US2023233689A1PendingUtilityA1
Bifunctional Small Molecules to Target the Selective Degradation of Circulating Proteins
Est. expiryApr 9, 2038(~11.7 yrs left)· nominal 20-yr term from priority
A61K 47/545A61K 47/55A61P 35/00A61K 47/54A61K 47/64A61K 47/549
70
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Claims
Abstract
The present disclosure is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In certain embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcγRI, FcRN, Transferrin or Macrophage Scavenger receptor.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A bifunctional compound according to the chemical structure:
wherein:
[CPBM] is a Circulating Protein Binding Moiety which binds to a circulating protein in a subject, wherein the circulating protein mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject;
[CRBM] is a Cellular Receptor Binding Moiety which binds to asialoglycoprotein receptors of hepatocytes or other cell receptors in the subject;
each [CON] is an optional connector chemical moiety which, when present, connects the [LINKER] to [CPBM] or to [CRBM];
[LINKER] is a chemical moiety having a valency from 1 to 15, which covalently attaches to one or more [CRBM] or [CPBM] groups, optionally through a [CON], wherein the [LINKER] optionally itself contains one or more [CON] groups;
k′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
j′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
h and h′ are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
with the proviso that at least one of h, h′, and i L is at least 1,
or a salt, stereoisomer, or solvate thereof.
2 . The compound of claim 1 , wherein k′, j′, h, h′, and i L are each independently 1, 2, or 3.
3 . The compound of claim 1 ,
wherein [CPBM] is a [MIFBM] moiety according to the chemical structure:
wherein:
X M is —(CH 2 ) IM —, —O—(CH 2 ) IM —, —S—(CH 2 ) IM —, —NR M —(CH 2 ) IM —, —C(O)—(CH 2 ) IM —, a PEG group containing from 1 to 8 ethylene glycol residues, or —C(O)(CH 2 ) IM NR M —;
each occurrence of R M is independently H or C 1 -C 3 alkyl optionally substituted with one or two hydroxyl groups;
each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6; or
wherein [CPBM] is a [IgGMB] group according to the chemical structure:
wherein DNP is 2,4-dinitrophenyl; or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein:
Y′ is H or NO 2 ;
X is O, CH 2 , NR 1 , S(O), S(O) 2 , S(O) 2 O, OS(O) 2 , or OS(O) 2 O; and
R 1 is H, C 1 -C 3 alkyl, or —C(O)(C 1 -C 3 alkyl); or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein
R 1 is H, C 1 -C 3 alkyl, or —C(O)(C 1 -C 3 alkyl); and
K″ is 1, 2, 3, 4, or 5; or
wherein [CPBM] is a [IgGBM] group represented by the chemical formula:
wherein:
X′ is CH 2 , O, N—R 1′ , or S;
R 1′ is H or C 1 -C 3 alkyl; and
Z is a bond, monosaccharide, disaccharide, or oligosaccharide; or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein:
X R is O, S, or NR 1 ;
X M is O, NR 1 , or S, and
each occurrence of R 1 is independently H or C 1 -C 3 alkyl; or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein:
X″ is O, CH 2 , NR 1 , or S; and
R 1 is H, C 1 -C 3 alkyl, or —C(O)(C 1 -C 3 alkyl); or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein:
X b is a bond, O, CH 2 , NR 1 , or S; and
R 1 is H, C 1 -C 3 alkyl, or —C(O)(C 1 -C 3 alkyl); o
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein R N02 is a dinitrophenyl group optionally linked through CH 2 , S(O), S(O) 2 , S(O) 2 O, OS(O) 2 , or OS(O) 2 O; or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein:
X is O, CH 2 , NR 1 , S(O), S(O) 2 , S(O) 2 O, OS(O) 2 , or OS(O) 2 O; and
R 1 is H, C 1 -C 3 alkyl, or —C(O)(C 1 -C 3 alkyl), or
wherein [CPBM] is a [IgGBM] group according to the chemical structure:
wherein K′″ is 1, 2, 3, or 4, or
wherein [CPBM] is a [IgGBM] group according to a chemical structure selected from the group consisting of:
which is covalently attached to a [CON] group, a [LINKER] group, or a [CRBM] group, which is optionally an [ASGPRBM] group, through an amine group optionally substituted with C 1 -C 3 alkyl; or
wherein [CPBM] is a [IgGBM] group which is a peptide 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-Lact-E)
cyclo[(N-Ac)S(A)-RWHYFK-Lact-E];
(SEQ ID NO: 10-Lact-E)
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;
(SEQ ID NO: 18)
KHRFNKD;
or
wherein [CPBM] is a CD40L-targeting motif according to the chemical structure:
or
wherein [CPBM] is a TNF alpha-targeting motif according to chemical structure:
or
wherein [CPBM] is a PCSK9-targeting motif according to the chemical structure:
wherein [CPBM] is a VEGF-targeting motif according to the chemical structure:
or
wherein [CPBM] is a TGF beta-targeting motif according to the chemical structure:
or
wherein [CPBM] is a TSP-1 targeting motif according to the chemical structure:
or
wherein [CPBM] is a soluble uPAR targeting motif according to the chemical structure:
or
wherein [CPBM] is a soluble PSMA targeting motif according to the chemical structure:
or
wherein [CPBM] is a IL-2 targeting motif according to the chemical structure:
or
wherein [CPBM] is a GP120-targeting motif according to the chemical structure:
4 . The compound of claim 1 ,
wherein [CRBM] is an [ASGPRBM] group according to the chemical structure:
wherein X is 1-4 atoms in length and comprises O, S, N(R N1 ) or C(R N1 )(R N1 ) groups, such that: when X is 1 atom in length, X is O, S, N(R N1 ), or C(R N1 )(R N1 ), when X is 2 atoms in length, no more than 1 atom of X is O, S, or N(R N1 ), when X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S, or N(R N1 );
wherein R N1 is H or C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups;
wherein R 1 and R 3 are each independently H, —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 4 alkyl optionally substituted with 1-3 halogen groups, —(CH 2 ) K vinyl, —O—(CH 2 ) K vinyl, —(CH 2 ) K alkynyl, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R 1 and R 3 are each independently
which is optionally substituted with up to three halogen groups; C 1 -C 4 alkyl, each of which alkyl group is optionally substituted with from one to three halogen groups or one or two hydroxyl groups; or O—(C 1 -C 4 alkyl), each of which alkyl groups is optionally substituted with from one to three halogen groups or one or two hydroxyl groups; or
R 1 and R 3 are each independently a group according to the chemical structure:
wherein R 7 is O—(C 1 -C 4 alkyl) optionally substituted with 1 to 3 halogen groups or 1-2 hydroxy groups, —NR N3 R N4 , or
R 1 and R 3 are each independently a group according to the structure:
or a
wherein CYC is a ring selected from the group consisting of:
and C 3 -C 8 saturated carbocyclic, wherein each of LINKERX, R C , and —(CH 2 ) K — are attached to an open valence in CYC;
wherein R C is absent, H, C 1 -C 4 alkyl optionally substituted with from 1-3 halogen groups or 1-2 hydroxyl groups, or a group according to the structure:
wherein R 4 , R 5 and R 6 are each independently, H, halogen, CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups, —O—(C 1 -C 3 -alkyl) optionally substituted with 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
wherein R C is
wherein R N , R N1 , and R N2 are each independently H or C 1 -C 3 alkyl optionally substituted with one to three halogen groups or one or two hydroxyl groups;
wherein K is independently 0, 1, 2, 3, or 4;
wherein K′ is 1, 2, 3, or 4;
wherein R N3 is H, or C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups;
wherein R N4 is H, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups, or
wherein
is a linker group which comprises at least one [CPBM] group and links the [CPBM] group to the [CRBM] through one or more optional [CON] groups, or is a linker group which contains at least one or more functional groups which can be used to covalently bond the linker group to at least one [CPBM]group or optional [CON] group;
wherein R 2 is
wherein R AM is H, C 1 -C 4 alkyl optionally substituted with up to 3 halogen groups and one or two hydroxyl groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —(CH 2 ) K —NR N3 R N4 ; or
R 2 is
wherein:
R TA is H, CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 4 alkyl optionally substituted with 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R TA is a C 3 -C 10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of the aryl or heteroaryl groups being optionally substituted with up to three CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups, —O—(C 1 -C 3 -alkyl) optionally substituted from 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or —(CH 2 ) K C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R TA is
optionally substituted with up to three C 1 -C 3 alkyl groups which are optionally substituted with up to three halogen groups, or
R TA is
wherein R N , R N1 , and R N2 are each independently H or C 1 -C 3 alkyl optionally substituted with one to three halogen groups or one or two hydroxyl groups and each —(CH 2 ) K group is optionally substituted with 1-4 C 1 -C 3 alkyl groups which are optionally substituted with 1-3 fluoro groups or 1-2 hydroxyl groups; or
wherein [CRBM] is a LRP1 (Low density lipoprotein receptor-related protein 1) peptide binding group according to the peptide sequence:
(SEQ ID NO: 19)
Ac-VKFNKPFVFLNleIEQNTK-NH 2 ,
(SEQ ID NO: 20)
VKFNKPFVFLMIEQNTK,
(SEQ ID NO: 21)
TWPKHFDKHTFYSILKLGKH-OH,
(SEQ ID NO: 22)
TFFYGGSRGKRNNFKTEEY-OH,
(SEQ ID NO: 23)
LRKLRKRLLRDADDLLRKLRKRLLRDADDL,
(SEQ ID NO: 24)
TEELRVRLASHLRKLRKRLL,
(SEQ ID NO: 25)
EAKIEKHNHYQKQLEIAHEKLR,
or
(SEQ ID NO: 26)
ANG: TFFYGGSRGKRNNFKTEEY;
or
wherein [CRBM] is a LDLR (low density lipoprotein receptor) binding group according to the peptide sequence:
(cyclized c-Pen)
(SEQ ID NO: 27)
cM″Thz″RLRG″Pen″,
(cyclized C-C)
(SEQ ID NO: 28)
CMPRLRGC,
(cyclized C-C)
(SEQ ID NO: 29)
HLDCMPRGCFRN,
(cyclized C-C)
(SEQ ID NO: 30)
CQVKSMPRC,
(cyclized C-C)
(SEQ ID NO: 31)
CTTPMPRLC,
(cyclized C-C)
(SEQ ID NO: 32)
CKAPQMPRC,
(cyclized C-C)
(SEQ ID NO: 33)
CLNPSMPRC,
(cyclized C-C)
(SEQ ID NO: 34)
CLVSSMPRC,
(cyclized C-C)
(SEQ ID NO: 35)
CLQPMPRLC,
(cyclized C-C)
(SEQ ID NO: 36)
CPVSSMPRC,
(cyclized C-C)
(SEQ ID NO: 37)
CQSPMPRLC,
(cyclized C-C)
(SEQ ID NO: 38)
CLTPMPRLC,
(cyclized C-C)
(SEQ ID NO: 39)
DSGLCMPRLRGCDPR,
(SEQ ID NO: 40)
TPSAHAMALQSLSVG,
(cyclized C-C)
(SEQ ID NO: 41)
Ac-DSGLCMPRLRGCDPR-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 42)
Pr VH434: Pr-CMPRLRGC-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 43)
Pr-cMPRLRGC-NH 2 ,
(cyclized C-Pen)
(SEQ ID NO: 44)
Pr-cMThzRLRG″Pen″-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 45)
Ac-CMPRLGC-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 46)
Ac-cMPRLRGC-NH 2 ,
(cyclized Pen-C)
(SEQ ID NO: 47)
Ac-D-″Pen″M″Thz″RLRGC-NH 2 ,
(cyclized c-Pen)
(SEQ ID NO: 48)
Pr-cM″Thz″RLRG″Pen-NH 2 ,
(cyclized C-Pen)
(SEQ ID NO: 49)
Pr-cM″Thz″RLR″Sar″″Pen″-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 50)
Pr-cM″Pip″RLR″Sar″C-NH 2 ,
(cyclized c-Pen)
(SEQ ID NO: 51)
Pr-cM″Pip″RLRG″Pen″-NH 2 ,
or
(cyclized c-Pen)
(SEQ ID NO: 52)
Pr-[cM″Pip″RLR″Sar″″Pen″-+-NH 2 ;
or
wherein [CRBM] is a FcγRJ binding group according to the peptide sequence:
(cyclized C-C)
(SEQ ID NO: 53)
TDT C LMLPLLLG C DEE,
(cyclized C-C)
(SEQ ID NO: 54)
DPI C WYFPRLLG C TTL,
(cyclized C-C)
(SEQ ID NO: 55)
WYP C YIYPRLLG C DGD,
(cyclized C-C)
(SEQ ID NO: 56)
GNI C MLIPGLLG C SYE,
(cyclized C-C)
(SEQ ID NO: 57)
VNS C LLLPNLLG C GDD,
(cyclized C-C)
(SEQ ID NO: 58)
TPV C ILLPSLLG C DTQ,
(cyclized C-C)
(SEQ ID NO: 59)
TVL C SLWPELLG C PPE,
(cyclized C-C)
(SEQ ID NO: 60)
TFS C LMWPWLLG C ESL,
(cyclized C-C)
(SEQ ID NO: 61)
FGT C YTWPWLLG C EGF,
(cyclized C-C)
(SEQ ID NO: 62)
SLF C RLLLTPVG C VSQ,
(cyclized C-C)
(SEQ ID NO: 63)
HLL V LPRGLLG C TTLA,
(cyclized C-C)
(SEQ ID NO: 64)
TSL C SMFPDLLG C FNL,
(cyclized C-C)
(SEQ ID NO: 65)
SHP C GRLPMLLG C AES,
(cyclized C-C)
(SEQ ID NO: 66)
TST C SMVPGPLGAV STW,
(cyclized C-C)
(SEQ ID NO: 67)
KDP C TRWAMLLG C DGE,
(cyclized C-C)
(SEQ ID NO: 68)
IMT C SVYPFLLG C VDK,
or
(cyclized C-C)
(SEQ ID NO: 69)
IHS C AHVMRLLG C WSR;
or
wherein [CRBM] is a FcRN binding moiety according to the peptide sequence: Ac-NH-QRFCTGHFGGLYPCNGP-CONH 2 (cyclized C-C) (SEQ ID NO:70), Ac-NH-RF-Pen-TGHFG-Sar-NMeLeu-YPC-CONH 2 (cyclized C-C) (SEQ ID NO:71), or Succinic anhydride N-N dimerized SYN1327 (each cyclized C-C); or
wherein [CRBM] is a Transferrin Receptor binding group according to the peptide sequence:
(SEQ ID NO: 72)
CGGGPFWWWP,
(SEQ ID NO: 73)
CGGGHKYLRW,
(SEQ ID NO: 74)
CGGGKRIFMV,
(SEQ ID NO: 75)
CGGGKWHYLR,
(SEQ ID NO: 76)
THRPPMWSPVWP,
(SEQ ID NO: 77)
HAIYPRH,
(SEQ ID NO: 78)
THRPPMWSPVWP,
or
(SEQ ID NO: 79)
THRPPMWSPVWP;
or
wherein [CRBM] is a Macrophage Scavenger Receptor Binding Moiety according to the peptide sequence:
(SEQ ID NO: 80)
LSLERFLRCWSDAPA,
(SEQ ID NO: 81)
LERFLRCWSDAPA,
(SEQ ID NO: 82)
RFLRCWSDAPA,
(SEQ ID NO: 83)
LRCWSDAPA,
(SEQ ID NO: 84)
CWSDAPA,
(SEQ ID NO: 85)
DWFKAFYDKVAEKFKEAF;
where Pen is Penicillamine, Thz is thiazolidine-4-carboxylic acid, Sar is sarcosine, Pip is pipecolic acid, Nleu is norleucine, and NMeLeu is N-methylleucine;
or a salt, stereoisomer, or solvate thereof.
5 . The compound of claim 1 , wherein the [CPBM] group is a [MIFMB] group according to the chemical structure:
wherein:
each occurrence of X M is independently —(CH 2 ) IM —, —O—(CH 2 ) IM —, —S—(CH 2 ) IM —, —NR M —(CH 2 ) IM —, —C(O)—(CH 2 ) IM —, a PEG group containing from 1 to 8 ethylene glycol residues, or —C(O)(CH 2 ) IM NR M —;
each occurrence of R M is independently H or C 1 -C 3 alkyl optionally substituted with one or two hydroxyl groups; and
each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6,
or a pharmaceutically acceptable salt or stereoisomer thereof.
6 . The compound of claim 1 , wherein the [CRBM] is an [ASGPRBM] group according to the chemical structure:
wherein X is 1-4 atoms in length and comprises O, S, N(R N1 ) or C(R N1 )(R N1 ) groups, such that:
when X is 1 atom in length, X is O, S, N(R N1 ), or C(R N1 )(R N1 ),
when X is 2 atoms in length, no more than 1 atom of X is O, S, or N(R N1 ),
when X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S, or N(R N1 );
wherein R N1 is H or C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups;
wherein R 1 and R 3 are each independently H, —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 4 alkyl optionally substituted with 1-3 halogen groups, —(CH 2 ) K vinyl, —O—(CH 2 ) K vinyl, —(CH 2 ) K alkynyl, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R 1 and R 3 are each independently
which is optionally substituted with up to three halogen groups; C 1 -C 4 alkyl, each of which alkyl group is optionally substituted with from one to three halogen groups or one or two hydroxyl groups; or O—(C 1 -C 4 alkyl), each of which alkyl groups is optionally substituted with from one to three halogen groups or one or two hydroxyl groups;
R 1 and R 3 are each independently a group according to the chemical structure:
wherein R 7 is O—(C 1 -C 4 alkyl) optionally substituted with 1 to 3 halogen groups or 1-2 hydroxy groups, —NR N3 R N4 , or
R 1 and R 3 are each independently a group according to the structure:
or a
wherein CYC is a ring selected from the group consisting of:
and C 3 -C 8 saturated carbocyclic, wherein each of LINKERX, R C , and —(CH 2 ) K — are attached to an open valence in CYC;
wherein R C is absent, H, C 1 -C 4 alkyl optionally substituted with from 1-3 halogen groups or 1-2 hydroxyl groups, or a group according to the structure:
wherein R 4 , R 5 and R 6 are each independently, H, halogen, CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups, —O—(C 1 -C 3 -alkyl) optionally substituted with 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
wherein R C is
wherein R N , R N1 , and R N2 are each independently H or C 1 -C 3 alkyl optionally substituted with one to three halogen groups or one or two hydroxyl groups;
wherein K is independently 0, 1, 2, 3, or 4;
wherein K′ is 1, 2, 3, or 4;
wherein R N3 is H, or C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups;
wherein R N4 is H, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups, or
wherein
is a linker group which comprises at least one [CPBM] group and links the [CPBM] group to the [CRBM] through one or more optional [CON] groups, or is a linker group which contains at least one or more functional groups which can be used to covalently bond the linker group to at least one [CPBM] group or optional [CON] group;
wherein R 2 is
wherein R AM is H, C 1 -C 4 alkyl optionally substituted with up to 3 halogen groups and one or two hydroxyl groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —(CH 2 ) K —NR N3 R N4 ; or
R 2 is
wherein:
R TA is H, CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 4 alkyl optionally substituted with 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, —C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R TA is a C 3 -C 10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of the aryl or heteroaryl groups being optionally substituted with up to three CN, NR N1 R N2 , —(CH 2 ) K OH, —(CH 2 ) K O(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, C 1 -C 3 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups, —O—(C 1 -C 3 -alkyl) optionally substituted from 1-3 halogen groups, —(CH 2 ) K COOH, —(CH 2 ) K C(O)O—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, O—C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or —(CH 2 ) K C(O)—(C 1 -C 4 alkyl) optionally substituted with 1-3 halogen groups, or
R TA is
optionally substituted with up to three C 1 -C 3 alkyl groups which are optionally substituted with up to three halogen groups, or
R TA is
wherein R N , R N1 , and R N2 are each independently H or C 1 -C 3 alkyl optionally substituted with one to three halogen groups or one or two hydroxyl groups and each —(CH 2 ) K group is optionally substituted with 1-4 C 1 -C 3 alkyl groups which are optionally substituted with 1-3 fluoro groups or 1-2 hydroxyl groups;
or a salt, stereoisomer, or solvate thereof.
7 . The compound of claim 4 , wherein:
X in [ASGPRBM] is —O—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—O—, —S—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—S—, —N(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—N(R N1 )—, or —C(R N1 )(R N1 )—C(R N1 )—, when X is 2 atoms in length, or X in [ASGPRBM] is —O—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—O—C(R N1 )(R N1 )—, —O—C(R N1 )(R N1 )—O—, —O—C(R N1 )(R N1 )—S—, —O—C(R N1 )(R N1 )—N(R N1 )—, —S—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—S—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—C(R N1 )(R N1 )—S, —S—C(R N1 )(R N1 )—S—, —S—C(R N1 )(R N1 )—O—, —S—C(R N1 )(R N1 )—N(R N1 )—, —N(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—N(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—C(R N1 )(R N1 )—N(R N1 )—, —N(R N1 )—C(R N1 )(R N1 )—N(R N1 )—, or —C(R N1 )(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 ), when X is 3 atoms in length, or X in [ASGPRBM] is —O—C(R N1 )(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )—O—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —O—C(R N1 )(R N1 )—O—C(R N1 )(R N1 )—, —S—C(R N1 )(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, —C(R N1 )(R N1 )(R N1 )(R N1 )—, —C(R N1 )(R N1 )—C(R N1 )(R N1 )—S—C(R N1 )(R N1 )—, —S—C(R N1 )(R N1 )—S—C(R N1 )(R N1 )—, —N(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 )—, or —C(R N1 )(R N1 )—N(R N1 )—C(R N1 )(R N1 )—C(R N1 )(R N1 ), when X is 4 atoms in length.
8 . The compound of claim 4 , wherein X in [ASGPRBM] is OCH 2 or CH 2 O and wherein R N1 is H.
9 . The compound of claim 3 ,
wherein X M is a PEG group containing from 1 to 8 ethylene glycol residues, or wherein X M is —C(O)—(CH 2 ) IM — and IM is 1, 2, or 3.
10 . The compound of claim 4 , wherein the [ASGPRBM] group is a group according to the chemical structure:
or a salt, stereoisomer, or solvate thereof.
11 . The compound of claim 4 , wherein the [ASGPRBM] group is a group according to the chemical structure:
wherein:
R A is C 1 -C 3 alkyl optionally substituted with 1-5 halogen groups;
Z A is —(CH 2 ) IM —, —O—(CH 2 ) IM —, —S—(CH 2 ) IM —, —NR M —(CH 2 ) IM —, —C(O)—(CH 2 ) IM —, a PEG group containing from 1 to 8 ethylene glycol residues, or —C(O)(CH 2 ) IM NR M —; and
Z B is absent, —(CH 2 ) IM —, —C(O)—(CH 2 ) IM —, or —C(O)—(CH 2 ) IM —NR M —.
12 . The compound of claim 11 , wherein at least one applies:
R A is a methyl or ethyl group which is optionally substituted with 1-3 fluoro groups, or Z A is a PEG group containing from 1 to 4 ethylene glycol residues.
13 . The compound of claim 4 , wherein R 1 and R 3 of the [ASGPRBM] are each independently a group according to the chemical structure:
14 . The compound of claim 4 , wherein R 1 and R 3 of the [ASGPRBM] group are each independently a moiety selected from the group consisting of
15 . The compound of claim 4 , where R 2 of the [ASGPRBM] group is a moiety selected from the group consisting of:
16 . The compound of claim 3 , wherein the [IgGBM] group is a group according to the chemical structure:
where K′″ is 1, 2, 3, or 4.
17 . The compound of claim 4 , wherein the [CRBM] group is a peptide moiety according to the chemical structure:
18 . The compound of claim 3 ,
wherein the [CPBM] group is a peptide 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-Lact-E)
cyclo[(N-Ac)S(A)-RWHYFK-Lact-E];
(SEQ ID NO: 10-Lact-E)
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;
(SEQ ID NO: 17)
RRGW,
or
(SEQ ID NO: 18)
KHRFNKD;
or
the [CPBM] group is a CD40L-targeting motif according to the chemical structure:
or
the [CPBM] group is a TNF alpha-targeting motif according to chemical structure:
or
the [CPBM] group is a PCSK9-targeting motif according to the chemical structure:
or
the [CPBM] group is a VEGF-targeting motif according to the chemical structure:
or
the [CPBM] group is a TGF beta-targeting motif according to the chemical structure:
or
the [CPBM] group is a TSP-1 targeting motif according to the chemical structure:
or
the [CPBM] group is a soluble uPAR targeting motif according to the chemical structure:
or
the [CPBM] group is a soluble PSMA targeting motif according to the chemical structure:
or
the [CPBM] group is a IL-2 targeting motif according to the chemical structure:
or
the [CPBM] group is a GP120-targeting motif according to the chemical structure:
19 . The compound of claim 1 , wherein:
the [CRBM] group is a LRP1 (Low density lipoprotein receptor-related protein 1) binding group according to the peptide sequence:
(SEQ ID NO: 19)
Ac-VKFNKPFVFLNleIEQNTK-NH 2 ,
where Nle is neorleucine,
(SEQ ID NO: 20)
VKFNKPFVFLMIEQNTK,
(SEQ ID NO: 21)
TWPKHFDKHTFYSILKLGKH-OH,
(SEQ ID NO: 22)
TFFYGGSRGKRNNFKTEEY-OH,
(SEQ ID NO: 23)
LRKLRKRLLRDADDLLRKLRKRLLRDADDL,
(SEQ ID NO: 24)
TEELRVRLASHLRKLRKRLL,
(SEQ ID NO: 25)
EAKIEKHNHYQKQLEIAHEKLR,
or
(SEQ ID NO: 26)
ANG: TFFYGGSRGKRNNFKTEEY;
or
the [CRBM] is a LDLR (low density lipoprotein receptor) binding group according to the peptide sequence:
(cyclized c-Pen)
(SEQ ID NO: 27)
cM″Thz″RLRG″Pen″,
(cyclized C-C)
(SEQ ID NO: 28)
CMPRLRGC,
(cyclized C-C)
(SEQ ID NO: 29)
HLDCMPRGCFRN,
(cyclized C-C)
(SEQ ID NO: 30)
CQVKSMPRC,
(cyclized C-C)
(SEQ ID NO: 31)
CTTPMPRLC,
(cyclized C-C)
(SEQ ID NO: 32)
CKAPQMPRC,
(cyclized C-C)
(SEQ ID NO: 33)
CLNPSMPRC,
(cyclized C-C)
(SEQ ID NO: 34)
CLVSSMPRC,
(cyclized C-C)
(SEQ ID NO: 35)
CLQPMPRLC,
(cyclized C-C)
(SEQ ID NO: 36)
CPVSSMPRC,
(cyclized C-C)
(SEQ ID NO: 37)
CQSPMPRLC,
(cyclized C-C)
(SEQ ID NO: 38)
CLTPMPRLC,
(cyclized C-C)
(SEQ ID NO: 39)
DSGLCMPRLRGCDPR,
(SEQ ID NO: 40)
TPSAHAMALQSLSVG,
(cyclized C-C)
(SEQ ID NO: 41)
Ac-DSGLCMPRLRGCDPR-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 42)
Pr VH434: Pr-CMPRLRGC-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 43)
Pr-cMPRLRGC-NH 2 ,
(cyclized C-Pen)
(SEQ ID NO: 44)
Pr-cMThzRLRG″Pen″-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 45)
Ac-CMPRLGC-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 46)
Ac-cMPRLRGC-NH 2 ,
(cyclized Pen-C)
(SEQ ID NO: 47)
Ac-D-″Pen″M″Thz″RLRGC-NH 2 ,
(cyclized c-Pen)
(SEQ ID NO: 48)
Pr-cM″Thz″RLRG″Pen-NH 2 ,
(cyclized C-Pen)
(SEQ ID NO: 49)
Pr-cM″Thz″RLR″Sar″″Pen″-NH 2 ,
(cyclized C-C)
(SEQ ID NO: 50)
Pr-cM″Pip″RLR″Sar″C-NH 2 ,
(cyclized c-Pen)
(SEQ ID NO: 51)
Pr-cM″Pip″RLRG″Pen″-NH 2 ,
or
(cyclized c-Pen)
(SEQ ID NO: 52)
Pr-[cM″Pip″RLR″Sar″″Pen″-+-NH 2 ;
or
the [CRBM] group is a FcγRI binding group according to the peptide sequence
(cyclized C-C)
(SEQ ID NO: 53)
TDT C LMLPLLLG C DEE,
(cyclized C-C)
(SEQ ID NO: 54)
DPI C WYFPRLLG C TTL,
(cyclized C-C)
(SEQ ID NO: 55)
WYP C YIYPRLLG C DGD,
(cyclized C-C)
(SEQ ID NO: 56)
GNI C MLIPGLLG C SYE,
(cyclized C-C)
(SEQ ID NO: 57)
VNS C LLLPNLLG C GDD,
(cyclized C-C)
(SEQ ID NO: 58)
TPV C ILLPSLLG C DTQ,
(cyclized C-C)
(SEQ ID NO: 59)
TVL C SLWPELLG C PPE,
(cyclized C-C)
(SEQ ID NO: 60)
TFS C LMWPWLLG C ESL,
(cyclized C-C)
(SEQ ID NO: 61)
FGT C YTWPWLLG C EGF,
(cyclized C-C)
(SEQ ID NO: 62)
SLF C RLLLTPVG C VSQ,
(cyclized C-C)
(SEQ ID NO: 63)
HLL V LPRGLLG C TTLA,
(cyclized C-C)
(SEQ ID NO: 64)
TSL C SMFPDLLG C FNL,
(cyclized C-C)
(SEQ ID NO: 65)
SHP C GRLPMLLG C AES,
(cyclized C-C)
(SEQ ID NO: 66)
TST C SMVPGPLGAV STW,
(cyclized C-C)
(SEQ ID NO: 67)
KDP C TRWAMLLG C DGE,
(cyclized C-C)
(SEQ ID NO: 68)
IMT C SVYPFLLG C VDK,
or
(cyclized C-C)
(SEQ ID NO: 69)
IHS C AHVMRLLG C WSR;
or
the [CRBM] group is a FcRN binding moiety according to the peptide sequence:
(cyclized C-C)
(SEQ ID NO: 70)
Ac-NH-QRFCTGHFGGLYPCNGP-CONH 2 ,
(cyclized C-C)
(SEQ ID NO: 71)
Ac-NH-RF-Pen-TGHFG-Sar-NMeLeu-YPC-CONH 2 ,
or
Succinic anhydride N-N dimerized SYN1327 (each cyclized C-C); or
the [CRBM] group is a Transferrin Receptor binding group according to the peptide sequence:
(SEQ ID NO: 72)
CGGGPFWWWP,
(SEQ ID NO: 73)
CGGGHKYLRW,
(SEQ ID NO: 74)
CGGGKRIFMV,
(SEQ ID NO: 75)
CGGGKWHYLR,
(SEQ ID NO: 76)
THRPPMWSPVWP,
(SEQ ID NO: 77)
HAIYPRH,
(SEQ ID NO: 78)
THRPPMWSPVWP,
(SEQ ID NO: 79)
THRPPMWSPVWP,
or
the [CRBM] group is a Macrophage Scavenger Receptor Binding Moiety according to the peptide sequence:
(SEQ ID NO: 80)
LSLERFLRCWSDAPA,
(SEQ ID NO: 81)
LERFLRCWSDAPA,
(SEQ ID NO: 82)
RFLRCWSDAPA,
(SEQ ID NO: 83)
LRCWSDAPA,
(SEQ ID NO: 84)
CWSDAPA,
or
(SEQ ID NO: 85)
DWFKAFYDKVAEKFKEAF,
wherein Pen is Penicillamine, Thz is thiazolidine-4-carboxylic acid, Sar is sarcosine, Pip is pipecolic acid, Nleu is norleucine and NMeLeu is N-methylleucine.
20 . The compound of claim 1 , wherein the LINKER is according to the chemical structure:
or a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing between 1 and 100 alkylene glycol units;
wherein R a is H, C 1 -C 3 alkyl or alkanol or forms a cyclic ring with R 3 to form a pyrrolidine or hydroxypyrroline group and R 3 is a side chain derived 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 forms a cyclic ring with R a and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl); and
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
21 . The compound of claim 1 ,
wherein the LINKER is a group according to the chemical formula:
wherein:
each occurrence of R am is independently H or C 1 -C 3 alkyl optionally substituted with one or 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; or
wherein the 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], [CPBM] or [CRBM];
each R is H, or C 1 -C 3 alkyl or alkanol;
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 0 to 100;
D is
or
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, or C 1 -C 3 alkyl or alkanol.
22 . The compound of claim 1 ,
wherein the LINKER is or comprises a group according to the chemical structure:
wherein each n and n′ is independently 1 to 25; and each n″ is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; or
wherein the 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
23 . The compound of claim 1 ,
wherein the [CON] is a group according to the structure:
wherein R CON1 and R CON2 are each independently H, methyl, a bond (for attachment to another moiety); or a diamide 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;
X 3 is O, S, or NR 4 ;
R 4 is H, C 1 -C 3 alkyl or alkanol, or —C(O)(C 1 -C 3 alkyl);
R 1 is H or C 1 -C 3 alkyl; and
n″ is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; or
the [CON] is a group according to the chemical structure:
wherein 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 MC1 is independently 1, 2, 3, or 4;
each MC1a is independently 0, 1, 2, 3, or 4;
each XA is 0 or 1; and
R 4 is H, C 1 -C 3 alkyl or alkanol, or —C(O)(C 1 -C 3 alkyl),
with the proviso that MC1a and XA in a moiety are not all simultaneously 0.
24 . The compound of claim 1 ,
wherein the [CON] is a group according to the chemical structure:
25 . The compound of claim 1 , having one of the following formula:
of a pharmaceutically acceptable salt thereof,
wherein:
Extracellular Protein Targeting Ligand is a CPBM;
X 1 is 1 to 5 groups independently selected from the group consisting of O, S, N(R 6 ), and C(R 4 )(R 4 ), wherein if X 1 is 1 atom then X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ), if X 1 is 2 atoms then no more than 1 atom of X 1 is O, S, or N(R 6 ), if X 1 is 3, 4, or 5 atoms then no more than 2 atoms of X 1 are O, S, or N(R 6 );
R 2 is selected from the group consisting of:
(i) aryl, heterocycle, and heteroaryl containing 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, each of which aryl, heterocycle, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents;
(ii)
(iii) —NR 8 —S(O)—R 3 , —NR 8 —C(S)—R 3 , —NR 8 —S(O)(NR 6 )—R 3 , —N═S(O)(R 3 ) 2 , —NR 8 C(O)NR 9 S(O) 2 R 3 , —NR 8 —S(O) 2 —R 10 , and —NR 8 —C(NR 6 )—R 3 each of which is optionally substituted with 1, 2, 3, or 4 substituents; and
(iv) hydrogen, R 10 , alkyl-C(O)—R 3 , —C(O)—R 3 , alkyl, haloalkyl, —OC(O)R 3 , and —NR 8 —C(O)R 10 ;
R 10 is selected from the group consisting of aryl, alkyl-NR 8 —C(O)—R 3 , alkyl-aryl, alkyl-heteroaryl with 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 , alkyl-NR 6 R 8 , NR 8 —NR 6 —C(O)R 3 , NR 8 —S(O) 2 —R 3 , alkenyl, allyl, alkynyl, —NR 6 -alkenyl, —O-alkenyl, —NR 6 -alkynyl, —O-alkynyl, —NR 6 -heteroaryl, —NR 6 -aryl, —O-heteroaryl, —O-aryl, and —O-alkynyl, each of which R 10 is optionally substituted with 1, 2, 3, or 4 substituents;
R 1 and R 5 are independently selected from the group consisting of hydrogen, heteroalkyl, C 0 -C 6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, —O-alkenyl, —O-alkynyl, C 0 -C 6 alkyl-OR 6 , C 0 -C 6 alkyl-SR 6 , C 0 -C 6 alkyl-NR 6 R 7 , C 0 -C 6 alkyl-C(O)R 3 , C 0 -C 6 alkyl-S(O)R 3 , C 0 -C 6 alkyl-C(S)R 3 , C 0 -C 6 alkyl-S(O) 2 R 3 , C 0 -C 6 alkyl-N(R 8 )—C(O)R 3 , C 0 -C 6 alkyl-N(R 8 )—S(O)R 3 , C 0 -C 6 alkyl-N(R 8 )—C(S)R 3 , C 0 -C 6 alkyl-N(R 8 )—S(O) 2 R 3 C 0 -C 6 alkyl-O—C(O)R 3 , C 0 -C 6 alkyl-O—S(O)R 3 , C 0 -C 6 alkyl-O—C(S)R 3 , —N═S(O)(R 3 ) 2 , C 0 -C 6 alkyN 3 , and C 0 -C 6 alkyl-O—S(O) 2 R 3 , each of which is optionally substituted with 1, 2, 3, or 4 substituents;
R 3 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR 8 , and —NR 8 R 9 ;
R 4 is independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR 6 , —NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 ;
R 6 and R 7 are independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 ;
R 8 and R 9 are independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
Cycle is a 3-8 membered fused cyclic group optionally substituted with 1, 2, 3, or 4 substituents;
each Linker 4 is a bond or moiety that covalently links the [ASGPRBM] group to Linker B ,
Linker B is a bond or moiety that covalently links Linker A group to the Extracellular Protein Targeting Ligand;
Linker C is a chemical group that links each Linker A group to the Extracellular Protein Targeting Ligand;
Linker D is a chemical group that links each Linker A group to the Extracellular Protein Targeting Ligand;
wherein, when R 2 is —NR 6 -alkenyl, —NR 6 -alkynyl, —NR 8 —C(O)R 10 , —NR 8 —S(O) 2 -alkenyl, —NR 8 —S(O) 2 -alkynyl, —NR 6 -heteroaryl, or —NR 6 -aryl, then Extracellular Protein Targeting Ligand does not comprise an oligonucleotide; and
the optional substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, —OR 6 , F, Cl, Br, I, —NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 ,
as allowed by valence such that a stable compound results;
or a salt, stereoisomer, or solvate thereof.
26 . A compound selected from the group consisting of
or a salt, stereoisomer, or solvate thereof.
27 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, additive, or excipient, optionally further comprising an additional bioactive agent that is effective to treat cancer, autoimmune disease, or inflammatory disease in a patient or that is associated with the upregulation of a circulating protein in the patient.
28 . The composition of claim 27 , wherein at least one applies:
(a) the circulating protein is MIF, IgG, CD40L, TNFalpha, PCSK9, VEGf, TGFbeta, TSP-1, uPAR, PSMA, or IL-2; (b) the composition comprises an additional anticancer 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, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-1-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, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258), 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2 acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) x where x=1 to 2.4], 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, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SI 1248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, 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, gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, 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-mecaptopurine, 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, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, 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, immunotherapy agents PDL1 inhibitors, PD1 inhibitors, and CTLA-4 inhibitors.Join the waitlist — get patent alerts
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