Phosphorus-containing compounds and uses thereof

A compound of the formula:

• 74
• and pharmaceutically acceptable derivatives thereof, wherein
• A is —O—, —S— or —NR2— or is absent;
• 75
• K is O or S;
• each occurrence of Y is independently —O—, —S—, —NR2—, or a bond linking a R5 moiety to P;
• each occurrence of R2 and R5 is independently an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or H;
• and
• each occurrence of R6 is independently —PK(YR5)(YR5), —SO2(YR5) or —C(O)(YR5);
• so long as any R2 or R5 moiety linked directly to P is not H;
• wherein two R2, R5 and/or R6 moieties may be chemically linked to one another to form a ring;
• each occurrence of G is independently —O—, —S—, —NR2— or (M)x;
• each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be saturated or unsaturated;
• each occurrence of x is independently an integer from 1-6;
• wherein each of the foregoing aliphatic and heteroaliphatic moieties is independently linear or branched, or cyclic or acyclic, and substituted or unsubstituted, and each of the aryl, heteoraryl, acyl, aroyl or heteroaroyl moieties is independently substituted or unsubstituted;
• with the proviso that (a) J-A- is not (HO)2(P═O)O— or (MeO)2(P═O)O—, and (b) if JA- is (R2Y)(Me)(P═O)O—, then (R2Y) is not an immunogenic carrier material, detector carrier material or a solid matrix.

A compound of the formula:

• 76
• and pharmaceutically acceptable derivatives thereof, wherein
• J is chosen from:
• 77
• A is absent or is —O—, —S— or —NR2—;
• Q is absent or (if A is —O—, —S— or —NR2—) Q may be —V—, —OV—, —SV—, or —NR2V—, where V is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such that J is linked to the cyclohexyl ring directly, through A or through VA, OVA, SVA or NR2VA;
• K is O or S;
• each occurrence of Y is independently —O—, —S—, —NR2—, or a chemical bond linking a R5 moiety to P;
• each occurrence of R2 and R5 is independently an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or H;
• and each occurrence of R6 is independently —PK(YR5)(YR5), —SO2(YR5) or —C(O)(YR5);
• so long as any R2 or R5 moiety linked directly to P is not H;
• wherein two R2, R5 and/or R6 moieties may be chemically linked to one another to form a ring;
• each occurrence of G is independently —O—, —S—, —NR2— or (M)x;
• each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be saturated or unsaturated;
• each occurrence of x is independently an integer from 1-6;
• wherein each of the foregoing aliphatic and heteroaliphatic moieties is independently linear or branched, or cyclic or acyclic, and substituted or unsubstituted, and each of the aryl, heteoraryl, acyl, aroyl or heteroaroyl moieties is independently substituted or unsubstituted;
• in which each occurrence of R2 and R5 is an independently chosen lower aliphatic or aryl moiety, which may be substituted or unsubstituted, except that in addition, —OR5 and —NR2R5, may be —OH and —NHR5;
• with the proviso that if J-Q-A- is (R2Y)(Me)(P═O)O—, then (R2Y) is not an immunogenic carrier material, detector carrier material or a solid matrix, or a salt thereof.

A compound of the formula:

• 78
• and pharmaceutically acceptable derivatives thereof, wherein
• J is chosen from:
• 79
• A is absent or is —O—, —S— or —NR2—.
• Q is absent or (if A is —O—, —S— or —NR2—) Q may be —V—, —OV—, —SV—, or —NR2V—, where V is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such that J is linked to the cyclohexyl ring directly, through A or through VA, OVA, SVA or NR2VA;
• K is O or S;
• each occurrence of Y is independently —O—, —S—, —NR2—, or a chemical bond linking a R5 moiety to P;
• in which each occurrence of R2 and R5 is an independently chosen lower aliphatic or aryl moiety, which may be substituted or unsubstituted, except that in addition, —OR5 and —NR2R5, may be —OH and —NHR5;
• each occurrence of R6 is independently —PK(YR5)(YR5), —SO2(YR5) or —C(O)(YR5);
• so long as any R2, or R5 moiety linked directly to P is not H;
• wherein two R2, R5 and/or R6 moieties may be chemically linked to one another to form a ring;
• wherein each of the foregoing aliphatic and heteroaliphatic moieties is independently linear or branched, or cyclic or acyclic, and substituted or unsubstituted, and each of the aryl, heteoraryl, acyl, aroyl or heteroaroyl moieties is independently substituted or unsubstituted;
• with the proviso that if J-Q-A- is (R2Y)(Me)(P═O)O—, then (R2Y) contains 15 or fewer carbon atoms.

A compound comprising a derivative of rapamycin or 43-epi-rapamycin in which the hydroxyl group at position 43 is replaced by a group JQA-, wherein:

• A is —O—, —S— or —NR2— or is absent;
• Q is absent or (if A is —O—, —S— or —NR2—) Q may be —V—, —OV—, —SV—, or —NR2V—, where V is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such that J is linked to the cyclohexyl ring directly,
• 82
• through A or through VA, OVA, SVA or NR2VA;
• K is O or S;
• each occurrence of Y is independently —O—, —S—, —NR2—, or a bond linking a R5 moiety to P;
• each occurrence of R2 and R is independently an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or H;
• and each occurrence of R6 is independently —PK(YR5)(YR5), —SO2(YR5) or —C(O)(YR5);
• so long as any R2 or R5 moiety linked directly to P is not H;
• wherein two R2, R5 and/or R6 moieties may be chemically linked to one another to form a ring;
• each occurrence of G is independently —O—, —S—, —NR2— or (M)x;
• each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be saturated or unsaturated;
• each occurrence of x is independently an integer from 1-6;
• wherein each of the foregoing aliphatic and heteroaliphatic moieties is independently linear or branched, or cyclic or acyclic, and substituted or unsubstituted, and each of the aryl, heteoraryl, acyl, aroyl or heteroaroyl moieties is independently substituted or unsubstituted;
• with one or more of the following additional features:
• (a) epimerization at position 28, or replacement of the position 28 hydroxyl group (in either sterochemical orientation) with halo, —OR2 or —OC(═O)AR2;
• (b) replacement of the ketone at position 24 with a substituted or unsubstituted oxime, or with a hydroxyl group or derivative thereof of the formula —OR2 or —OC(═O)AR2;
• (c) replacement of the ketone at position 24 with a substituted or unsubstituted oxime, or with a hydroxyl group or derivative thereof of the formula —OR2 or —OC(═O)AR2;
• (d) epimerization of the —OMe at position 7 and/or replacement of the —OMe with a moiety selected from H, halo, —RA, —ORA, —SRA, —OC(O)RA, —OC(O)NRARB, —NRARB, —NRBC(O)RA, —NRBC(O)ORA, —NRBSO2RA or —NRBSO2NRARB;
• where RA is R2 and where RB is OH or R2;
• and
• (e) elimination of the —OMe at position 7 yielding the tetra-ene moiety:
• 83