
 R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
 R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 L 3  is selected from the group consisting of —NR 48 —, —S—, —O—, —NR 48 CH(R 49 )—, —SCH(R 49 )—, —OCH(R 49 )—, —C(O)NR 48 —, —S(O) 2 NR 48 —, —CH(R 49 )NR 48 —, —CH(R 49 )O—, —CH(R 49 )S—, —NR 48 C(O)—, and —NR 48 S(O) 2 —; 
 R 53  and R 55  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino or cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the —O— of lower alkoxy is fluoro; 
 R 52  and R 56  are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; 
 R 49  is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl; 
 Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; 
 R 39  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally, substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 50  is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino; 
 R 51  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 23  at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 57 , —SR 57 , —NR 48 R 57 , —NR 48 C(O)R 57 , —NR 48 S(O) 2 R 57 , —S(O) 2 R 57 , —C(O)R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , —S(O) 2 NR 48 R 57 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 23 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 57  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 57 , —SR 57 , —NR 48 R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , or —S(O) 2 NR 48 R 57  is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 57  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 58  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 58 , —SR 58 , —NR 48 R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , or —S(O) 2 NR 48 R 58  is fluoro; 
 R 48  at each occurrence is independently hydrogen or lower alkyl; and 
 
         t is  0 ,  1 ,  2 , or  3 . 
       
     
     
         4 . The compound according to laim  2  having structure of Formula IIIp: 
       
         
           
           
               
               
           
         
       
       all salts, prodrugs, tautomers, and isomers thereof,
 wherein: 
 A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
 Z 22  is N or CR 62 ; 
 Z 26  is N or CR 66 ; 
 r is 0, 1, or 2; 
 R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or
 R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 62 , R 63 , R 65  and R 66  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the —O— of lower alkoxy is fluoro; 
 Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; 
 R 39  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 50  is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino; 
 R 51  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 23  at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 57 , —SR 57 , —NR 48 R 57 , —NR 48 C(O)R 57 , —NR 48 S(O) 2 R 57 , —S(O) 2 R 57 , —C(O)R 57 , —C(O)()R 57 , —C(O)NR 48 R 57 , —S(O) 2 NR 48 R 57 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 23 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 57  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 57 , —SR 57 , —NR 48 R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , or —S(O) 2 NR 48 R 57  is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 57  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 58  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 58 , —SR 58 , —NR 48 R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , or —S(O) 2 NR 48 R 58  is fluoro; 
 R 48  at each occurrence is independently hydrogen or lower alkyl; and 
 t is 0, 1, 2, or 3. 
 
 
     
     
         5 . The compound according to  claim 1  having structure of Formula IIIc: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 1  having structure of Formula IIIo: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 6  having structure of Formula IIId: 
       
         
           
           
               
               
           
         
         wherein: 
         r is 0, 1, or 2. 
       
     
     
         8 . The compound according to  claim 7  of structure of Formula IIIe: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
         Z 22  is N or CR 62 ; 
         Z 24  is N or CR 64 ; 
         Z 25  is N or CR 65 ; 
         Z 26  is N or CR 66 ; 
         r is 0, 1, or 2;
 R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
 R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 R 62 , R 64 , R 65  and R 66  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the —O— of lower alkoxy is fluoro; 
 Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; 
 R 39  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 50  is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino; 
 R 51  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 23  at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 57 , —SR 57 , —NR 48 R 57 , —NR 48 C(O)R 57 , —NR 48 S(O) 2 R 57 , —S(O) 2 R 57 , —C(O)R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , —S(O) 2 NR 48 R 57 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 23 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 57  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 57 , —SR 57 , —NR 48 R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , or —S(O) 2 NR 48 R 57  is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 57  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 58  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 58 , —SR 58 , —NR 48 R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , or —S(O) 2 NR 48 R 58  is fluoro; 
 R 48  at each occurrence is independently hydrogen or lower alkyl; and 
 t is 0, 1, 2, or 3. 
 
       
     
     
         9 . The compound according to  claim 6  having structure of Formula IIIq: 
       
         
           
           
               
               
           
         
       
       all salts, prodrugs, tautomers, and isomers thereof,
 wherein: 
 A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
 Z 12  is N or CR 52 ; 
 Z 14  is N or CR 54 ; 
 Z 15  is N or CR 55 ; 
 Z 16  is N or CR 56 ; 
 R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
 R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
 L 3  is selected from the group consisting of —NR 48 —, —S—, —O—, —NR 48 CH(R 49 )—, —SCH(R 49 )—, —OCH(R 49 )—, —C(O)NR 48 —, —S(O) 2 NR 48 —, —CH(R 49 )NR 48 —, —CH(R 49 )O—, —CH(R 49 )S—, —NR 48 C(O)—, and —NR 48 S(O) 2 —; 
 R 54  and R 55  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino or cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the —O— of lower alkoxy is fluoro; 
 R 52  and R 56  are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; 
 R 49  is selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl; 
 Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; 
 R 39  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl, heteroaryl, and NR 50 R 51 , wherein the alkyl chain of lower alkyl or lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, and wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 50  is hydrogen or lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino; 
 R 51  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more independent substituents R 23 ; 
 R 23  at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 57 , —SR 57 , —NR 48 R 57 , —NR 48 C(O)R 57 , —NR 48 S(O) 2 R 57 , —S(O) 2 R 57 , —C(O)R 57 , —C(O)OR 57 , —C(O)NR 4 SR 57 , —S(O) 2 NR 48 R 57 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 23 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 57  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 57 , —SR 57 , —NR 48 R 57 , —C(O)OR 57 , —C(O)NR 48 R 57 , or —S(O) 2 NR 48 R 57  is fluoro, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as 
 R 57  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —OR 58 , —SR 58 , —NR 48 R 58 , —NR 48 C(O)R 58 , —NR 48 S(O) 2 R 58 , —S(O) 2 R 58 , —C(O)R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , —S(O) 2 NR 48 R 58 , halogen, 
 lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; 
 R 58  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —OR 58 , —SR 58 , —NR 48 R 58 , —C(O)OR 58 , —C(O)NR 48 R 58 , or —S(O) 2 NR 48 R 58  is fluoro; 
 R 48  at each occurrence is independently hydrogen or lower alkyl; and 
 t is 0, 1, 2, or 3. 
 
     
     
         10 . The compound according to  claim 1  having structure of Formula IIIf: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 10  having structure of Formula IIIg: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
         Z 32  is N or CR 72 ; 
         Z 34  is N or CR 74 ; 
         Z 35  is N or CR 75 ; 
         Z 36  is N or CR 76 ; 
         X is O or S; 
         R 48  at each occurrence is independently hydrogen or lower alkyl; 
         R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
         R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         R 72 , R 74 , R 75  and R 76  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl and lower alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution on the alkyl carbon bound to the —O— of lower alkoxy is fluoro; 
         R 67  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , and —S(O) 2 R 68 ; 
         one of R 60  and R 61  is lower alkyl, fluoro substituted lower alkyl, or —(CH 2 ) 0-2 R 70 , and the other of R 60  and R 61  is hydrogen or lower alkyl; or 
         R 60  and R 61  together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; 
         R 68  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted lower alkynyl, provided, however, that when R 68  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 69  is hydrogen or optionally substituted lower alkyl; 
         R 70  is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 82  is hydrogen or lower alkyl. 
       
     
     
         12 . The compound according to  claim 1  having structure of Formula IIIh: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 12  having structure of Formula IIIi: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
         X is O or S; 
         R 48  at each occurrence is independently hydrogen or lower alkyl; 
         R 40  and R 41  are independently selected from the group consisting of hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or 
         R 40  and R 41  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         R 67  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , and —S(O) 2 R 68 ; 
         one of R 60  and R 61  is lower alkyl, fluoro substituted lower alkyl, or —(CH 2 ) 0-2 R 70  and the other of R 60  and R 61  is hydrogen or lower alkyl; or 
         R 60  and R 61  together with the nitrogen to which they are attached form optionally substituted 5-7 membered heterocycloalkyl or optionally substituted 5 or 7 membered nitrogen containing heteroaryl; 
         R 68  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted lower alkynyl, provided, however, that when R 68  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 ) —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 69  is hydrogen or optionally substituted lower alkyl; and 
         R 70  is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 
       
     
     
         14 . The compound according to  claim 1  having structure of Formula IIIj: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 14  having structure of Formula IIIk: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is —O—, —CR 40 R 41 —, —C(O)—or —NR 48 —; 
         R 81  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , and —S(O) 2 R 68 ; 
         R 71  and R 78  are independently selected from the group consisting of hydrogen, halogen, C 1-3  alkyl, and fluoro substituted C 1-3  alkyl; 
         R 77  is selected from the group consisting of substituted methyl, optionally substituted C 2-6  alkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR 79 R 80 , wherein methyl is substituted with one or more substituents selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; 
         R 68  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted lower alkynyl, provided, however, that when R 68  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 69  is hydrogen or optionally substituted lower alkyl; and 
         R 79  and R 80  are independently hydrogen or optionally substituted lower alkyl, or R 79  and R 80  combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl. 
       
     
     
         16 . The compound according to  claim 15  having structure of Formula IIIm: 
       
         
           
           
               
               
           
         
         wherein: 
         R 81  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , and —S(O) 2 R 68 ; 
         R 83  is selected from the group consisting of hydrogen, fluoro and chloro; 
         R 112  is selected from the group consisting of optionally substituted C 2-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR 79 R 80 ; 
         R 68  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 68  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 , —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted lower alkynyl, provided, however, that when R 68  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 68 , —SR 68 , —NR 69 R 68 , —C(O)R 68 , —C(S)R 68 , —C(O)OR 68 , —C(O)NR 69 R 68 , —C(S)NR 69 R 68 , —S(O) 2 NR 69 R 68 , —NR 69 C(O)R 68 , —NR 69 C(S)R 68 , —NR 69 S(O) 2 R 68 , —NR 69 C(O)NH 2 , —NR 69 C(O)NR 69 R 68 , —NR 69 C(S)NH 2 ) —NR 69 C(S)NR 69 R 68 , —NR 69 S(O) 2 NH 2 , —NR 69 S(O) 2 NR 69 R 68 , —S(O)R 68 , or —S(O) 2 R 68 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 69  is selected from the group consisting of hydrogen and optionally substituted lower alkyl; and 
         R 79  and R 80  are independently hydrogen or optionally substituted lower alkyl, or R 79  and R 80  combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl. 
       
     
     
         17 . The compound according to  claim 1  having structure of Formula IIIn: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound of Formula II having the following structure: 
       
         
           
           
               
               
           
         
         all salts, prodmgs, tautomers, and isomers thereof,
 wherein: 
 
         R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —CR a R b R 26 , and -LR 26 ; 
         R 12 , R 13 , R 14 , R 15  and R 16  are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —CR a R b R 24 , and -LR 24 ; 
         A is selected from the group consisting of —O—, —S—, —CR a R b —, —NR 1 —, —C(O)—, —C(S)—, —S(O)—, and —S(O) 2 —; 
         R a  and R b  at each occurrence are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro; or 
         R a  and R b  combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         R 1  is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)R 7 , —C(S)R 7 , —S(O) 2 R 7 , —C(O)NHR 7 , —C(S)NHR 7 , and —S(O) 2 NHR 7 , wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro, further provided that when R 1  is lower alkyl, any substitution on the lower alkyl carbon bound to the N of —NR 1 — is fluoro, and wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         R 7  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , provided, however, that any substitution of the alkyl carbon bound to the N of —C(O)NHR 7 , —C(S)NHR 7  or —S(O) 2 NHR 7  is fluoro, wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro, and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         L at each occurrence is independently selected from the group consisting of-(alk) a -S-(alk) b -, -(alk) a -O-(alk) b -, -(alk) a -NR 25 -(alk) b -, -(alk) a -C(O)-(alk) b -, -(alk) a -C(S)-(alk) b -, -(alk) a -S(O)-(alk) b -, -(alk) a -S(O) 2 -(alk) b -, -(alk) a -OC(O)-(alk) b -, -(alk) a -C(O)O-(alk) b -, -(alk) a -OC(S)-(alk) b -, -(alk) a -C(S)O-(alk) b -, -(alk) a -C(O)NR 25 -(alk) b -, -(alk) a -C(S)NR 25 -(alk) b -, -(alk) a -S(O) 2 NR 25 -(alk) b -, -(alk) a -NR 25 C(O)-(alk) b -, -(alk) a -NR 25 C(S)-(alk) b -, -(alk) a -NR 25  S(O) 2 -(alk) b -, -(alk) a -NR 25 C(O)O-(alk) b -, -(alk) a -NR 25 C(S)O-(alk) b -, -(alk) a -OC(O)NR 25 -(alk) b -, -(alk) a -OC(S)NR 25 -(alk) b -, -(alk) a -NR 25 C(O)NR 25 -(alk) b -, -(alk) a -NR 25 C(S)NR 25 -(alk) b -, and -(alk) a -NR 25 S(O) 2 NR 25 -(alk) b -; 
         a and b are independently 0 or 1; 
         alk is C 1-3  alkylene or C 1-3  alkylene substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and —NR 8 R 9 , wherein lower alkyl or the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro; 
         R 8  and R 9  combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; 
         R 25  at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
         R 24  and R 26  at each occurrence are independently selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 24  or R 26  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted lower alkynyl, provided, however, that when R 24  or R 26  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of L, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, provided, however that the at least one of R 12 , R 13 , R 14 , R 15  and R 16  is -LR 24 , wherein R 24  is substituted methyl, optionally substituted C 2-6  alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, further provided, however, that R 13  is not 
       
       
         
           
           
               
               
           
         
       
       and that R 14  is not 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       indicates the bond to the phenyl ring. 
     
     
         19 . The compound according to  claim 18  wherein R 24  is optionally substituted C 2-6  alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or substituted methyl, wherein methyl is substituted with optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
     
     
         20 . The compound of  claim 19 , wherein R 5  is other than hydrogen. 
     
     
         21 .- 39 . (canceled)