Cyclohexane-1,3-diones for use in the treatment of amyotrophic lateral sclerosis

1. A method comprising administering to a subject suffering from or susceptible to amyotrophic lateral sclerosis (ALS) an effective amount of a compound of a formula:

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted benzyl, or two R on the same carbon are taken together to form a 5-6 membered saturated, partially saturated, or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 1 , R 2 , and R 3 are each independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)(CO)R, —NRC(O)N(R) 2 , —NRC(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 , or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L is a valence bond or a bivalent saturated or partially unsaturated, branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of L are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —, and wherein L is optionally substituted with 1-4 R groups, wherein two R on the same carbon or on adjacent carbons are optionally taken together to form a 3-6 membered saturated spirocyclic or fused monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0-5;

each R a is independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)(CO)R, —NRC(O)N(R) 2 , —NRC(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 , or:

two R a on adjacent carbons are taken together to form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl fused ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

at least one R a is independently

wherein Q is a valence bond or a bivalent optionally substituted saturated or partially unsaturated, branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of Q are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —;

Ring B is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-5;

each R b is independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)C(O)R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 ; and

R 4 and R 4′ are each independently R, or R 4 and R 4′ are taken together to form an alkenylene optionally substituted with one or two R c groups; wherein

each R c is independently —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R c is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R c is optionally substituted with p occurrences of R d , wherein:

p is 0 to 5; and

each R d is independently —R, —OR, —CN, —C(R) 3 , —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 , thereby reducing the severity or incidence of one or more symptoms of ALS or delaying onset thereof.

2. The method according to claim 1 wherein L is a bivalent saturated branched or unbranched C 1-10 hydrocarbon chain.

3. The method according to claim 2 , wherein Ring A is a 5-6 membered aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The method according to claim 3 , wherein Ring A is of the formula:

wherein m is 0-5.

5. The method according to claim 2 , wherein 1 methylene unit of L is replaced by —NR—, —O—, —S—, —C(O)—, or —C(O)O—.

6. The method according to claim 5 , wherein L is selected from a bivalent saturated C 2 -C 3 hydrocarbon chain and a bivalent saturated C 2 -C 3 hydrocarbon chain wherein 1 methylene unit of L is replaced by —O—, and wherein L is substituted with 1-2 R groups.

7. The method according to claim 6 , wherein Ring A is of the formula:

wherein m is 1-5.

8. The method according to claim 7 , wherein each R a is independently fluorine, chlorine, methyl, ethyl, propyl, butyl, methoxy, propoxy, butoxy or trifluoromethyl.

9. The method according to claim 8 , wherein m is 1-2.

10. The method according to claim 9 , wherein Ring A is of the formula:

11. The method according to claim 10 , wherein R 3 is selected from H, methyl and trifluoromethyl.

12. The method according to claim 1 , of any of the formulae:

or a stereochemically isomeric form thereof.

13. The method according to claim 1 wherein a symptom of ALS is abnormal aggregation of an SODI protein.

14. The method of claim 13 wherein said subject is a human.

15. A method comprising administering to a subject suffering from or susceptible to amyotrophic lateral sclerosis (ALS) an effective amount of a compound of formula I-a or I-b:

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic;

R 1 , R 2 , and R 3 are each independently —R, or —OR;

L is a bivalent saturated branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of L are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 , —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —, and wherein L is optionally substituted with 1-4 R groups, wherein two R on the same carbon or on adjacent carbons are optionally taken together to form a 3-6 membered saturated spirocyclic or fused monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0-5; and

each R a is independently —R, or —OR, thereby reducing the severity or incidence of one or more symptoms of ALS or delaying onset thereof.

16. The method according to claim 15 , of the formula:

where each of R, R 1 , R 2 and R 3 is independently selected from H, C 1 -C 4 alkyl and trifluoromethyl.

17. The method according to claim 16 , wherein each of R 1 , R 2 and R 3 is H.

18. The method according to claim 17 , wherein each R taken together forms a 3-membered ring.

19. The method according to claim 18 , wherein Ring A is substituted phenyl.

20. The method according to claim 19 , selected from

21. The method according to claim 15 of the formula:

22. The method according to claim 21 , wherein R 1 and R 2 are H, and R 3 and each R is independently selected from H, CH 3 and CF 3 .

23. The method according to claim 22 , wherein Ring A is substituted phenyl.

24. The method according to claim 23 , selected from

25. The method according to claim 15 wherein a symptom of ALS is abnormal aggregation of an SODI protein.

26. The method of claim 25 wherein said subject is a human.

27. A method comprising administering to a subject suffering from or susceptible to amyotrophic lateral sclerosis (ALS) an effective amount of a compound of a formula:

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently hydrogen, halogen, or optionally halo-substituted C 1-6 aliphatic;

L is a bivalent saturated unbranched C 1-6 hydrocarbon chain, wherein 1-3 methylene units of L are optionally and independently replaced by —NR— or —O, and wherein L is optionally substituted with 1-4 R groups, wherein two R on the same carbon or on adjacent carbons are optionally taken together to form a 3-6 membered saturated spirocyclic or fused monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0-5; and

each R a is independently —R or —OR, thereby reducing the severity or incidence of one or more symptoms of ALS or delaying onset thereof.

28. The method according to claim 27 , wherein L is selected from a bivalent saturated C 2 -C 3 hydrocarbon chain and a bivalent saturated C 2 -C 3 hydrocarbon chain wherein 1 methylene unit of L is replaced by —O—, and wherein L is substituted with 1-2 R groups.

29. The method according to claim 28 , wherein L is a bivalent saturated C 2 hydrocarbon chain, and Ring A is substituted phenyl.

30. The method according to claim 29 , selected from

31. The method according to claim 28 , wherein L is a bivalent saturated C 2 hydrocarbon chain wherein one methylene unit is replaced by —O—, and Ring A is substituted phenyl.

32. The method according to claim 31 , wherein L is substituted with a trifluoromethyl group.

33. The method according to claim 32 , selected from

34. The method of claim 27 in a pharmaceutical composition comprising a pharmaceutically-acceptable excipient.

35. The method according to claim 27 wherein a symptom of ALS is abnormal aggregation of an SODI protein.

36. The method of claim 35 wherein said subject is a human.