Isoindoline compositions and methods for treating neurodegenerative disease

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from H, C 1 -C 6 alkyl, or CH 2 OR′;

wherein each R′ if present in R 1 , and R 2 is independently H or C 1 -C 6 alkyl;

each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCF 3 , OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R′, C(O)R′, NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR′ 2 , NC(O)R′, NS(O) n R′, S(O) n NR′ 2 , S(O) n R′, C(O)O(C 1 -C 4 alkyl), OC(O)N(R′) 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); wherein each R′ if present in R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 , wherein the optionally substituted group is selected from C 1 -C 6 alkyl or C 2 -C 7 acyl;

or R 3 and R 4 , together with the C atom to which they are attached form a 4-, 5-, 6-7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl or R 3 and R 4 are linked together to form a —O—C 1 -C 2 methylene-O-group;

or R 4 and R 5 , together with the C atom to which they are attached form a 4-, 5-, 6-7- or 8-membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl or R 4 and R 5 are linked together to form a —O—C 1-2 methylene-O-group;

each of R 7 , R 8 , R 9 , R 10 , and R 11 is independently selected from the group consisting of H, C 1 -C 6 alkyl, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCF 3 , OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), O(CO)R′, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R′, C(O)R′, NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR′ 2 , NC(O)R′, NS(O) n R′, S(O) n NR′ 2 , S(O) n R′, C(O)O(C 1 -C 4 alkyl), OC(O)N(R′) 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); wherein each R′ if present in R 7 , R 8 , R 9 , R 10 , and R il is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 ;

or R 7 and R 8 , together with the N or C atoms to which they are attached form a 4-, 5-, 6-7- or 8-membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl or R 7 and R 8 are linked together to form a —O—C 1-2 methylene-O-group;

or R 8 and R 9 , together with the N or C atoms to which they are attached form a 4-, 5-, 6-7- or 8-membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl or R 8 and R 9 are linked together to form a —O—C 1-2 methylene-O-group;

each n is independently 0, 1, or 2;

with the proviso that R 7 , R 8 , R 9 , R 10 , and R il are not all H; and

with the proviso that the following compounds, or pharmaceutically acceptable salts thereof are excluded:

2. The compound of claim 1 wherein

each R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, aryl, heteroaryl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R′, C(O)R′, N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR′ 2 , NC(O)R′, NS(O) n R′, S(O) n NR′ 2 , S(O) n R′, C(O)O(C 1 -C 4 alkyl), OC(O)N(R′) 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); each n is independently 0, 1, or 2; each R′ is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 , wherein the optionally substituted group is selected from C 1 -C 6 alkyl or C 2 -C 7 acyl.

3. The compound of claim 1 wherein each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, CO 2 R′, C(O)R′, CONR′ 2 , and S(O) n R′; each n is independently 0, 1, or 2; and each R′ if present in R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 , wherein the optionally substituted group is selected from C 1 -C 6 alkyl or C 2 -C 7 acyl.

4. The compound of claim 1 wherein at least one of R 3 , R 4 , R 5 , and R 6 is S(O) n R′; and n is 2.

5. The compound of claim 1 of Formula II

wherein at least one of R 3 , R 4 , R 5 , and R 6 is not H; and at least one of R 8 , and R 9 is not H.

6. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

7. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

8. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the amyloid beta effect is associated with cognitive decline and the subject exhibits or is at risk of exhibiting cognitive decline.

11. The method of claim 10 , wherein the amyloid beta effect is associated with cognitive impairment in Alzheimer's disease.

12. A method of treating Alzheimer's disease comprising administering to a subject having said disease an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. A composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

14. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the amyloid beta effect is associated with cognitive decline and the subject exhibits or is at risk of exhibiting cognitive decline.

16. The method of claim 15 , wherein the amyloid beta effect is associated with cognitive impairment in Alzheimer's disease.

17. A method of treating Alzheimer's disease comprising administering to a subject having said disease an effective amount of a compound of claim 6 or a pharmaceutically acceptable salt thereof.

18. A composition comprising a compound of claim 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

19. A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of claim 7 or a pharmaceutically acceptable salt thereof.

20. A method of treating Alzheimer's disease comprising administering to a subject having said disease an effective amount of a compound of claim 7 or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from H or C 1 -C 6 alkyl;

each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R′, C(O)R′, NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR′ 2 , NC(O)R′, NS(O) n R′, S(O) n NR′ 2 , S(O) n R′, C(O)O(C 1 -C 4 alkyl), OC(O)N(R′) 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); wherein each R′ if present in R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 , wherein the optionally substituted group is selected from C 1 -C 6 alkyl or C 2 -C 7 acyl;

each of R 7 , R 8 , R 9 , R 10 , and R 11 is independently selected from the group consisting of H, C 1 -C 6 alkyl, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , O(C 1 -C 6 alkyl), OCF 3 , OCH 2 CH 2 OH, O(C 1 -C 6 alkyl)OH, O(C 1 -C 6 haloalkyl), O(CO)R′, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R′, C(O)R′, NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , NH(C 3 -C 7 cycloalkyl), NHC(O)(C 1 -C 4 alkyl), CONR′ 2 , NC(O)R′, NS(O) n R′, S(O) n NR′ 2 , S(O) n R′, C(O)O(C 1 -C 4 alkyl), OC(O)N(R′) 2 , C(O)(C 1 -C 4 alkyl), and C(O)NH(C 1 -C 4 alkyl); wherein each R′ if present in R 7 , R 8 , R 9 , R 10 , and R u is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkoxy, NH(C 1 -C 4 alkyl), and N(C 1 -C 4 alkyl) 2 ;

each n is independently 0, 1, or 2;

with the proviso that R 7 , R 8 , R 9 , R 10 , and R u are not all H; and

with the proviso that the following compounds, or pharmaceutically acceptable salts thereof are excluded:

22. The compound of claim 1 wherein R 1 and R 2 are each methyl or wherein one of R 1 or R 2 is methyl, and the other is H.