Biheteroaryl compounds and uses thereof

Abstract

The present invention provides for compounds of Formula 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 all have the meaning as defined herein.

1 . Compounds 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; 
         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, 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(═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 C Y) 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, 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. 
       
     
     
         2 - 4 . (canceled) 
     
     
         5 . A compound of  claim 1 , wherein X 2  is N. 
     
     
         6 . A compound of  claim 1 , wherein X 2  is C(H). 
     
     
         7 - 12 . (canceled) 
     
     
         13 . 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. 
     
     
         14 . A compound of  claim 1 , wherein R 1 , R 2  and R 3  are each hydrogen. 
     
     
         15 . 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. 
     
     
         16 . 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. 
     
     
         17 . (canceled) 
     
     
         18 . 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,5 S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5 S)-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. 
     
     
         19 . A compound of  claim 1 , wherein is A is selected from the group consisting of methyl, ethyl, isopropyl, 
       
         
           
           
               
               
           
         
       
     
     
         20 . 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. 
     
     
         21 . 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. 
     
     
         22 . A compound of  claim 1 , wherein Cy is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         23 - 27 . (canceled) 
     
     
         28 . A compound of claim of  claim 1 , wherein Cy is optionally substituted with 1 to 5 R Cy  substituents selected from the group consisting of F, Cl, Br, I, CN, OH, 2,3-difluorophen-1-yl-C(═O)—, 4-fluorophen-1-yl-C(═O)—, 3-fluorophen-1-yl-C(═O)—, 3,5-difluorophen-1-yl-C(═O)—, 3-fluoro-4-methyl-phen-1-yl-C(═O)—, 2,5-difluorophen-1-yl-C(═O)—, oxetane, oxetan-3-yl, thiazole, thiazol-2-yl, —CH 3 CH 2 C(═O)—, CH 3 C(═O)—, CF 3 CH 2 —, (HO)C(CH 3 ) 2 CH 2 —, CH 3 OCH 2 CH 2 —, CH 3 OC(CH 3 ) 2 C(═O)—, CH 3 OCH 2 C(═O)—, isopropyl, ethyl and methyl. 
     
     
         29 . 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. 
     
     
         30 . A compound of  claim 1 , wherein said compound is selected from the subformula consisting of 
       
         
           
           
               
               
           
         
       
     
     
         31 . (canceled) 
     
     
         32 . 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. 
       
     
     
         33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         35 - 46 . (canceled) 
     
     
         47 . 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 or a pharmaceutically acceptable salt thereof. 
     
     
         4 - 49 . (canceled) 
     
     
         50 . The method of  claim 47 , wherein the compound of formula I is administered in combination with one or more additional pharmaceutical agents. 
     
     
         51 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, said compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         52 . A method of preparing a compound of  claim 1 .