Substituted 6,6-Fused Nitrogenous Heterocyclic Compounds and Uses Thereof

Abstract

The invention provides novel compounds having the general formula: wherein X 1 is N or N + O − , and one of X 2 , X 3 and X 4 is N or N + —O − and the remainder of X 2 , X 3 and X 4 is C. R 2 , R 3 , R 4 , R 5 , R 6 . A, B and Y are as described herein. Additionally compositions compounds of Formula I and methods of use are further described herein.

We claim: 
     
         1 . Compounds of formula (I) 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof; wherein
 Y is absent or is selected from the group consisting
 of —C(═O)—, —N(H)C(═O)—, —N(R a )C(═O)—, —O—C(═O)—, —N(H)S(O) 1-2 —, —N(R a )S(O) 1-2 — and —S(O) 2 —, wherein R a  is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  heteroalkyl, C 2-6  alkenyl and C 2-6  alkynyl; 
 
 R 2  is —(X b ) 0-1 —R b , wherein X b  is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 1-6  heteroalkylene, 3-6 membered cycloalkylene and 3-6 membered heterocycloalkylene, R b  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the aliphatic and aromatic portions of X b  and R b  are each independently optionally substituted with 1 to 5 R b1  substituents selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —N 3 , —C(═O)OH, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, —(C 1-4  alkenylene) 0-1 -C(═O)—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)O—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)N(H)—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)N(C 1-4  alkyl) 2 , —(C 1-4  alkenylene) 0-1 -S(O) 2 —(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)—(C 1-4  heteroalkyl) and —(C 1-4  alkenylene) 0-1 -C(═O)—(C 3-6  heterocycloalkyl), and wherein if R b  is a 6 membered aryl or a 5-6 membered heteroaryl then any two substituents attached to adjacent atoms said aryl or heteroaryl are optionally combined to from a 3-6 membered carbocyclic or a 3-6 membered heterocyclic ring comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with 1 to 3 R b1  substituents; 
 X 1  is N or N + —O − ; 
 X 2 , X 3  and X 4  are each C, or one of X 2 , X 3  and X 4  is N or N + —O −  and the remainder of X 2 , X 3  and X 4  are each C; 
 R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, F, Cl, Br, I, —CN, —CF 3 , —OCF 3 , —SF 5  and —N 3 ; 
 R 4  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, F, Cl, Br, I, —CN, —NO 2 , —N 3 , —SH, —OH, C 1-6  alkoxy, —CF 3 , —OCF 3 , —SF 5 , C 1-6  alkylamino and C 1-6  dialkylamino, or is absent if X 4  is N or N + —O; 
 R 5  is (X e ) 0-1 —R c , wherein X c  is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  heteroalkylene, C 2-6 alkynylene, —N(H)—, —N(R xc )—, —O—, —S(O) 2 —, —C(═O)—, —C(═O)O—, —C(═O)N(H)—, —N(H)C(═O)— and —OC(═O)—, wherein R xc  is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and wherein R c  is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN, —NO 2 , —NH 2 , —OH, —CF 3 , —OCF 3 , —SF 5 , C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 membered aryl and 5-6 membered heteroaryl, wherein the aliphatic and aromatic portions of X c  and R c  are optionally substituted with 1 to 5 R c1  substituents selected from the group consisting of C 1-6  alkyl, C 1-6  heteroalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —N 3 , —C(═O)OH, —N(C 1-6  alkyl) 2 , —NH(C 1-6  alkyl), —O(C 1-6  alkyl), alkenylene) 0-1 -C(═O)—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)O—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)N(H)—(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)N(C 1-4  alkyl) 2 , —(C 1-4  alkenylene) 0-1 -S(O) 2 —(C 1-4  alkyl), —(C 1-4  alkenylene) 0-1 -C(═O)—(C 1-4  heteroalkyl) and —(C 1-4  alkenylene) 0-1 -C(═O)—(C 3-6  heterocycloalkyl), or R 5  is absent if X 3  is N or N + —O − ; 
 R 6  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 2-6  alkenyl, C 2-6  alkynyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5  and —N 3 , or R 6  is absent if X 2  is N or N + —O − ; 
 A is absent or is selected from the group consisting of —O—, —N(H)—, —N(R d )—, —S(O) 2 —, —S(O)—, —S—, —(X d ) 0-1 —N(H)C(═O)—, —(X d ) 0-1 —N(R d )C(═O)—, —X d —, —(X d ) 0-1 —C(═O)N(H)—, —(X d ) 0-1 —C(═O)N(R d )—, —(X d ) 0-1 —C(═O)—, —C(═O)—(X d ) 0-1 —, —(X d ) 0-1 —OC(═O)— and —(X d ) 0-1 C(═O)O—, wherein X d  is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 1-6  heteroalkylene, 6-10 membered arylene, 5-10 membered heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, and R d  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 1-6  heteroalkyl and C 1-6  haloalkyl, wherein the aliphatic or aromatic portions of X d  and R d  are each independently optionally substituted with 1 to 5 R d1  substituents selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkylamino, C 1-6  dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5 , and —N 3 ; 
 B is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3-6 membered cycloalkyl, 4-9 membered heterocycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, wherein the aliphatic or aromatic portions of B are independently optionally substituted with 1 to 5 R B1  substituents selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 3-6  heterocycloalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CF 3 , —SF 5 , —(X e ) 0-1 —CN, —(X e ) 0-1 —N 3 , —(X e ) 0-1 —OH, —(X e ) 0-1 —H, —(X e ) 0-1 —N(H)R e , —(X e ) 0-1 —N(R e ) 2 , —(X e ) 0- 1 —SR e , —(X e ) 0-1 —C(O)R e , —(X e ) 0-1 —S(O)R e , —N(H)S(O) 2 R e , —N(R e )S(O) 2 R e , —(X e ) 0-1 —C(═O)OR e , —(X e ) 0-1 —C(═O)OH, —(X e ) 0-1 —C(═O)N(H)R e , —(X e ) 0-1 —C(═O)N(R e )R e , —(X e ) 0-1 —N(H)C(═O)R e , —(X e ) 0-1 —N(R e )C(═O)R e , wherein if B is a 6 membered aryl or a 5-6 membered heteroaryl then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally combined to from a 3-6 membered carbocyclic or a 3-6 membered heterocyclic ring optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with 1 to 3 R B1  substituents; wherein X e  is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 1-6  heteroalkylene, C 3-6  cycloalkylene and C 3-6  heterocycloalkylene, and R e  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the aliphatic or aromatic portions of X e  and R e  are each independently optionally substituted with 1 to 5 R e1  substituents selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkylamino, C 1-6  dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5  and —N 3 , and wherein any two R e  groups attached to the same nitrogen atom are optionally combined to form a 3-7 membered heterocyclic or 5-10 membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S; and 
 wherein if X 3  is N, R 3  is H, R 4  is H or NH 2 , R 6  is —OH and —Y—R 2  is other than H, then -A-B is not thiazol-4-yl substituted with 2-thiophenyl-S(O) 2 CH 2 —, phenyl-S(O) 2 —CH 2 —, 4-pyridyl, or pyridyl-S(O) 2 CH 2 —, if X 3  is N, R 3  is H or Cl, R 4  is H, R 6  is —OH, —NH 2 , or —NHCH 3  and —Y—R 2  is hydrogen, 4-tetrahydropyranyl, 4-((CH 3 CH 2 ) 2 N(CH 2 ) 3-4 O)-phenyl, (CH 3 CH 2 ) 2 N(CH 2 ) 4 —, 3-(4-methylpiperazinyl)-propyl or trifluoroacetyl, then -A-B is not 2-chlorophenyl, 2-methylphenyl, 2,6-dichlorophenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, phenyl, 2-chloro-6-(2-ethoxyethoxy)phenyl, if X 3  is N, R 3 , R 4  and R 6  are each H, and —Y—R 2  is hydrogen, cyclohexyl, (CH 3 CH 2 ) 2 NCH 2 CH 2 —, CH 3 N(H)CH 2 CH 2 —, (CH 3 ) 2 NCH 2 CH 2 —, (CH 3 ) 3 CC(═O)— or 2-(4-morpholinyl)ethyl, then -A-B is not 3,4-dimethoxyphenyl or optionally substituted pyridine-2-on-3-yl, if X 4  is N, R 3  is H, R 5  is isopropyl, R 6  is methoxy, -A-B is propyl or isopropyl, then —Y—R 2  is other than optionally substituted pyridyl, if X 4  is N, R 3 , R 5 , R 6  are each H, -A-B is methyl, then —Y—R 2  is other than hydrogen, if R 3 , R 4 , R 5  and R 6  are each H, and —Y—R 2  is hydrogen, cyclohexyl, (CH 3 CH 2 ) 2 NCH 2 CH 2 —, CH 3 N(H)CH 2 CH 2 —, (CH 3 ) 2 NCH 2 CH 2 —, (CH 3 ) 3 CC(═O)— or 2-(4-morpholinyl)ethyl, then -A-B is not 3,4-dimethoxyphenyl or optionally substituted pyridine-2-on-3-yl, if R 3 , R 4  and R 5  are each hydrogen, —Y—R 2  is other than hydrogen, then one of R 6  and -A-B is other than ethoxy. 
 
     
     
         2 . The compound of  claim 1 , wherein a compound of formula I has the subformula Ia-Id selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or an N-oxide thereof. 
     
     
         3 . The compound of  claim 2 , wherein R 3 , R 4  and R 6 , if present, are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, —CF 3 , —OCF 3 , —SF 5 , F, Cl, Br and I. 
     
     
         4 . The compound of  claim 2 , wherein in R 2 , X b  is absent or is selected from C 1-6  alkylene and 3-6 membered cycloalkylene; and R b  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein X b  and R b  are each independently optionally substituted. 
     
     
         5 . The compound of  claim 4 , wherein in R 2 , X b  is absent. 
     
     
         6 . The compound of  claim 4 , wherein in R 2 , R b  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 2-6  alkenyl and C 2-6  alkynyl. 
     
     
         7 . The compound of  claim 4 , wherein in R 2 , R b  is optionally substituted with from 1 to 5 R b1  groups selected from the group consisting of F, Cl, Br, I, OH, NH 2 , SH, CN, NO 2 , C 1-6  alkoxy, C 1-6  alkylamino and C 1-6  dialkylamino. 
     
     
         8 . The compound of  claim 2 , wherein in R 2 , R b  is selected from the group consisting of cycloprop-1-yl, cyclobut-1-yl, cyclopent-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-on-6-yl, pyridine-2-on-5-yl, pyridine-2-on-4-yl, pyridine-2-on-3-yl, cyclohex-1-yl, phenyl, 4,5-dihydrooxazol-2-yl, oxazol-2-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperidin-1-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, oxetan-3-yl, oxetan-2-yl, pyrazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pyrrolidin-3-yl, pyrrolidin-2-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and 3-oxabicyclo[3.1.0]hexan-6-yl, wherein said R b  is further optionally substituted. 
     
     
         9 . The compound of  claim 2 , wherein Y is absent or is selected from the group consisting of —C(═O)—, —N(H)C(═O)—, —N(R a )C(═O)— and —S(O) 2 —. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is selected from the group consisting of cycloprop-1-yl, cyclobut-1-yl, cyclopent-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-on-6-yl, pyridine-2-on-5-yl, pyridine-2-on-4-yl, pyridine-2-on-3-yl, cyclohex-1-yl, phenyl, 4,5-dihydrooxazol-2-yl, oxazol-2-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperidin-1-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, oxetan-3-yl, oxetan-2-yl, pyrazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pyrrolidin-3-yl, pyrrolidin-2-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and 3-oxabicyclo[3.1.0]hexan-6-yl, and wherein R 2  is optionally substituted. 
     
     
         11 . The compound of  claim 10 , wherein the Y is —C(═O)—. 
     
     
         12 . The compound of  claim 8 , wherein in R 2 , R b  is selected from the group as set forth on  FIG. 1-A  and  FIG. 1-B . 
     
     
         13 . The compound of  claim 2 , wherein A is absent. 
     
     
         14 . The compound of  claim 2 , wherein A is present is selected from the group consisting of O—, —N(H)—, —N(R d )—, —S(O) 2 —, —S(O)— and —S—. 
     
     
         15 . The compound of  claim 2 , wherein A is present and is selected from the group consisting of —(X d ) 0-1 —N(H)C(═O)—, —(X d ) 0-1 —N(R d )C(═O)—, —X d —, —(X d ) 0-1 —C(═O)N(H)—, —(X d ) 0-1 —C(═O)N(R d )—, —(X d ) 0-1 —C(═O)—, —C(═O)—(X d ) 0-1 , —(X d ) 0-1 —OC(═O)—, —(X d ) 0-1 C(═O)O— and wherein the X d  group in A is selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene C 1-6  heteroalkylene, 6-10 membered arylene and a 5-10 membered heteroarylene comprising 1 to 3 heteroatoms selected from N, O and S, wherein said X d  is optionally substituted. 
     
     
         16 . The compound of  claim 15 , wherein the X d  group in A is selected from the group consisting of phenylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, and wherein said X d  is optionally substituted. 
     
     
         17 . The compound of  claim 16 , wherein A is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 2 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 2 , wherein B is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyridin-4-on-3-yl, pyridin-4-on-2-yl, pyridin-4-on-1-yl, pyridin-2-on-1-yl, pyridin-2-on-3-yl, pyridin-2-on-4-yl, pyrrol-1-yl, pyrrol-3-yl, pyrrol-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyrazin-2-yl, cyclohexyl, cyclobutyl, cyclopropyl, cyclopentyl, morpholin-4-yl, morpholin-2-yl, morpholin-3-yl, piperazin-1-yl, piperazin-2-yl, cyclopentyl, piperidin-1-yl, piperidin-4-yl, piperidin-2-yl, piperidin-3-yl, indol-5-yl, indol-4-yl, indol-3-yl, indol-2-yl, pyridimin-5-yl, pyridimin-4-yl, pyrimidin-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indolin-2-on-4-yl, indolin-2-on-5-yl, indolin-2-on-6-yl, indolin-2-on-7-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, wherein B is optionally substituted and wherein any two substituent located on adjacent atoms of B are optionally combined to form an optionally substituted 5 to 7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S. 
     
     
         20 . The compound of  claim 2 , wherein B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, wherein B is optionally substituted. 
     
     
         21 . The compound of  claim 16 , wherein B is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein the B is optionally substituted with 1 to 3 R B1  substitutents selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —(X e ) 0-1 —CN, —(X e ) 0-1 —NO 2 , —(X e ) 0-1 —N 3 , —(X e ) 0-1 —N(H)R e , —(X e ) 0-1 —N(R e ) 2 , —(X e ) 0-1 —SR e , —(X e ) 0-1 —C(O)R e , —(X e ) 0-1 —S(O) 2 R e , —(X e ) 0-1 , —S(O)R e , —(X e ) 0-1 —C(═O)OR e , —(X e ) 0-1 —C(═O)N(H)R e , —(X e ) 0-1 —C(═O)N(R e )R e , —(X e ) 0-1 —N(H)C(═O)R e  and —(X e ) 0-1 —N(R e )C(═O)R e , and wherein any two substituent located on adjacent atoms of B are optionally combined to form an optionally substituted 5 to 7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S. 
     
     
         22 . The compound of  claim 18 , wherein B is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 2 , wherein B is selected from the group as set forth on  FIG. 2-A ,  FIG. 2-B ,  FIG. 2-C ,  FIG. 2-D  and  FIG. 2-E . 
     
     
         24 . The compound of  claim 2 , wherein R 5  is (X c )—R c , wherein X c  is absent or is selected from the group consisting of C 1-6  alkylene, —N(H)—, —N(R xc )—, —O—, —S(O) 2 —, and R c  is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5 , C 1-6  alkyl, C 1-6  heteroalkyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, cyclopropyl, cyclopentyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-3-yl, thiazol-5-yl, piperazin-1yl, piperazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, wherein R c  is optionally substituted. 
     
     
         25 . A compound of formula I selected from the group consisting of the compounds in Table 1 and Table 1b. 
     
     
         26 . A pharmaceutical composition comprising a compound in accordance with  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         27 . A method for the treatment of a mammal having a disease or disorder selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, Pick's Disease, Niemann-Pick's Disease, Tauopathies and Amyoloidosis, comprising administering to said mammal an effective amount of a compound as defined in  claim 1 . 
     
     
         28 . A method for the treatment of a mammal having a cancer selected from the group consisting of breast, ovarian, NSCLC, acute lymphocytic leukemia, acute myelogeneous leukemia, chronic myelogenous leukemia and chronic lymphocytic leukemia, comprising administering to said mammal an effective amount of a compound as defined in  claim 1 .