Inhibitors of cognitive decline

Abstract

Compounds that are central nervous system drug candidates for the treatment of cognitive decline and, more particularly, Alzheimer's disease are provided. Methods of treating, inhibiting, and/or abatement of cognitive decline and/or Alzheimer's disease with a compound or pharmaceutically acceptable salt of the invention are also provided. Also provided are methods of preparing the compounds/compositions of the invention.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from (A1) and (A2): 
 
       
       
         
           
           
               
               
           
         
         
           R 2 , R 3 , R 4 , R 5 , and R 6  are each, independently, selected from H, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, halo, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, NH 2 , NH(C 1-4  alkyl), NH(C 3-7  cycloalkyl), N(C 1-4  alkyl) 2 , NHC(OX)(C 1-4  alkyl), SH, S(C 1-6  alkyl), C(O)OR a , C(O)R b , C(O)NR c R d , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O) 2 R b , and S(O) 2 NR c R d ; 
           R 7  is H, C 1-6  alkyl, C 1-6  haloalkyl, or C 3-7  cycloalkyl; 
           R 8  is C 1-6  alkyl, C 1-6  haloalkyl, or C 3-7  cycloalkyl; 
           R 9  is H, C 1-6  alkyl, C 1-6  haloalkyl, or C 3-7  cycloalkyl; 
           R 10  is H; 
           R 11  is H; 
           R 12 , R 13 , R 14 , R 15 , and R 16  are each, independently, selected from H, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, halo, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, NH 2 , NH(C 1-4  alkyl), NH(C 3-7  cycloalkyl), N(C 1-4  alkyl) 2 , NHC(O)(C 1-4  alkyl), SH, S(C 1-6  alkyl), C(O)OR a1 , C(O)R b1 , C(O)NR c1  R d1 , OC(O)R b1 , OC(O)NR c1  R d1 , NR c1  R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1  R d1 , S(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1  R d1 ; 
           each R a  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 
           each R b  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-4  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 
           R c  and R d  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 
           or R c  and R d  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
           each R a1  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
         
         each R b1  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
 R c1  and R d2  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1-10  alkyl, C 1-6  haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, d- 6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; 
 
         or R c1  and R d1  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and
 m is 0, 1, or 2, 
 
         with the proviso that
 (a) when R 1  is a moiety of (A1), then two of R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; and 
 (b) when R 1  is a moiety of (A1), then at least one of R 12 , R 13 , R 14 , R 15 , and R 16  is other than H. 
 
       
     
     
         2 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein two of R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy. 
     
     
         3 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , and R 6  are each, independently, selected from H, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, halo, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, NH 2 , NH(C 1-4  alkyl), NH(C 3-7  cycloalkyl), N(C 1-4  alkyl) 2 , NHC(OX C 1-6  alkyl), SH, S(C 1-6  alkyl), C(O)OH, C(O)O(C 1-4  alkyl), C(O)(C 1-4  alkyl), and C(O)NH(C 1-4  alkyl). 
     
     
         4 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is OH; and 
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is OH, C 1-6  alkoxy, or C 1-6 haloalkoxy. 
 
     
     
         5 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is OH; and 
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is C 1-3  alkoxy or C 1-3  haloalkoxy. 
 
     
     
         6 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is OH; and 
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is methoxy or trihalomethoxy. 
 
     
     
         7 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is OH; and 
 one of R 2 , R 3 , R 4 , R 5 , and R 6  is methoxy. 
 
     
     
         8 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 R 4  is OH; and 
 R 5  is methoxy. 
 
     
     
         9 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein:
 R 4  is OH; 
 R 5  is methoxy; and 
 R 2 , R 3 , and R 6  are each H. 
 
     
     
         10 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 7  is H or C 1-6  alkyl. 
     
     
         11 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 7  is H or C 1-3  alkyl. 
     
     
         12 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 7  is C 1-3  alkyl. 
     
     
         13 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 7  is H. 
     
     
         14 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 8  is C 1-6  alkyl. 
     
     
         15 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 8  is C 1-3  alkyl. 
     
     
         16 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 8  is methyl. 
     
     
         17 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 9  is H or C 1-6  alkyl. 
     
     
         18 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 9  is H or C 1-6  alkyl. 
     
     
         19 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 9  is H. 
     
     
         20 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 9  is C 1-3  alkyl. 
     
     
         21 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 10  is H or C 1-6  alkyl. 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 10  is H. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 11  is H. 
     
     
         27 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein at least one of R 2 , R 3 , R 4 , R 15 , and R 16  is other than H. 
     
     
         28 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 12 , R 13 , R 14 , R 15 , and R 16  are each, independently, selected from H, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, halo, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, NH 2 , NH(C 1-4  alkyl), NH(C 3-7  cycloalkyl), N(C 1-4  alkyl) 2 , NHC(O)(C 1-6  alkyl), SH, S(C 1-6  alkyl), C(O)OH, C(O)O(C 1-6  alkyl), C(O)(C 1-4  alkyl), and C(O)NH(C 1-4  alkyl). 
     
     
         29 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 12 , R 13 , R 14 , R 15 , and R 16  are each, independently, selected from H, halo, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, C(O)O(C 1-4  alkyl), C(O)(C 1-4  alkyl), and C(O)NH(C 1-4  alkyl). 
     
     
         30 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein at least one of R 12 , R 13 , R 14 , R 15 , and R 16  is selected from halo, CN, NO 2 , C 1-6  haloalkyl, C(O)O(C 1-6  alkyl), C(O)(C 1-4  alkyl), and C(O)NH(C 1-4  alkyl). 
     
     
         31 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein at least one of R 12 , R 13 , R 14 , R 15 , and R 16  is selected from halo and C 1-6  haloalkyl. 
     
     
         32 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 14  is halo. 
     
     
         33 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 14  is C 1-6  haloalkyl. 
     
     
         34 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein R 14  and R 15  are independently halo. 
     
     
         35 . (canceled) 
     
     
         36 . The compound of  claim 35  or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IIa: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 35  or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IIb: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 1  or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 38  or pharmaceutically acceptable salt thereof, wherein m is 1. 
     
     
         40 . The compound of  claim 38  or pharmaceutically acceptable salt thereof, wherein m is 0. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . A pharmaceutical composition comprising a compound of  claim 1  or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . A method of inhibiting, treating, and/or abatement of cognitive decline and/or inhibiting Alzheimer's disease in a patient comprising administrating to the patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method of  claim 53  wherein the method comprises inhibiting, treating, or abatement of one or more symptoms of cognitive decline selected from the group consisting of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. 
     
     
         55 . The method of  claim 53  wherein the method comprises one or more of:
 (i) restoration of long term potentiation; and/or 
 (ii) inhibiting, treating, and/or abatement of neurodegeneration; and/or 
 (iii) inhibiting, treating, and/or abatement of general amyloidosis; and/or 
 (iv) inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition; and/or 
 (v) inhibiting, treating, and/or abatement of the activity/effect of one or more of Abeta oligomers on a neuron cell. 
 
     
     
         56 . The method of  claim 53  wherein the method comprises inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition. 
     
     
         57 . The method of  claim 53  wherein the method comprises inhibiting, treating, and/or abatement of one or more of the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition. 
     
     
         58 . A method of inhibiting, treating, and/or abatement of cognitive decline and/or inhibiting Alzheimer's disease in a patient comprising administrating to the patient a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 58  wherein the method comprises inhibiting, treating, or abatement of one or more symptoms of cognitive decline selected from the group consisting of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. 
     
     
         60 . The method of  claim 58  wherein the method one or more of:
 (i) restoration of long term potentiation; and/or 
 (ii) inhibiting, treating, and/or abatement of neurodegeneration; and/or 
 (iii) inhibiting, treating, and/or abatement of general amyloidosis; and/or 
 (iv) inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, amyloid oligomer binding, and amyloid deposition; and/or 
 (v) inhibiting, treating, and/or abatement of the activity/effect of one or more of Abeta oligomers on a neuron cell. 
 
     
     
         61 . The method of  claim 58  wherein the method comprises inhibiting, treating, and/or abatement of one or more of amyloid production, amyloid assembly, the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition. 
     
     
         62 . The method of  claim 58  wherein the method comprises inhibiting, treating, and/or abatement of one or more of the activity/effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition.