Bi-functional molecules to degrade circulating proteins

A bifunctional compound according to the chemical structure:

• wherein [IgGBM] is a peptide IgG binding moiety selected from the group consisting of
• PAM;
• D-PAM;
• D-PAM-Φ;
• (SEQ ID NO:
• 1)
• TWKTSRISIF;
• (SEQ ID NO:
• 2)
• FGRLVSSIRY;
• Fc-III;
• FcBP-1;
• FcBP-2;
• Fc-III-4c;
• (SEQ ID NO:
• 3)
• EPIHRSTLTALL;
• (SEQ ID NO:
• 4)
• APAR;
• FcRM;
• (SEQ ID NO:
• 5)
• HWRGWV;
• (SEQ ID NO:
• 6)
• HYFKFD;
• (SEQ ID NO:
• 7)
• HFRRHL;
• (SEQ ID NO:
• 8)
• HWCitGWV;
• D2AAG;
• DAAG;
• (SEQ ID NO:
• 9)
• cyclo[(N-Ac)S(A)-RWHYFK-Lact-E];
• (SEQ ID NO:
• 10)
• cyclo[(N-Ac)-Dap(A)-RWHYFK-Lact-E];
• (SEQ ID NO:
• 11)
• cyclo[Link-M-WFRHYK];
• (SEQ ID NO:
• 12)
• NKFRGKYK;
• (SEQ ID NO:
• 13)
• NARKFYKG;
• (SEQ ID NO:
• 14)
• FYWHCLDE;
• (SEQ ID NO:
• 15)
• FYCHWALE;
• (SEQ ID NO:
• 16)
• FYCHTIDE;
• Dual 1/3;
• (SEQ ID NO:
• 17)
• RRGW;
• and
• (SEQ ID NO:
• 18)
• KHRFNKD;
• wherein [ASGPRBM] is an asialoglycoprotein receptor binding moiety according to the chemical structure:
• wherein X is 1 to 4 atoms in length and is independently at each occurrence selected from the group consisting of O, S, N(RN1), and C(RN1)(RN1), provided that:
• when X is 1 atom in length, X is O, S, N(RN1), or C(RN1)(RN1),
• when X is 2 atoms in length, no more than 1 atom of X is O, S, or N(RN1),
• when X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S, or
• N(RN1);
• wherein RN1 is H or C1-C3 alkyl optionally substituted with 1 to 3 halogen groups;
• wherein:
• R1 and R3 are each independently H, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, C1-C4 alkyl optionally substituted with 1 to 3 halogen groups, —(CH2)Kvinyl, —O—(CH2)Kvinyl, —(CH2)Kalkynyl, —(CH2)KCOOH, —(CH2)KC(O)O—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, O—C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, —C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, or
• R1 and R3 are each independently
• which is optionally substituted with up to three halogen groups;
• C1-C4 alkyl, each of which alkyl group is optionally substituted with from one to three halogen groups or one or two hydroxyl groups:
• or O—(C1-C4 alkyl), each of which alkyl groups is optionally substituted with from one to three halogen groups or one or two hydroxyl groups:
• R1 and R3 are each independently a group according to the chemical structure:
• wherein R7 is O—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups or 1-2 hydroxy groups, —NRN3RN4, or
• R1 and R3 are each independently a group according to the structure:
• or
• R1 and R3 are each independently
• wherein
• is a C3-C8 saturated carbocyclic group;
• wherein:
• RC is absent, H, C1-C4 alkyl optionally substituted with from 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or a group according to the structure:
• wherein R4, R5 and R6 are each independently, H, halogen, CN, NRN1RN2, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, C1-C3 alkyl optionally substituted with 1-3 halogen groups, —O—(C1-C3-alkyl) optionally substituted with 1-3 halogen groups, —(CH2)KCOOH, —(CH2)KC(O)O—(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, or —C(O)—(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, or
• wherein RC is
• wherein RN, RN1, and RN2 are each independently H or C1-C3 alkyl optionally substituted with 1 to 3 halogen groups or 1 or 2 hydroxyl groups:
• wherein each K is independently 0, 1, 2, 3, or 4:
• wherein each —(CH2)K group is optionally substituted with 1 to 4 C1-C3 alkyl groups which are optionally substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups;
• wherein each K′ is independently 1, 2, 3, or 4;
• wherein RN3 is H, or C1-C3 alkyl optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxy groups;
• wherein RN4 is H, C1-C3 alkyl optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxy groups, or
• wherein
• is a linker group comprising at least one [IgGBM] group and links the at least one [IgGBM] group to the [ASGPRBM] through one or more optional [CON] groups,
• or
• is a linker group comprising at least one or more functional groups that covalently bond the linker group to at least one [IgGBM] group or optional [CON] group;
• wherein:
• R2 is
• wherein RAM is H, C1-C4 alkyl optionally substituted with up to 3 halogen groups and one or two hydroxyl groups, —(CH2)KCOOH, —(CH2)KC(O)O—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, —O—C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, —C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, —(CH2)K—NRN3RN4;
• or
• R2 is
• wherein:
• RTA is H, CN, NRN1RN2, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, C1-C4 alkyl optionally substituted with 1 to 3 halogen groups, —(CH2)KCOOH, —(CH2)KC(O)O—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, —O—C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, or —C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, or
• RTA is C3-C10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroatoms, each of the aryl or heteroaryl groups being optionally substituted with up to three CN, NRN1RN2, —(CH2)KOH, —(CH2)KO(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, C1-C3 alkyl optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxy groups, —O—(C1-C3-alkyl) optionally substituted from 1-3 halogen groups, —(CH2)KCOOH, —(CH2)KC(O)O—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, O—C(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, or —(CH2)KC(O)—(C1-C4 alkyl) optionally substituted with 1 to 3 halogen groups, or
• RTA is
• optionally substituted with up to three C1-C3 alkyl groups which are optionally substituted with up to three halogen groups, or
• RTA is
• each [CON] is an optional connector chemical moiety which, when present, is a group according to the structure:
• i) a group according to:
• wherein:
• RCON1 and RCON2 are each independently H, methyl, or a bond;
• X2 is CH2, O, S, NR4, C(O), S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
• X3 is O, S, or NR4;
• and
• R4 is H, C1-C3 alkyl or alkanol, or —C(O)(C1-C3 alkyl);
• or
• ii) a group according to the structure:
• wherein:
• R1 is H or C1-C3 alkyl, and
• n″ is independently an integer from 0 to 8;
• or
• iii) a group according to the chemical structure:
• wherein R1CON, R2CON, and R3CON are each independently H, —(CH2)MC1—, —(CH2)MC1aC(O)XA(N4)XA—(CH2)MC1a—, —(CH2)MC1a(NR4)XAC(O)XA—(CH2)MC1a—, or —(CH2)MC1aO—(CH2)MC1—C(O)NR4—,
• with the proviso that R1CON, R2CON, and R3CON are not simultaneously H;
• each MC1 is independently 1, 2, 3, or 4;
• each MC1a is independently 1, 2, 3, or 4;
• each XA is independently 0 or 1;
• and
• R4 is H, C1-C3 alkyl, C1-C3 alkanol, or —C(O)(C1-C3 alkyl),
• with the proviso that MC1a and XA in a moiety are not all simultaneously 0;
• wherein [LINKER] is:
• i) a polyethyleneglycol linker having from 1 to 12 ethylene glycol residues,
• ii) a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing 1 to 100 alkylene glycol units,
• iii) a group according to the chemical structure:
• wherein
• Ra is H, C1-C3 alkyl or alkanol, or Ra taken together with R3 forms a pyrrolidine ring or a hydroxypyrrolidine ring,
• m is independently an integer from 1 to 15, and
• R3 is an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R3 forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl);
• iv) a group according to the chemical structure:
• wherein:
• Ram is H or C1-C3 alkyl optionally substituted with one or two hydroxyl groups;
• na is an integer from 1 to 15;
• and
• m is an integer from 1 to 100;
• v) a group according to the chemical formula:
• wherein:
• Z and Z′ are each independently a bond, —(CH2)i—O—, —(CH2)i—S—, —(CH2)i—N(R)—,
• wherein:
• the —(CH2)i group, if present in Z or Z′, is bonded to a connector group
• [CON], [IgGBM], or [ASGPRBM];
• each R is H, or C1-C3 alkyl or alkanol;
• each R2 is independently H or C1-C3 alkyl;
• each Y is independently a bond, O, S, or N—R;
• each i is independently 0 to 100;
• D is
• or a bond, with the proviso that Z, Z′, and D are not each simultaneously bonds;
• j is an integer from 1 to 100:
• m′ is an integer from 1 to 100
• n is an integer from 1 to 100;
• X1 is O, S, or N—R:
• R is H, C1-C3 alkyl, or C1-C3 alkanol;
• and
• vi) a group with the chemical structure:
• wherein
• n is an integer from 1 to 25;
• n′ is an integer from 1 to 25;
• n″ is an integer from 0 to 8;
• or
• vii) a group with the chemical formula:
• PEG-[CON]-PEG,
• wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues and [CON] is a triazole group
• wherein k′ is independently 1, 2, or 3;
• wherein j′ is independently 1, 2, or 3;
• wherein h is independently 1, 2, or 3;
• wherein h′ is independently 1, 2, or 3,
• wherein iL is independently 1, 2, or 3,
• or a salt, stereoisomer, or solvate thereof.