Bi-functional molecules to degrade circulating proteins

1 . A compound, or a pharmaceutically acceptable salt thereof, according to the chemical structure:

wherein:

[IgGBM] is an IgG binding moiety selected from the group consisting of

FcBP-1,

FcBP-2, and

[ASGPRBM] has the structure

wherein:

Z B is absent, —(CH 2 ) IM —, —C(═O)—(CH 2 ) IM —, or —C(═O)—(CH 2 ) IM —NR M —,

each occurrence of IM is independently 1, 2, or 3, and

R M is H or C 1 -C 3 alkyl;

each [CON] is independently selected from the group consisting of:

i) a group according to the structure:

wherein:

X 2 is independently at each occurrence —CH 2 —, —O—, —S—, —NR 4 —, —C(═O)—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, or —OS(═O) 2 O—;

X 3 is independently at each occurrence —O—, —S—, or —N(R 4 )—; and

R 4 is independently at each occurrence H, C 1 -C 3 alkyl, C 1 -C 3 alkanol, or —C(═O)(C 1 -C 3 alkyl);

or

ii) a group according to the structure:

wherein:

each R 1 is independently H or C 1 -C 3 alkyl; and

n″ is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8,

or

iii) a group according to the structure:

wherein

each occurrence of R 1CON , R 2CON , and R 3CON are each independently H, —(CH 2 ) MC1 —, —(CH 2 ) MC1a C(═O) XA (NR 4 ) XA —(CH 2 ) MC1a —, —(CH 2 ) MC1a (NR 4 ) XA C(═O) XA —(CH 2 ) MC1a —, or —(CH 2 ) MC1a O—(CH 2 ) MC1 —C(═O)NR 4 —,

with the proviso that R 1CON , R 2CON , and R 3CON are not simultaneously H;

each occurrence of MC1 is independently 1, 2, 3, or 4;

each occurrence of MC1a is independently 0, 1, 2, 3, or 4;

each occurrence of XA is independently 0 or 1; and

each R occurrence of 4 is independently H, C 1 -C 3 alkyl, C 1 -C 3 alkanol, or —C(═O)(C 1 -C 3 alkyl),

with the proviso that MC1a and XA in a moiety are not all simultaneously 0;

and

[LINKER] is independently at each occurrence selected from the group consisting of:

i) a polyethyleneglycol linker having from 2 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 structure:

wherein

each R a is independently H, C 1 -C 3 alkyl, or C 1 -C 3 alkanol, or R a combines with R 3 , the adjacent nitrogen, and the alpha carbon within the

 unit to form a pyrrolidine ring or a hydroxypyrrolidine ring,

each occurrence of m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and

R 3 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 (R 3 combines with R a , the adjacent nitrogen, and the alpha carbon within the

 unit 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 structure:

wherein:

each R am is independently H or C 1 -C 3 alkyl optionally substituted with up to two hydroxyl groups;

each occurrence of na is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

m is an integer ranging from 1 to 100;

v) a group according to the structure:

wherein:

Z and Z′ are each independently a bond, —(CH 2 ) i —O—, —(CH 2 ) i —S—, —(CH 2 ) i —N(R)—,

 wherein the —(CH 2 ) i group, if present in Z or Z′, is bonded to a connector group [CON], [IgGBM], or [ASGPRBM];

each R 2 is independently H or C 1 -C 3 alkyl;

each Y is independently a bond, —O—, —S—, or —N(R)—;

each i is independently an integer ranging from 0 to 100;

D is a bond, —(CH 2 ) i —Y—C(═O)—Y—(CH 2 ) i —, —(CH 2 ) m′ —, or

 with the proviso that Z, Z′, and D are not each simultaneously bonds;

j is an integer ranging from 1 to 100;

m′ is an integer ranging from 1 to 100;

n is an integer ranging from 1 to 100;

each occurrence of X 1 is —O—, —S—, or —N(R)—;

each occurrence of R is independently H, C 1 -C 3 alkyl, or C 1 -C 3 alkanol;

vi) a group according to the structure:

wherein

n is an integer ranging from 1 to 25;

n′ is an integer ranging from 1 to 25;

n″ is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

or

vii) a group with the formula: PEG-[CON]-PEG, wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues and [CON] is a triazole group

k′ is 1;

j′ is 1;

h and h′ are each independently 0, 1, 2, 3, 4, 5, or 6;

i L is 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

with the proviso that at least one of h and h′ is at least 1.

2 . A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

wherein:

Extracellular Protein Targeting Ligand is an IgG binding moiety selected from the group consisting of Fc-III, FcBP-1, FcBP-2, and Fc-III-4c,

R 2 is —NR 8 —C(═O)R 10 ;

R 8 is hydrogen;

R 10 is hydrogen, methyl, or —NR 6 -heteroaryl, wherein the heteroaryl is a 5- or 6-membered ring containing one to three atoms independently selected from the group consisting of N, O, and S;

R 5 at each occurrence is independently selected from the group consisting of hydrogen, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-SR 6 , and C 0 -C 6 alkyl-NR 6 R 7 ;

R 6 and R 7 are independently at each occurrence hydrogen or methyl;

each occurrence of Linker A is independently:

wherein:

R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are independently at each occurrence selected from the group consisting of a bond, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NR 6 —, —NR 6 C(O)—, —O—, —NR 6 —, —CH 2 CH 2 —[O—(CH 2 ) 2 ] n —O—, CH 2 CH 2 —[O—(CH 2 ) 2 ] n —NR 6 —, —CH 2 CH 2 —[O—(CH 2 ) 2 ] n —,

—[—(CH 2 ) 2 —O—] n —, —[O—(CH 2 ) 2 ] n —, —[O—CH(CH 3 )C(O)] n —, —[C(O)—CH(CH 3 )—O] n —, —[O—CH 2 C(O)] n —, —[C(O)—CH 2 —O] n —, and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, or 7;

each Linker D is independently selected from the group consisting of:

3 . The compound of claim 2 , wherein R 10 is methyl.

4 . The compound of claim 2 , wherein R 10 is —NR 6 -heteroaryl.

5 . The compound of claim 2 , wherein R 6 is H.

6 . The compound of claim 2 , wherein —NR 6 -heteroaryl is selected from the group consisting of:

7 . The compound of claim 1 , wherein the [IgGBM] group is a peptide moiety according to the chemical structure:

8 . The compound of claim 1 ,

wherein LINKER comprises a group according to the chemical structure:

wherein:

each occurrence of R am is independently H or C 1 -C 3 alkyl optionally substituted with one or two hydroxyl groups;

na is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

m is an integer ranging from 1 to 100; or

wherein LINKER is a group according to the chemical formula:

wherein:

Z and Z′ are each independently a bond, —(CH 2 ) i —O—, —(CH 2 ) i —S—, —(CH 2 ) i —N(R)—,

wherein the —(CH 2 ) i group, if present in Z or Z′, is bonded to a connector group [CON], [MIFBM]/[IgGBM] or [ASGPRBM];

each occurrence of R is H, C 1 -C 3 alkyl or alkanol;

each occurrence of R 2 is independently H or C 1 -C 3 alkyl;

each occurrence of Y is independently a bond, O, S, or N—R;

each occurrence of i is independently 0 to 100;

D is —(CH 2 ) i —Y—C(═O)—Y—(CH 2 ) i —, —(CH 2 ) m′ —,

 or a bond, with the proviso that Z, Z′ and D are not each simultaneously bonds;

j is an integer ranging from 1 to 100;

m′ is an integer ranging from 1 to 100;

n is an integer ranging from 1 to 100;

each occurrence of X 1 is independently O, S, or N—R; and

each occurrence of R is independently H, C 1 -C 3 alkyl, or alkanol.

9 . The compound of claim 1 ,

wherein LINKER comprises a group according to the chemical structure:

wherein each n and n′ is independently an integer ranging from 1 to 25; and each n″ is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; or

wherein LINKER is a group represented by the chemical formula:

PEG-[CON]-PEG

wherein each PEG is independently a polyethylene glycol group containing from 1-12 ethylene glycol residues and [CON] is a triazole group

10 . The compound of claim 1 , wherein the [CON] is a group according to the structure:

wherein:

X 2 is CH 2 , O, S, NR 4 , C(O), S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;

R 4 is H, C 1 -C 3 alkyl or alkanol, or —C(O)(C 1 -C 3 alkyl).

11 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and at least one pharmaceutically acceptable carrier, additive, or excipient.

12 . The composition of claim 11 , further comprising an additional bioactive agent selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatinib nilotinib, panitumumab, amrubicin, oregovomab, LEP-ETU, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1 KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, RTA-744, SDX-102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, diethylstilbestrol, estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoyl anilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer sodium, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab, erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, a PD-L1 checkpoint inhibitor, a PD-1 checkpoint inhibitor, and a CTLA-4 inhibitor.

13 . A method of removing excess circulating IgG in a subject in need thereof, or treating a disease state or condition which is associated with the upregulation of IgG in a subject in need thereof,

the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

14 . A method of treating or ameliorating cancer, an autoimmune disease, or an inflammatory disease in a subject in need thereof,

the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

15 . The compound of claim 1 , wherein

has the structure:

wherein:

X 2 is —CH 2 —;

X 1 is —O—;

n is 2;

m is independently at each occurrence 1, 2, 3, or 4; and

j is 1, 2, 3, 4, 5, or 6.

16 . The compound of claim 1 , wherein LINKER is a group consisting of two independently selected groups of formula

connected through a CON group, wherein:

CON is selected the group consisting of

each occurrence of Z and Z′ is independently a bond or —(CH 2 ) i —O;

each occurrence of D is a bond, —(CH 2 ) m′ —, or —[(CH 2 ) n —X 1 ] j —;

X 1 is —O—;

with the proviso that Z, Z′, and D are not each simultaneously bonds;

i is 2;

each occurrence of m′ is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each occurrence of m′ is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and at least one pharmaceutically acceptable carrier, additive, or excipient.

18 . A method of removing excess circulating IgG in a subject in need thereof, or treating a disease state or condition which is associated with the upregulation of IgG in a subject in need thereof, the method comprising

administering to the subject therapeutically effective amount of the compound of claim 2 .

19 . A method of treating or ameliorating cancer, an autoimmune disease, or an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 2 .