Rapafucin derivative compounds and methods of use thereof

A tagged compound of macrocyclic compound according to Formula (XII):

• or a pharmaceutically acceptable salt or stereoisomer thereof
• with a compound of Formula (XIV):
• wherein
• Ring A is a 5-10 membered aryl, cycloalkyl, heteroaryl or heterocycloalkyl, optionally substituted with 1-17 substituents, each of which is independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, dialkylamino,
• wherein is a resin;
• Lb and Lc are independently selected from the group consisting of a bond, —O—, —S—, —OC(O)—, —C(O)O—, —(CH2)nC(O)—, —(CH2)nC(O)C(O)—, —(CH2)nNR5C(O)C(O)—, —NR5(CH2)nC(O)C(O)—, optionally substituted (CH2)nC1-6 alkylene-(CH2)n—, optionally substituted (CH2)nC(O)C1-6 alkylene-(CH2)n—, optionally substituted (CH2)nNR5C1-6 alkylene-(CH2)n—, optionally substituted (CH2)nC(O)NR5C1-6 alkylene-(CH2)n—, optionally substituted (CH2)nNR5C(O)C1-6 alkylene-(CH2)n—, optionally substituted (CH2)nC(O)OC1-6 alkylene-(CH2)n—, optionally substituted (CH2)nOC(O)C1-6 alkylene-(CH2)n—, optionally substituted (CH2)˜OC1-6 alkylene-(CH2)n—, optionally substituted (CH2)nNR5C1-6 alkylene-(CH2)n—, optionally substituted (CH2)n—S—C1-6 alkylene-(CH2)n—, and optionally substituted (CH2CH2O)n;
• wherein each alkylene is optionally substituted with 1 or 2 groups independently selected from the group consisting of of halo, hydroxy, haloalkyl, haloalkoxy, alkyl, alkoxy, amino carboxyl, cyano, nitro, NHFmoc;
• wherein each R5 is independently hydrogen, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• Q and Q′ are independently selected from the group consisting of —N3, —C—C≡H, NR6R7, —COOH, —ONH2, —SH, —NH2,
• —(C═O)R′,
• wherein R6 and R7is each independently hydrogen, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• and R′ is hydrogen, alkyl, arylalkyl, or haloalkyl;
• X is O, S or NR8, wherein R8 is hydrogen, hydroxy, OR9, NR10R11, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• wherein R9, R10 and R11 are each independently hydrogen or alkyl;
• V1 and V2 are each independently
• W is
• wherein Ring B is a 4-10 membered heterocycloalkyl, optionally substituted with 1-10 substituents, each of which is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, dialkylamino, arylalkyl,
• wherein R12 is aryl, alkyl, or arylalkyl;
• wherein R13 is hydrogen, hydroxy, OR16, NR17R18, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• R14 and R15 is each independently hydrogen, hydroxy, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, arylalkyl, or heteroaryl;
• Z is bond,
• wherein R16 and R17 are each independently selected from the group consisting of of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, cyano, alkylthio, amino, alkylamino, and dialkylamino;
• K is O, CHR18, CR18, N, and NR18, wherein R18 is hydrogen or alkyl;
• La, L1, L2, L3, L4, L5, L6, L7 and L8 are each independently a bond, —O—, —NR19—, —SO—, —SO2—, —(CH2)n—,
• or optionally substituted (CH2)nN20C1-6 alkylene;
• wherein Ring C is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents, each of which is independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy haloalkyl haloalkoxy, cyano, alkylthio, amino, alkylamino, dialkylamino and
• wherein R19 is selected from the group consisting of hydrogen, hydroxy, OR22, NR23R24, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• wherein R22, R23, and R24 are each independently hydrogen or alkyl;
• n is 0, 1, 2, 3, 4, 5 or 6;
• wherein the Effector Domain has Formula (XIIa):
• each ka, kb, kc, kd ke, kf, kg, kh, and ki is independently 0 or 1;
• each Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, and Xi is independently a bond, —S—, —S—S—, —S(O)—, —S(O)2—, substituted or unsubstituted —(C1-C3) alkylene-, —(C2-C4) alkenylene-, —(C2-C4) alkynylene-, or
• wherein Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl;
• wherein each w is independently 0, 1, or 2;
• each R1, R1a, R1b, R1c, R1d, R1e, R1f, R1g, R1h, R1i, and R4 is independently hydrogen, alkyl, arylalkyl or NR25, wherein R25 is hydrogen, hydroxy, OR26, NR27R28, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• wherein R26, R27, and R28 are each independently hydrogen or alkyl;
• each R2, R3, R2a, R3a, R2b, R3b, R2c, R3c, R2d, R3d, R2e, R3e, R2f, R3f, R2g, R3g, R2h, R3h, R2i, and R3i is independently selected from the group consisting of hydrogen, halo, amino, cyano, nitro, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and
• or wherein the Effector Domain has Formula (XIIb):
• wherein each of AA1, AA2, . . . , and AAr is an natural or unnatural amino acid residue;
• and r is 3, 4, 5, 6, 7, 8, 9, or 10;
• or wherein the Effector Domain has Formula (XIIc):
• each t is independently an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• R29 is hydrogen, hydroxy, OR30, NR31R32, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• wherein R30, R31, and R32 are each independently hydrogen or alkyl;
• X3 is substituted or unsubstituted —(C1-C6) alkylene-, —(C2-C6) alkenylene-, —(C2-C6) alkynylene-, or
• wherein Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl;
• wherein each w is independently 0, 1, or 2;
• or wherein the Effector Domain has Formula (XIId):
• X4 is substituted or unsubstituted —(C1-C6) alkylene-, —(C2-C6) alkenylene-, —(C2-C6) alkynylene-, or
• wherein Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl;
• wherein each w is independently 0, 1, or 2;
• or wherein the Effector Domain has Formula (XIIe):
• R33, R34, R35 and R36 are each hydrogen or alkyl;
• X5 is substituted or unsubstituted —(C1-C6) alkylene-, —(C2-C6) alkenylene-, —(C2-C6) alkynylene-, or
• wherein Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl;
• wherein each w is independently 0, 1, or 2;
• or wherein the Effector Domain has Formula (XIIf):
• X6 is substituted or unsubstituted —(C1-C6) alkylene-, —(C2-C6) alkenylene-, —(C2-C6) alkynylene-, or
• wherein Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl;
• wherein each w is independently 0, 1, or 2;
• and provided that when Ring A is
• La is ethylene, X is O, W is
• V1 is
• V2 is
• Z is
• -L6-L7-L8- is
• and -L1-L2-L3-L4-L5- is not
• D is an oligonucleotide;
• wherein Ring A is substituted with at least one
• or at least one of R2, R3, R2a, R3a, R2b, R3b, R2c, R3c, R2d, R3d, R2e, R3e, R2f, R3f, R2g, R3g, R2h, R3h, R2i, and R3i is
• or at least one of La, L1, L2, L3, L4, L5, L6, L7 and L8 is Ring C substituted with at least one
• or wherein the optionally substituted (CH2)nNR20C1-6 alkylene is substituted with at least one
• each R20 is independently selected from the group consisting of hydrogen, OR22, NR23R24, alkyl, arylalkyl,
• wherein RN is aryl, alkyl, or arylalkyl;
• wherein R22, R23, and R24 are each independently hydrogen or alkyl;
• and
• wherein the oligonucleotide (D) is linked to at least one of X—V1-W—V2—Z, L1-L2-L3-L4-L5, L6-L7-L8, or the effector domain of Formula (XII).