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

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 C1-6 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;
• R1, R2, and R3 are each independently —R, —OR, —SR, —S(O)R, —SO2R, —OSO2R, 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)SO2R, —N(R)SO2OR, —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 C1-10 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)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO2—, 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 Ra is independently —R, —OR, —SR, —S(O)R, —SO2R, —OSO2R, 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)SO2R, —N(R)SO2OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R)2, —OC(O)N(R)2, or:
• two Ra 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 Ra is independently
• wherein Q is a valence bond or a bivalent optionally substituted saturated or partially unsaturated, branched or unbranched C1-10 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)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO2—;
• 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 Rb is independently —R, —OR, —SR, —S(O)R, —SO2R, —OSO2R, 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)SO2R, —N(R)SO2OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R)2, —OC(O)N(R)2;
• and
• R4 and R4′ are each independently R, or R4 and R4′ are taken together to form an alkenylene optionally substituted with one or two Rc groups;
• wherein
• each Rc is independently —R, —OR, —CN, —NO2, —SR, —S(O)R, —SO2R, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, —N(R)2, or wherein Rc 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 Rc is optionally substituted with p occurrences of Rd, wherein:
• p is 0 to 5;
• and
• each Rd is independently —R, —OR, —CN, —C(R)3, —NO2, —SR, —S(O)R, —SO2R, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2, thereby reducing the severity or incidence of one or more symptoms of ALS or delaying onset thereof.