Bilobalide derivative compounds for treating neurological diseases and cancers

A compound of Formula I:

• or a stereomer, a tautomer, or a pharmaceutically acceptable salt thereof,
• wherein
• X is —O—, —NR1—, —N═CR1—NH—, or —NR1—NH—;
• wherein when X is —O—, R1 is absent;
• bond Y1 is between R4 and R5 and is a single bond or a double bond;
• R1 is H, R1B, or -(L1)u-(Z1)v;
• wherein
• L1 is C1-C10 aliphatic wherein up to three carbon atoms of the C1-C10 aliphatic are optionally replaced by N, O, or S;
• wherein L1 is optionally substituted with 1-3 occurrences of halo, CN, R, OR′, or R1C;
• u is 0 or 1;
• v is 0 or 1;
• Z1 is a 5-16 membered aromatic or nonaromatic monocyclic, bicyclic, or tricyclic ring system having 0-7 heteroatoms selected from O, N, or S;
• wherein Z1 is optionally substituted with 1-5 occurrences of R1A, R1C or combinations thereof;
• R1A is -(L2)m-(Z2)w;
• wherein
• L2 is C1-C10 aliphatic wherein up to three carbon atoms of the C1-C10 aliphatic are optionally replaced by N, NR, O, S, C═O, SO2, S═O, (C═O)N, N(C═O)N, (C═O)O, or Si;
• wherein L2 is optionally substituted with 1-3 occurrences of halo, CN, R, OR′ or R1C;
• m is 0 or 1;
• w is 0 or 1;
• Z2 is a C1-C10 aliphatic, or 3-16 membered aromatic or nonaromatic monocyclic, bicyclic or tricylic ring system having 0-7 heteroatoms selected from O, N, or S;
• wherein Z2 is optionally substituted with 1-5 occurrences of R1B;
• R1B is H, halo, CN, R*, OR*, NRR*;
• or two R1B, taken together with the atom to which they are attached, form a 3-6 membered ring having 0-4 heteroatoms;
• R1C is H, halo, CN, a 5-10 membered aromatic or nonaromatic monocyclic or bicyclic ring system having 0-5 heteroatoms selected from O, N, or S;
• R*, OR*, NRR*;
• or two R1C, taken together with the atom or atoms to which they are attached, optionally form a 3-16 membered ring having 0-4 heteroatoms;
• wherein R1C is optionally substituted with 1-3 occurrences of halo, CN, R′ or OR′;
• R* is C1-C6 aliphatic wherein up to three methylene units of the C1-C6 aliphatic are optionally replaced by N, NR, O, S, C═O, SO, SO2 or Si and wherein the C1-C6 aliphatic is optionally substituted with 1-3 occurrences of halo, CN, R′ or OR′;
• R2 is R2A or OR2A, wherein R2A is H, a C1-C16 aliphatic, a 5-10 membered aromatic or nonaromatic monocyclic or bicyclic ring system, or —(C1-C16 aliphatic)-(5-10 membered aromatic or nonaromatic monocyclic or bicyclic ring system);
• wherein up to five carbon atoms of the C1-C16 aliphatic or the 5-10 membered aromatic or nonaromatic monocyclic or bicyclic ring system are optionally replaced by N, NR, O, S, C═O, SO2, S═O, (C═O)N, N(C═O)N, (C═O)O, or Si;
• wherein R2A is optionally substituted with 1-5 occurrences of R2B, wherein R2B is halo, R′ or OR′;
• R3 is OH, R3A, or OR3A;
• wherein R3A is C1-C10 aliphatic optionally substituted with 1-3 occurrences of halo, R or OR′;
• R4 is OH, R4A, OR4A;
• or when bond Y1 between R4 and R5 is a double bond, R4 is absent;
• wherein R4A is C1-C7 aliphatic and R4A is optionally substituted with 1-3 occurrences of halo, R′ or OR′;
• R5 is H or OH;
• R6 is H;
• or when bond Y1 between R4 and R5 is a double bond, R6 is absent;
• R is H or C1-C6 aliphatic optionally substituted by 1-3 occurrences of F;
• or two R, taken together with the atom(s) to which they are attached, form a 3-6 membered ring having 0-4 heteroatoms;
• and
• R′ is H, a C1-C6 aliphatic wherein up to three carbon atoms of the C1-C6 aliphatic are optionally replaced with O, NH, N(C1-C6 alkyl), C(O), or S(O)2;
• wherein said C1-C6 aliphatic is optionally substituted by 1-3 occurrences of F, OR, NH2, NHR″, or NR″2, wherein R″ is C1-C6 aliphatic or a 5-10 membered aromatic or nonaromatic monocyclic or bicyclic ring system having 0-5 heteroatoms selected from O, N, or S;
• wherein when R2 is OH, R3 is tert-butyl, R4 is OH, R5 is H, and R6 is H, X is not —O—.