Biheteroaryl compounds and uses thereof

Abstract

The present invention provides for compounds of Formula I-I and embodiments and salts thereof for the treatment of diseases (e.g., neurodegenerative diseases). R 1 , R 2 , R 3 , X 1 , X 2 , A and Cy variable in Formula I-I all have the meaning as defined herein.

1 . A compound of Formula (I-I) 
       
         
           
           
               
               
           
         
       
       or salts thereof wherein
 R 1 , R 2  and R 3  are each independently H, F, Cl, Br, I, C 1-6  alkyl or C 1-6  haloalkyl; 
 X 1  is N or C—R 4 , wherein R 4  is selected from the group consisting of —F, —Cl, —Br, I, -(L 1 ) 0-1 -C 1-6  alkyl, -(L 1 ) 0-1 -C 1-6  haloalkyl, -(L 1 ) 0-1 -C 1-6  heteroalkyl, -(L 2 ) 0-1 -C 3-8  cycloalkyl, -(L 2 ) 0-1 -3 to 7 membered heterocycloalkyl, -(L 2 ) 0-1 -6-10 membered aryl, -(L 2 ) 0-1 -5-10 membered heteroaryl, wherein L 1  is selected from the group consisting of —O—, —N(H)—, —S—, —N(C 1-6  alkyl)-, ═O, and L 2  is selected from the group consisting of —O—, —N(H)—, —N(C 1-6  alkyl)-, —S—, ═O, C 1-4  alkylene, C 1-4  alkenylene, C 1-4  alkynylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene and C 1-4  heteroalkylene, and wherein R 4  is optionally substituted on carbon atoms and heteroatoms with R R4  substituents selected from the group consisting of F, Cl, Br, I, C 1-6  alkyl, C 1-6  haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  alkylthio, ═O, —NH 2 , —CN, —NO 2  and —SF 5 ; 
 or R 1  and R 4  taken together form a 5 to 6 membered heterocycloalkyl; 
 X 2  is N or CH; 
 A is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, and 5 to 6 membered heteroaryl, wherein A is optionally substituted with 1-5 R A  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L A ) 0-1 -3-8 membered cycloalkyl, -(L A ) 0-1 -3-8 membered heterocycloalkyl, -(L A ) 0-1 -5 to 6 membered heteroaryl, -(L A ) 0-1 -C 6  aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 -SR R1a , -(L A ) 0-1 -N(R R1a )C(═Y 1 )OR R1c , -(L A ) 0-1 -OC(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(═O)R R1b , -(L A ) 0-1 -C(═O)OR R1a , -(L A ) 0-1 -OC(═O)R R1a , -(L A ) 0-1 -P(═O)(OR R1a )(OR R1b ), -(L A ) 0-1 -S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c ), wherein L A  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene, C 2-4  alkenylene, and C 2-4  alkynylene; wherein R R1a  and R R1b  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R R1c  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl; Y 1  is O or S, and wherein R A  is optionally substituted on carbon atoms and heteroatoms with R RA  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino; and 
 Cy is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, and 5 to 6 membered heteroaryl, wherein Cy is optionally substituted on carbon or heteroatoms with R Cy  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L Cy ) 0-1 -3-8 membered cycloalkyl, -(L Cy ) 0-1 -3-8 membered heterocycloalkyl, -(L Cy ) 0-1 -5 to 6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(═Y 1 )OR RCc , -(L Cy ) 0-1 -OC(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)R RCb , -(L Cy ) 0-1 C(═O)OR RCa , -(L Cy ) 0-1 -OC(═O)R RCa , -(L Cy ) 0-1 -P(═O)(OR RCa )(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 1-1 -N(R RCa )S(O) 1-2 (R RCc ), wherein L Cy  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene, C 2-4  alkenylene, and C 2-4  alkynylene; wherein R RCa  and R RCb  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R RCc  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl; Y 1  is O or S, and wherein R Cy  is optionally substituted on carbon atoms and heteroatoms with from 1 to 5 R RCy  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , —O—, ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkyl-C(═O)—, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino. 
 
     
     
         2 . The compound of  claim 1 , further defined as a compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or salts thereof wherein
 R 1 , R 2  and R 3  are each independently H, F, Cl, Br, I, C 1-6  alkyl or C 1-6  haloalkyl; 
 X 1  is N or C—R 4 , wherein R 4  is selected from the group consisting of —F, —Cl, —Br, I, -(L 1 ) 0-1 -C 1-6  alkyl, -(L 1 ) 0-1 -C 1-6  haloalkyl, -(L 1 ) 0-1 -C 1-6  heteroalkyl, -(L 2 ) 0-1 -C 3-8  cycloalkyl, -(L 2 ) 0-1 -3 to 7 membered heterocycloalkyl, -(L 2 ) 0-1 -6-10 membered aryl, -(L 2 ) 0-1 -5-10 membered heteroaryl, wherein L 1  is selected from the group consisting of —O—, —N(H)—, —S—, —N(C 1-6  alkyl)-, ═O, and L 2  is selected from the group consisting of —O—, —N(H)—, —N(C 1-6  alkyl)-, —S—, ═O, C 1-4  alkylene, C 1-4  alkenylene, C 1-4  alkynylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene and C 1-4  heteroalkylene, and wherein R 4  is optionally substituted on carbon atoms and heteroatoms with R R4  substituents selected from the group consisting of F, Cl, Br, I, C 1-6  alkyl, C 1-6  haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  alkylthio, ═O, —NH 2 , —CN, —NO 2  and —SF 5 ; 
 X 2  is N or CH; 
 A is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein A is optionally substituted with 1-5 R A  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L A ) 0-1 -3-8 membered cycloalkyl, -(L A ) 0-1 -3-8 membered heterocycloalkyl, -(L A ) 0-1 -5 to 6 membered heteroaryl, -(L A ) 0-1 -C 6  aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 -SR R1a , -(L A ) 0-1 -N(R R1a )C(═Y 1 )OR R1c , -(L A ) 0-1 -OC(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -C(═O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(═O)R R1b , -(L A ) 0-1 -C(═O)OR R1a , -(L A ) 0-1 -OC(═O)R R1a , -(L A ) 0-1 -P(═O)(OR R1a )(OR R1b ), -(L A ) 0-1 -S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c ), wherein L A  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene, C 2-4  alkenylene, and C 2-4  alkynylene; wherein R R1a  and R R1b  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R R1c  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl; Y 1  is O or S, and wherein R A  is optionally substituted on carbon atoms and heteroatoms with R RA  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino; and 
 Cy is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein Cy is optionally substituted on carbon or heteroatoms with R Cy  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L Cy ) 0-1 -3-8 membered cycloalkyl, -(L Cy ) 0-1 -3-8 membered heterocycloalkyl, -(L Cy ) 0-1 -5 to 6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(═O)OR RCc , -(L Cy ) 0-1 -OC(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(═O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(═O)R RCb , -(L Cy ) 0-1 -C(═O)OR RCa , -(L Cy ) 0-1 -OC(═O)R RCa , -(L Cy ) 0-1 -P(═O)(OR RCa )C(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 -S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 (R RCc ), wherein L Cy  is selected from the group consisting of C 1-4  alkylene, C 1-4  heteroalkylene, C 1-4  alkoxylene, C 1-4  aminoalkylene, C 1-4  thioalkylene, C 2-4  alkenylene, and C 2-4  alkynylene; wherein R RCa  and R RCb  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; R RCc  is selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl; Y 1  is O or S, and wherein R Cy  is optionally substituted on carbon atoms and heteroatoms with from 1 to 5 R RCy  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino. 
 
     
     
         3 . A compound according to  claim 1 , wherein either A or Cy is a polycyclic carbocycle or polycyclic heterocycle. 
     
     
         4 . A compound according to  claim 1 , wherein X 1  is N. 
     
     
         5 . A compound according to  claim 1 , wherein X 1  is C—R 4 . 
     
     
         6 . A compound of  claim 1 , wherein X 2  is N. 
     
     
         7 . A compound of  claim 1 , wherein X 2  is C(H). 
     
     
         8 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of —F, —Cl, —CN, -(L 2 ) 0-1 -C 3-8  cycloalkyl, -(L 2 ) 0-1 -3 to 7 membered heterocycloalkyl, -(L 1 ) 0-1 -C 1-6  alkyl, -(L) 0-1 -C 1-6  haloalkyl, -(L 1 ) 0-1 -C 1-6  heteroalkyl, -(L 2 ) 0-1 -6-10 membered aryl and -(L 2 ) 0-1 -5-10 membered heteroaryl, and is optionally substituted. 
     
     
         9 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of —F, —Cl, C 3-8  cycloalkyl, 3 to 7 membered heterocycloalkyl, C 1-6  alkyl, C 1-6  haloalkyl, —(O)—C 3-8  cycloalkyl, —(O)-3 to 7 membered heterocycloalkyl, —(O)—C 1-6  alkyl and —(O)—C 1-6  haloalkyl, and is optionally substituted. 
     
     
         10 . A compound of  claim 1 , wherein R 4  is selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl, monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl. 
     
     
         11 . A compound of  claim 1 , wherein R 1 , R 2  and R 3  are each independently selected from the group consisting of F, Cl, CN, hydrogen, C 1-4  alkyl and C 1-4  haloalkyl. 
     
     
         12 . A compound of  claim 1 , wherein R 1 , R 2  and R 3  are each hydrogen. 
     
     
         13 . A compound of  claim 1 , wherein A and Cy are independently selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, 7-azaspiro[3.5]nonane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane, 2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane, 2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted. 
     
     
         14 . A compound of  claim 1 , wherein A is selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, cyclopropane, cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane, 3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and is optionally substituted. 
     
     
         15 . A compound of  claim 1 , wherein A is selected from the group consisting of 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, azetidine, pyrrolidine, cyclopropane, cyclobutane, cyclopentane, and is optionally substituted. 
     
     
         16 . A compound of  claim 1 , wherein A is selected from the group consisting of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted. 
     
     
         17 . A compound of  claim 1 , wherein is A is selected from the group consisting of methyl, ethyl, isopropyl, 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound of  claim 1 , wherein Cy is selected from the group consisting of 2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine, azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, 2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted. 
     
     
         19 . A compound of  claim 1 , wherein Cy is selected from the group consisting of azetidine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted. 
     
     
         20 . A compound of  claim 1 , wherein Cy is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound of  claim 1 , wherein A is optionally substituted with from 1 to 5 R A  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L A ) 0-1 -3-8 membered cycloalkyl, -(L A ) 0-1 -3-8 membered heterocycloalkyl, -(L A ) 0-1 -5 to 6 membered heteroaryl, -(L A ) 0-1 -C 6  aryl, wherein L A  is selected from the group consisting of —C(O)—, —C(O)CH 2 —, —OCH 2 —, —CH 2 O—, —CH 2 —, —CH 2 CH 2 —, —CH 2 OCH 2 —, —N(H)CH 2 —, —N(C 1-3  alkyl)CH 2 —, CH 2 N(H)—, —CH 2 N(C 1-3  alkyl)-; wherein said 3-8 membered cycloalkyl is selected from the group consisting of propane, butane, pentane and hexane; wherein said 3 to 8 membered heterocycloalkyl is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6 membered heteroaryl is selected from the group consisting of pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine, pyrazine, pyridazine; wherein said C 6  aryl is phenyl; and wherein R A  is optionally substituted with from 1 to 5 R RA  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino. 
     
     
         22 . A compound of  claim 1 , wherein Cy is optionally substituted with from 1 to 5 R Cy  substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO 2 , —SF 5 , C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  heteroalkyl, -(L Cy ) 0-1 -3-8 membered cycloalkyl, -(L Cy ) 0-1 -3-8 membered heterocycloalkyl, -(L Cy ) 0-1 -5 to 6 membered heteroaryl, -(L Cy ) 0-1 -C 6  aryl, wherein L Cy  is selected from the group consisting of —C(O)—, —C(O)CH 2 —, —OCH 2 —, —CH 2 O—, —CH 2 —, —CH 2 CH 2 —, —CH 2 OCH 2 —, —N(H)CH 2 —, —N(C 1-3  alkyl)CH 2 —, CH 2 N(H)—, —CH 2 N(C 1-3  alkyl)-; wherein said 3-8 membered cycloalkyl is selected from the group consisting of propane, butane, pentane and hexane; wherein said 3 to 8 membered heterocycloalkyl is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6 membered heteroaryl is selected from the group consisting of pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, trizole, pyridine, pyrimidine, pyrazine, pyridazine; wherein said C 6  aryl is phenyl; and wherein R Cy  is optionally substituted with from 1 to 5 R RCy  substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , ═O, —SF 5 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  (halo)alkyl-C(═O)—, C 1-4  (halo)alkyl-S(O) 0-2 —, C 1-4  (halo)alkyl-N(H)S(O) 0-2 —, C 1-4  (halo)alkyl-S(O) 0-2 N(H)—, (halo)alkyl-N(H)—S(O) 0-2 N(H)—, C 1-4  (halo)alkyl-C(═O)N(H)—, C 1-4  (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl) 2 N—C(═O)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, C 1-4  (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl) 2 N—C(═O)O—, C 1-4  alkylthio, C 1-4  alkylamino and C 1-4  dialkylamino. 
     
     
         23 . A compound of  claim 1 , wherein A is optionally substituted with 1 to 5 R A  substituents selected from the group consisting of F, Cl, Br, I, CN, CH 3 O—, CH 3 , cyclopropylmethyl, CF 3  and butyl. 
     
     
         24 . A compound of  claim 1 , wherein said compound is selected from the subformula consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A compound of  claim 1 , wherein said compound is selected from the subformula consisting of 
       
         
           
           
               
               
           
         
       
       wherein R Cy  if present replaces a hydrogen atom attached to a carbon or nitrogen atom of the Cy ring. 
     
     
         26 . A compound of  claim 1  selected from the group as set forth in Table 1. 
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         28 . A method for inhibiting or preventing degeneration of a central nervous system (CNS) neuron or a portion thereof, the method comprising administering to the CNS neuron a compound of Formula I-I or Formula I. 
     
     
         29 . The method of  claim 28 , wherein said administering to the CNS neuron is performed in vitro. 
     
     
         30 . The method of  29 , wherein the method further comprises grafting or implanting the CNS neuron into a human patient after administration of the agent. 
     
     
         31 . The method of  claim 29 , wherein the CNS neuron is present in a human patient. 
     
     
         32 . The method of  claim 28 , wherein administering to the CNS neuron comprises administration of said compound of Formula I-I or Formula I in a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         33 . The method of  claim 28 , wherein administering to the CNS neuron is carried out by an administration route selected from the group consisting of parenteral, subcutaneous, intravenous, intraperitoneal, intracerebral, intralesional, intramuscular, intraocular, intraarterial interstitial infusion and implanted delivery device. 
     
     
         34 . The method of  claim 28 , further comprising administering one or more additional pharmaceutical agents. 
     
     
         35 . The method of  claim 28 , wherein the administering of a compound of Formula I-I or Formula I results in a decrease in JNK phosphorylation, JNK activity and/or JNK expression. 
     
     
         36 . The method of  claim 35 , wherein the administering of a compound of Formula I-I or Formula I results in a decrease of cJun phosphorylation, cJun activity, and/or cJun expression. 
     
     
         37 . The method of  claim 35 , wherein the administering of a compound of Formula I-I or Formula I results in a decrease in p38 phosphorylation, p38 activity, and/or p38 expression. 
     
     
         38 . A method for inhibiting or preventing degeneration of a central nervous system (CNS) neuron in a patient having or at risk of developing a neurodegenerative disease or condition comprising administering to said patient a therapeutically effective amount of a compound of Formula I-I or Formula I, or a pharmaceutically acceptable salt thereof. 
     
     
         39 . A method for decreasing or preventing one or more symptoms of a neurodegenerative disease or condition in a patient suffering therefrom comprising administering to said patient a therapeutically effective amount of a compound of Formula I-I or Formula I or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method for decreasing the progression of a neurodegenerative disease or condition in a patient suffering therefrom comprising administering to said patient a therapeutically effective amount of a compound of Formula I-I or Formula I or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 40 , wherein said neurodegenerative disease of condition is selected from the group consisting of: Alzheimer's disease, Huntington's disease, Parkinson's disease, Parkinson's-plus diseases, amyotrophic lateral sclerosis (ALS), ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, invertebrate disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, prophyria, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, frontotemporal dementia, demyelinating diseases, Guillain-Barré syndrome, multiple sclerosis, Charcot-Marie-Tooth disease, prion disease, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, AIDS demential complex, nerve damage caused by exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents; injury to the nervous system caused by physical, mechanical or chemical trauma, glaucoma, lattice dystrophy, retinitis pigmentosa, age-related macular degeneration (AMD), photoreceptor degeneration associated with wet or dry AMD, other retinal degeneration, optic nerve drusen, optic neuropthy and optic neuritis. 
     
     
         42 . The method of  claim 40 , wherein the compound of Formula I-I or Formula I is administered in combination with one or more additional pharmaceutical agents.